CN206814791U - Disposable intelligent digester systems for animal cell culture - Google Patents
Disposable intelligent digester systems for animal cell culture Download PDFInfo
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- CN206814791U CN206814791U CN201720348413.8U CN201720348413U CN206814791U CN 206814791 U CN206814791 U CN 206814791U CN 201720348413 U CN201720348413 U CN 201720348413U CN 206814791 U CN206814791 U CN 206814791U
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Abstract
The utility model discloses a kind of disposable intelligent digester systems for animal cell culture, including disposable digester unit and intelligent control unit, the disposable digester unit includes at least filling the closed chamber of fluid, retention component and mixing component are provided with the closed chamber, retention component and the lower loop in the closed chamber is around being connected, wherein, the retention component is at least making scattered cell stream to next stage bioreactor and empty carrier and carrier with cell is trapped in the closed chamber, the mixing component is at least mixing the fluid in the closed chamber.Disposable intelligent digester systems of the present utility model eliminate the step such as sterilization system on line and on-line cleaning, rigging up and debugging, simplify operating process, save production cost and human cost, avoid cross pollution between batches；And control digestion process by using intelligent program so that cell dissociation loss late is minimum up to 2%.
Description
Technical field
It the utility model is related to a kind of separated for cell during animal cell culture with microcarrier and obtain free thin
The technology of born of the same parents, relate more particularly to the disposable intelligent digester systems for animal cell culture.
Background technology
When the high added value such as vaccine, antibody, protein medicaments biological products produce, some mammalian cells used
Growth in nutrient solution can not be directly suspended in, and, it is necessary to which depending on the carrier surface with a small amount of positive charge could grow, its is basic
Process is：Cell suspension is made in mammalian cell after mechanical dispersion or digestion, filtered, centrifugation, purifying, rinsing are followed by
Kind is cultivated into the reactor containing fresh culture.It is good with the cell growth of this method culture and be easy to observe, but this method
Only it is suitable to laboratory research.However, in cell pilot scale culture, be inoculated with and spread cultivation during, the cell of adherent growth has contact
The characteristic of suppression, once cell covers with surface, growth will be suppressed, and influence final cell yield.Therefore, it is necessary to will be thin
Born of the same parents separate with vector digestion, enter on new carrier.
At present, the method for cell dissociation mainly has the methods of digestive inoculation, digestion in site inoculation, be directly inoculated with.
But the above no matter which kind of digestion method, used digester still for rolling bottle, conical flask, mechanical agitation fermentation
Tank etc..These digesters are that the reaction vessel that is made up of glass, steel or preferred stainless steel and control unit are formed.Each
After use, to ensure that digester reaches sterile cleaning effect, it is necessary to which, through dismounting repeatedly, cleaning and sterilization treatment, those are clear
Clean process is a time-consuming, laborious process in itself, and used cleaning method adds production cost, and still suffers from remaining
The risk of Organic Pollution.
In addition, cell is simply simply detached from the carrier or directly carries out cell switching by traditional digestion method, entirely
Process simply leans on the manually operated digester of technical staff, and empirical to judge whether digestion process is completed, this not only causes to digest
Cell largely loses in journey, and criticizes the result between batch and be difficult to repeat.Therefore, cell is detached from the carrier acquisition free cell
It is still the big technical barrier during cell pilot scale culture.
Utility model content
Main purpose of the present utility model is to provide a kind of disposable intelligent digester system for animal cell culture
System, with overcome the deficiencies in the prior art.
To achieve these goals, the technical solution of the utility model is as follows：
The utility model embodiment provides a kind of disposable intelligent digester systems for animal cell culture, including
Disposable digester unit and intelligent control unit, the disposable digester unit include at least can be used for accommodating culture cell
Fluid and digestive juice sterile closed chamber, at least charging aperture connected with the closed chamber, an at least gas outlet, extremely
A few air inlet, an at least digestive juice entrance, an at least filter washing water inlet, an at least culture medium entrance, an at least cleaning fluid and
Digestive juice exports and an at least sample tap, and retention component and mixing component, institute are at least additionally provided with the closed chamber
Retention component is stated at least being retained in the closed chamber by the carrier in fluid and zooblast is passed through the stirring
Component is at least to by the material mixing in the closed chamber.
As one of preferable preferred embodiment, for the disposable intelligent digester systems of animal cell culture, including
Closed bag, the inner chamber of the closed bag form the closed chamber, be provided with the closed bag charging aperture, gas outlet,
Air inlet, digestive juice entrance, filter washing water inlet, culture medium entrance, while the closed bag bottom is additionally provided with described cleaning fluid
With digestive juice outlet and sample tap；
Further, the retention component is located at the closed bag inner chamber bottom, and close with the closed bag inner wall surrounding
Envelope connection；Preferably, at least an acid solution entrance and at least an alkali liquor inlet are additionally provided with the closed bag；
Further, an at least cell switching access and at least cell switching outlet are additionally provided with the closed bag；
Further, it is preferred that at the top of the closed bag and sidepiece forms multiple ports, and described multiple ports are used respectively
Make the charging aperture, gas outlet, air inlet, digestive juice entrance, filter washing water inlet, culture medium entrance, cleaning fluid and digestive juice to go out
Mouth and sample tap；
Further, the port at least through cap, female Luer, hose barb joint, check valve, sampler,
Any of sterilizing filter is isolated with external environment.
Further, an at least air inlet pipe inserts the closed chamber by the air inlet, the air inlet pipe lower end with
Air sparger connects, and the air sparger is located at below the fluid level in the closed chamber；
Further, the air sparger includes ventilation ring, and a plurality of ventilations are evenly distributed with the ventilation ring
Hole, the aperture of the passage are less than the diameter of carrier；
Further, flowmeter and filter are also connected with the air inlet pipe；
Further, pressure gauge or pressure sensor and pressure-control valve are also associated with the escape pipe；
Further, the pressure in the closed chamber is maintained between 0.01-0.05Mpa；
Further, the material of the closed bag includes rigid, semi-rigid or flexible plastics；
Further, the plastics include makrolon, polyester, fluoropolymer, acrylic acid, PET, polyvinyl chloride,
Any one in ABS, PC, PS, GAG, acrylic and polyolefin or two or more combinations；Further, the modeling
Material includes polyolefin.
As one of preferable preferred embodiment, the disposable digester unit includes supporting construction, the support knot
Structure is at least used to support the closed bag；
Further, the supporting construction is included in the fixed card buckle that the closed bag upper and lower part stretches out；
Further, the supporting construction includes the support frame being located at outside the closed bag, and the closed bag is arranged on
On support frame as described above or in support frame as described above, support frame as described above is fixing support rack or removable support frame；
Further, the supporting construction includes the support frame in the closed bag；
Further, any one of the supporting construction at least in metal drum, Plastic Drum, wooden barrel or glass tank.
As one of preferable preferred embodiment, the mixing component is connected with drive mechanism, the drive mechanism
It is connected, and is arranged on outside the closed bag or internal with the supporting construction；
Preferably, the drive mechanism includes motor.
As one of preferable preferred embodiment, the mixing component includes mechanical agitation mechanism and/or magnetic stirrer
Structure；
As one of preferable preferred embodiment, the mixing component includes agitating shaft and agitating paddle, the agitating paddle with
One end of the mixing shaft is fixedly connected and is located in the closed chamber, and the other end of the agitating shaft is located at outside the closed chamber
And be connected with drive mechanism, and the joint of the agitating shaft and the closed chamber locular wall is also through more than one sealing ring
It is tightly connected；
Further, in the agitating paddle at least straight oar selected from single or multiple lift, arrow leaf oar, curved leaf oar, propeller
Any one.
As one of preferable preferred embodiment, the retention component includes at least a sieve plate or filter screen, the sieve plate or
The aperture of filter screen is more than the diameter of zooblast and less than the diameter of microcarrier.
As one of preferable preferred embodiment, the intelligent control unit includes any one or two in following assemblies
The combination of the kind above：
Temperature-controlling module, at least controlling the temperature in the closed chamber；
PH control assemblies, at least monitoring the pH value of the fluid in the closed chamber；
Dissolved oxygen component, at least change to detect the dissolved oxygen in the closed chamber；
Online living cells sensor cluster, at least change to monitor the number of viable cells wandered about as a refugee in digestion process；
Weigh assembly, at least to on-line monitoring fluid inlet；
Central controller, at least controlling the running status of each component；
The temperature-controlling module, pH control assemblies, dissolved oxygen component, online living cells sensor cluster and weigh assembly are equal
It is connected with the central controller and the closed chamber；
Further, the temperature-controlling module, pH control assemblies, dissolved oxygen component, online living cells sensor cluster and
Weigh assembly is disposable assembly；
Preferably, the intelligent control unit also includes any one in following assemblies or two or more combinations, institute
The following assemblies stated are connected with the central controller：
Carbon dioxide sensing component, at least change to detect the carbon dioxide in the closed chamber；
Mixing rate sensory package, at least detecting the troubled water of the fluid in the closed chamber；
Photoelectric sensing component, at least detecting the turbidity of the fluid in the closed chamber.
Further, the temperature-controlling module includes heater, chuck circulation and plug-in type or non-intrusive
Formula temperature electrode.
Further, the PH control assemblies include pH value electrode.
Further, the dissolved oxygen component includes dissolved oxygen electrode.
Further, the online living cells sensor cluster is as a plug or non-insertion mode is installed on the closing
Chamber sidepiece, and the online living cells sensor cluster is close to the retention component.
Further, the weigh assembly include supporting more than one Weighing module of the disposable digester unit and
Terminal box, the Weighing module electrically connect with terminal box.
Further, the weigh assembly includes being installed on 3-4 at the leg of the disposable digester unit
Weighing module.
As one of preferable preferred embodiment, the intelligent control unit also includes liquid pumping component, the liquid
Pump include cleaning liquid pump, digestion liquid pump, culture medium pump, sour pump, alkali pump, cleaning fluid excavationg pump, digestive juice excavationg pump with
And any one in cell shifting pump or two or more combinations, it is described cleaning liquid pump, digestion liquid pump, culture medium pump, sour pump,
Alkali pump, cleaning fluid excavationg pump, digestive juice excavationg pump and cell shifting pump are connected with the central controller respectively.
As one of preferable preferred embodiment, the central controller also includes wireless communication module, the center control
Device processed is through the wireless communication module and remote terminal wireless connection.
Compared with prior art, the advantages of the utility model at least that:
1) the utility model eliminates SIP (sterilization system on line) and CIP (on-line cleaning), the equipment step such as installation and debugging repeatedly
Suddenly, simplify operating process, fundamentally alleviate the line service of instrument and equipment, because step simplify, saved steam,
The dosage of water, cleaning fluid, the rigging up and debugging time is saved, so as to save production cost and human cost.
2) abandoned after disposable assembly use, be not used in follow-up technological operation, avoid between batches
Cross pollution, improve production stability and product quality.
3) use of disposable assembly reduces the complexity of GMP checkings, because almost no repeatedly used component,
Substantial amounts of sterilizing, cleaning validation flow are saved, so as to simplify GMP authentication periods in R＆D process, when shortening launch
Between.
4) intelligent control unit designed by the utility model, the whole process of digestion reaction can be automatically controlled, is substantially reduced
Cell dissociation loss late, loss late are minimum up to 2%.
5) the disposable digester unit designed by the utility model is in terms of Vessel Design, stirring design, ventilation strategies
It is consistent with the muptiple-use digester design principle of classics, geometric similarity, therefore, process transfer are kept in different reactor scale
It will not increase extra risk with technique amplification, contribute to existing process transfer into existing industrial reaction equipment.
Brief description of the drawings
In order to illustrate more clearly of the utility model architectural feature and technical essential, below in conjunction with the accompanying drawings and specific embodiment party
The utility model is described in detail formula.
Fig. 1 is digestion reaction implementing procedure figure in comparative example 1；
Fig. 2 is the structural representation of disposable digester unit in the utility model embodiment 1；
Fig. 3 is the front view of the closed chamber of disposable digester unit in the utility model embodiment 1；
Fig. 4 is the rearview of the closed chamber of disposable digester unit in the utility model embodiment 1；
Fig. 5 is digestion reaction implementing procedure figure in the utility model embodiment 1；
Fig. 6 is digestion reaction implementing procedure figure in the utility model embodiment 2.
Description of reference numerals：1- motor, 2- supporting constructions, 3- weigh assemblies, 4- acid solution entrances, 5- alkali liquor inlets, 6-
Cell switching access, 7- filter washing water inlets, 8- closed chambers, 9- mixing components, 10- temperature-controlling modules, 11-pH control groups
Part, 12- sample taps 2,13- cleaning fluids/digestive juice outlet, 14- charging apertures, 15- digestive juice entrances, 16- sample taps 1,17- dissolved oxygens
Component, 18- living cells sensor clusters, 19- cells switching outlet, 20- escape pipes, 21- air inlet pipe, 22- air spargers,
23- retains component.
Embodiment
Below with reference to the accompanying drawing in the present embodiment, the technical scheme in embodiment is carried out specifically, clearly and completely to retouch
State.
Term defines
When term " digestion " refers to there is the zooblast of adherent growth characteristic to cover with carrier surface, to avoid between cell
Mutually suppress, it is necessary to cell be separated with old carrier, the process being transferred on new support.
" disposable digester unit " mainly provides disposable reacting environment for cell dissociation course of reaction.
Referring to shown in Fig. 2-4, the utility model embodiment provides a kind of disposable intelligence for animal cell culture
Digester systems, including disposable digester unit and intelligent control unit, disposable digester unit include at least can be used for
The fluid of accommodating culture cell and the sterile closed chamber 8 of digestive juice, closed chamber 8 is interior to be provided with retention component 23 and stirring group
Part 9, retention component 23 and the inner wall surrounding of closed chamber 8 are tightly connected, wherein, retention component 23 is at least in closed chamber
Carrier in fluid is retained in 8 and make zooblast by, mixing component 9 at least the material in closed chamber 8 to be mixed
Close.
Preferably, intelligent control unit includes：Temperature-controlling module 10, at least controlling the temperature in closed chamber 8；
PH control assemblies 11, at least detecting the pH value of the fluid in closed chamber 8；Dissolved oxygen component 17, at least closed to detect
Dissolved oxygen change in chamber 8；Online living cells sensor cluster 18, at least monitoring the viable count wandered about as a refugee in digestion process
Mesh changes；Weigh assembly 3, at least to on-line monitoring fluid inlet, weigh assembly 3 by monitoring digester weight change,
So as to monitor the inlet of fluid；Central controller, at least controlling the running status of each component；Temperature-controlling module
10th, pH control assemblies 11, dissolved oxygen component 17, online living cells sensor cluster 18 and weigh assembly 3 respectively with central controller
And closed chamber 8 connects.
It is more highly preferred to, the intelligent control unit also includes any one in following assemblies or two or more groups
Close：Carbon dioxide sensing component, at least change to detect the carbon dioxide in the closed chamber；Mixing rate sensing group
Part, at least detecting the troubled water of the fluid in the closed chamber；Photoelectric sensing component, at least detecting the envelope
The turbidity of fluid in closed chamber room；Described carbon dioxide sensing component, mixing rate sensory package and photoelectric sensing component are equal
It is connected with the central controller：
It is more highly preferred to, temperature-controlling module 10, pH control assemblies 11, dissolved oxygen component 17, online living cells sensor group
Part 18 and weigh assembly 3 are disposable assembly.And each component is securable in closed chamber 8, also it can be embedded in or be bonded in
The surface of closed chamber 8.
Preferably, the port for material and gas disengaging is provided with closed chamber 8, port includes and closed chamber 8
The upper end charging aperture 14, digestive juice entrance 15, filter washing water inlet 7, acid solution entrance 4, alkali liquor inlet 5, the cell that are connected
Switching access 6 and each component interface, cleaning fluid/digestive juice outlet 13 that port also includes being connected with the bottom of closed chamber 8,
Sample tap 12 and cell switching outlet 19, port also include air inlet and the gas outlet communicated with the upper end of closed chamber 8.
Further, air inlet pipe 21 and escape pipe 20, air inlet pipe 21 and outlet are inserted with respectively in air inlet and gas outlet
Pipe 20 is extended in closed chamber 8, and the lower end of air inlet pipe 21 connects with air sparger, and air sparger is located in closed chamber
Fluid level below.
Further, air sparger should select ventilation ring, and passage is evenly equipped with ventilation ring, and the aperture of passage is small
Gas is passed through in the diameter of microcarrier, air inlet pipe 21, make it that pressure maintains setting value in closed chamber 8, and is caused close
Closed chamber body rapid shaping and sizing.Wherein, be passed through filtrated air, oxygen or carbon dioxide in air inlet pipe 21, air, oxygen,
The air inlet pipe 21 of carbon dioxide can be connected in parallel, there is provided the bubbling of closed bag content.
Further, connection flow gauge and filter in air inlet pipe 21, escape pipe 20 connect pressure gauge or pressure sensing
Device and pressure-control valve, pressure gauge or pressure sensor are used to detect the pressure in closed chamber 8 so that in closed chamber 8
Pressure is maintained between 0.01-0.05Mpa, to ensure the rapid shaping of closed chamber 8, avoids the formation of fold.Pressure-control valve
For discharging the waste gas in closed chamber 8.
Further, above-mentioned each port by cap, female Luer, hose barb joint, check valve, sampler,
Any of sterilizing filter mode is isolated from the outside.
Preferably, disposable digester unit can use this simple form of closed bag, and the inner chamber of closed bag forms institute
The closed chamber 8 stated, wherein, be provided with closed bag charging aperture 14, digestive juice entrance 15, filter washing water inlet 7, acid solution entrance 4,
Alkali liquor inlet 5, cell switching access 6, cleaning fluid/digestive juice outlet 13, sample tap 12, cell switching outlet 19, air inlet and
Gas outlet, it is inserted with air inlet pipe 21 and escape pipe 20 respectively in air inlet and gas outlet.
Further, the material of closed bag is rigid, semi-rigid or flexible plastics；Still more preferably, plastic bag
Include in makrolon, polyester, fluoropolymer, acrylic acid, PET, polyvinyl chloride, ABS, PC, PS, GAG, acrylic and polyolefin
Any one or two or more combinations；Still further preferably, plastics include polyolefin.
Preferably, disposable digester unit includes at least one supporting construction 2 for being used to support closed chamber 8.
Preferably, the upper and lower part of closed chamber 8 stretches out the fixation to be formed for fixing and supporting closed chamber 8
Buckle.
Further, supporting construction 2 includes the support frame being located at outside closed bag, and closed bag is arranged on support frame as described above
Or in support frame, support frame as described above is fixing support rack or removable support frame；Further, the supporting construction includes setting
Support frame in closed bag.
Further, supporting construction 2 at least uses any one in metal drum, Plastic Drum, wooden barrel or glass tank.
Preferably, at least closed chamber 8 and the sterilized processing of each component, sterilization treatment mode include gamma-ray irradiation, β
Any one or two or more combinations in x ray irradiation x, ethylene oxide gas processing and steam sterilizing, by gamma-rays,
β rays, ethylene oxide sterilizing, steam sterilizing processing can also reuse.
Preferably, retention component 23 includes sieve plate or filter screen made from least one layer of plastics, and the aperture of sieve plate or filter screen is big
Diameter in cell and the diameter less than microcarrier.
Preferably, mixing component 9 includes mechanical agitation mechanism and/or magnetic agitation mechanism；Mixing component 9 can use center
Setting, centroclinal, eccentric setting, eccentric inclined mode are installed.
Further, mixing component 9 includes agitating shaft and agitating paddle, and agitating paddle is fixedly connected and is located at one end of the mixing shaft
In closed chamber 8, the other end of agitating shaft is located at outside closed chamber 8 and is connected with motor 1, and agitating shaft and closing
The joint of the locular wall of chamber 8 is also tightly connected through more than one sealing ring.
Further, agitating paddle is using any in the straight oar of single or multiple lift, arrow leaf oar, curved leaf oar, propeller
One or more kinds of combinations.
Further, the material of agitating shaft and/or agitating paddle is through gamma-rays, β rays, ethylene oxide sterilizing or steam
The high density polyethylene (HDPE) of sterilization treatment.
Preferably, temperature-controlling module 10 includes heater, chuck circulation and plug-in type or non-insertion temperature
Electrode is spent, plug-in type or non-insertion temperature electrode are used for the keying for adjusting heater, chuck circulation.It is selectable
It is that temperature-controlling module 10 can be coupled on the housing of supporting construction 2.Temperature-controlling module 10 can also be applied to the cold of blast pipe
On solidifying, so that the gas condensation of discharge prevents filter is got wet from influenceing gas filtration effect.
Preferably, pH control assemblies 11 include pH value electrode, and control acid solution, alkali lye, the stream of culture medium add.
Preferably, dissolved oxygen component 17 includes dissolved oxygen electrode, and dissolved oxygen joins with rotating speed, feed supplement, pressure correlation.
Preferably, online living cells sensor cluster 18 is as a plug or non-insertion mode is installed on the side of closed chamber 8
Portion, and online living cells sensor cluster 18 is close to retention component 23.
Preferably, weigh assembly 3 includes 3-4 Weighing module being installed at the leg of disposable digester unit and connect
Line box, terminal box electrically connect with each Weighing module, and terminal box gets in touch with the signal of each Weighing module, and according to the stand under load feelings of each module
Condition adjusts the weight difference at each leg, and the signal after collecting is delivered to central controller by terminal box afterwards.
Preferably, intelligent control unit also includes liquid pumping component, and liquid pumping component includes cleaning liquid pump, digestive juice
Pump, culture medium pump, sour pump, alkali pump, cleaning fluid excavationg pump, digestive juice excavationg pump and cell shifting pump, cleaning liquid pump, digestive juice
Pump, culture medium pump, sour pump, alkali pump, cleaning fluid excavationg pump, digestive juice excavationg pump and cell shifting pump respectively with central controller
Connection, and be respectively used to shift cleaning fluid, digestive juice, culture medium, acid solution, alkali lye, the culture medium rich in free cell.Liquid
Pump connects central controller by data wire, and each pump housing is subjected to central controller instruction, realizes the automatic of pump operating
With manual control.
Preferably, the central controller also includes wireless communication module, and central controller is through wireless communication module and far
Journey terminal wireless connects.
Digestion process for the disposable intelligent digester systems of animal cell culture is as follows：
(i) the installation and debugging stage：Closed bag is fixed on by fixed card buckle on the outer wall of digester supporting construction 2, is passed through
Gas and fluid pipeline on the sterile closed bag of connection of snap joint, acid solution, alkali lye, digestive juice, cleaning fluid, culture medium, cleaning
Liquid and digestive juice discharge, cell adapting pipe are installed on corresponding peristaltic pump.Complete gas flow component 21, temperature control group
Part 10, pH control assemblies 11, dissolved oxygen control assembly 17, pressure control assembly (air inlet pipe, escape pipe, flowmeter, filter and pressure
Force control valve forms described pressure control assembly), weigh assembly 3, online living cells sensor cluster 18, mixing component 9 with
The connection of central controller.It is passed through compressed air, oxygen or carbon dioxide through air source inlet to enter inside closed bag, maintains pressure
In 0.01-0.05Mpa, to ensure closed bag rapid shaping, while the air-tightness that closed bag connects with each pipeline is checked.According to disappearing
Change condition, set initial parameter, including throughput, temperature, pH, dissolved oxygen, pressure, rotating speed.
(ii) incipient stage is digested：After debugging to be installed, open digestive juice and enter step, existed by weigh assembly 3
Line monitors digestive juice inlet；Meanwhile according to default pH, the stream of system automatic start acid solution or alkali lye adds；According to default
Temperature, system automatic start heater heated or started chuck circulation and cooled down；According to default dissolved oxygen,
The parameter association such as dissolved oxygen and throughput, pressure, rotating speed is controlled；With the progress of digestion reaction process, dissociate suspension living cells
Number is gradually risen, and after a certain time, free suspension number of viable cells is not further added by, and online living cells sensor 18 is online
Complete monitoring digestion process, the signal that free suspension number of viable cells changes is transferred to central control system；Suspended when free
After number of viable cells reaches preset value, the disposable intelligent digester systems close pH control assemblies 11, temperature control group automatically
Part 10, digestive juice discharge step is opened, digestive juice is quickly discharged through digesting liquid pump, and carrier is trapped component and is trapped in closed chamber
In 8.
(iii) wash phase is digested：After digestive juice drains, cleaning step is opened, reduces rotating speed, adjusts the temperature to cell training
Temperature is supported, sets cleaning fluid addition and wash number (generally 1-3 times), system is opened according to cleaning procedure set in advance
The cleaning liquid pump of cleaning fluid passage is opened, cleaning fluid enters in closed chamber 8, and online living cells sensor 18 monitors loss cell feelings
Condition.
(iv) termination phase is digested：It is to be cleaned finish after, open digestion terminate step.Improve speed of agitator, regulation temperature
Degree and pH controls set culture medium addition, dissolved oxygen and throughput, pressure, rotating speed etc. are joined in the range of cultivation temperature and pH
Number association, control is associated by pH with feed supplement, acid, alkali.System opens culture medium passage according to digestion terminator set in advance
Culture medium pump, culture medium enter closed chamber 8 in.The process can be with last longer, when free suspension cell number is protected
Maintain an equal level steady, or cytoactive is begun to decline, then is considered as digestion and terminates.
(v) cell transition phase：After digestion terminator terminates, cell can be transferred to down by following two modes
First-stage reactor：A) improve digester tank and be depressed into 0.03-0.05Mpa, the tank for reducing next stage reactor is depressed into 0.01-
0.02Mpa, by pressure differential method by nutrient solution force feed to next stage reactor；B) peristaltic pump of cell transfering channel is opened, is rich in
The cell transfer of free suspension cell is pumped to next stage reactor, and empty carrier is trapped component and is trapped in closed chamber 8.
1,5 and 6 pair of 1-2, comparative example 1 and accompanying drawing the technical solution of the utility model are done further with reference to embodiments
Explanation.
Embodiment 1
Shown in Figure 5, the 10L disposable bioreactors in the embodiment are used as seed reactor, carry out microcarrier
Cell suspension cultures；The disposable digesters of 10L are used as the place for the seed cell digestion reaction that culture is completed, and realize that PK-15 is thin
Born of the same parents and the separation of microcarrier, free cell are transferred to 50L disposable bioreactors and carry out continuing to cultivate.More times of 10L and 50L
The working volume of property bioreactor is 7L and 35L respectively, the ratio of height to diameter 1.8 of reactor：1.0, agitating paddle is lifted using individual layer
Band oar, oar footpath is with reactor diameter ratio：1.0:1.8.The disposable digester cellular constructions of 10L design as shown in Figure 2,3, 4, work
It is 7L as volume.The Cytodex-1 that the disposable digester mounting mediums of 10L are produced using GE companies, 3g/L, cell density are
2.5×106cells/mL.Digestion reaction implementation process is as shown in Fig. 2 specific implementation step is as follows：
(i) the liquid dosage stage：Prepare cleaning fluid 20L, digestive juice 1L, culture medium 5L, acid solution (1N HCl) 2L, alkali lye
(3N NaOH) 2L, 3% NBCS is contained wherein in culture medium.
(ii) the installation and debugging stage：Closed bag is fixed on by fixed card buckle on the outer wall of digester support, by quick
Joint causes gas pipeline and fluid pipeline (acid solution, alkali lye, digestive juice, cleaning fluid, culture medium pipeline) and phase on closed bag
The peristaltic pump answered realizes sterile connection；Completion temperature-controlling module, pH control assemblies, dissolved oxygen component, weigh assembly, online work are thin
The connection of born of the same parents' sensor cluster, mixing component and central controller.Compressed air, oxygen or carbon dioxide is passed through through air inlet pipe to enter
Enter inside closed bag, maintain pressure in 0.01-0.05Mpa, so as to realize the control of pressure, to ensure closed bag rapid shaping,
It is airtight to check that closed bag connects with each pipeline simultaneously；According to digestion condition, initial parameter is set, including throughput 0.5vvm,
37 DEG C of temperature, pH7.0, pressure 0.02Mpa, rotating speed 25rpm.
(iii) incipient stage is digested：After debugging to be installed, by the nutrient solution of the disposable bioreactor cultures of 10L
It is directly transferred in the disposable digesters of 10L.Open digestive juice and enter step, pass through weigh assembly on-line monitoring digestive juice
Inlet, 0.6L digestive juices are pumped in the closed bag of digester by digestive juice；Design temperature is 37 DEG C, and rotating speed is
25rpm, pH 7.0, while according to default pH, the stream of system automatic start acid solution or alkali lye adds；According to default temperature,
System automatic start heater heats or started the cooling of chuck circulation；According to default dissolved oxygen, by dissolved oxygen and throughput,
The parameter associations such as pressure, rotating speed control.The online complete monitoring digestion process of online living cells sensor, by free suspension living cells
The signal of number of variations is transferred to central control system；When cell number is not further added by, then it is considered as digestion process completion；Reach
After preset value, the digester systems close pH control assemblies, temperature-controlling module automatically, open digestive juice discharge step.Digestion
Liquid is quickly discharged through digesting liquid pump, and carrier is trapped component 23 and is trapped in the closed bag of the digester.
(iv) wash phase is digested：After digestive juice drains, cleaning step is opened, rotating speed is improved to 50rpm, adjusted the temperature to
37 DEG C, set cleaning fluid addition 5L and wash number 2 times, scavenging period 10min.System is according to cleaning journey set in advance
Sequence, opens the cleaning liquid pump of cleaning fluid passage, and cleaning fluid enters in the closed bag of digester；After cleaning, automatic start is clear
Washing lotion excavationg pump quickly drains cleaning fluid, online living cells Sensor monitoring loss cell situation.
(v) termination phase is digested：It is to be cleaned finish after, open digestion terminate step.Improve speed of agitator, design temperature
For 37 DEG C, rotating speed 100rpm, culture medium addition 5L is set, pH is associated into control with acid, alkali.System is according to set in advance
Terminator is digested, opens the culture medium pump of culture medium passage, culture medium enters in the closed bag of digester；After 5min,
The free suspension cell number of line living cells Sensor monitoring starts to raise, and then a period of time free suspension cell number keeps flat
Surely, digestion can be considered as to terminate.
(vi) cell transition phase：After digestion terminator terminates, the cell shifting pump of cell transfering channel is opened, it is rich
Culture medium containing free suspension cell is pumped to 50L disposable bioreactors, and carrier is trapped component and is trapped in 10L once
In property digester.Data monitoring obtains free cell number as 0.49 × 106Cells/mL, cell attachment is to new after 11 hours
On carrier, loss cell rate is only 2.01%.
Embodiment 2
Shown in Figure 6, the 90L disposable bioreactors in the embodiment are used as seed reactor, carry out microcarrier
Cell suspension cultures；The disposable digesters of 90L are used as the place for the seed cell digestion reaction that culture is completed, and realize that PK-15 is thin
Born of the same parents and the separation of microcarrier, free cell are transferred to 300L disposable bioreactors and carry out continuing to cultivate.90L and 300L mono-
The working volume of secondary property bioreactor is 63L and 210L respectively, the ratio of height to diameter 1.8 of reactor：1.0, agitating paddle uses individual layer
Elevator belt oar, oar footpath are with reactor diameter ratio：1.0:1.8.The disposable digesters of 90L and the disposable digesters of 10L have several
What similarity feature, other digestion reaction steps are with reference to embodiment 2, and specific implementing procedure figure is as shown in fig. 6, no longer superfluous herein
State.
Culture medium rich in free suspension cell is pumped to 300L disposable bioreactors, and carrier is trapped component and cut
Stay in the disposable digesters of 90L.Data monitoring obtains free cell number as 0.48 × 106Cells/mL is thin after 11 hours
Born of the same parents are pasted on new carrier, and loss cell rate is only 3.98%.
Comparative example 1
Shown in Figure 1, the muptiple-use bioreactors of 10L (stainless steel fermentation tank) in the comparative example react as seed
Device, carry out microcarrier cell suspension culture；The muptiple-use digesters of 10L are used as the field for the seed cell digestion reaction that culture is completed
Institute, the separation of PK-15 cells and microcarrier is realized, free cell is transferred to the muptiple-use bioreactors of 50L, and (stainless steel ferments
Tank) carry out continuing to cultivate.Wherein, the muptiple-use digesters of 10L are identical with the design of the muptiple-use bioreactors of 10L.10L and 50L
The working volume of muptiple-use bioreactor is 7L and 35L respectively, the ratio of height to diameter 1.8 of reactor：1.0, agitating paddle uses individual layer
Elevator belt oar, oar footpath are with reactor diameter ratio：1.0:1.8.1L bioreactors mounting medium is produced using GE companies
Cytodex-1,3g/L, cell density are 2.5 × 106cells/mL.Digestion reaction implementation process is as shown in figure 1, specific implementation
Step is as follows：
(i) the liquid dosage stage：Prepare cleaning fluid 20L, digestive juice 1L, culture medium 5L, acid solution (1N HCl) 2L, alkali lye
(3N NaOH) 2L, 3% NBCS is contained wherein in culture medium.
(ii) digester erection stage：Come loose reactor cap and each line connection screw, covers, unloads on reactor of dismantling
Each electrode, stopple, cap head, are cleaned up with rag, and clean with pure water rinsing.At docking port, reactor wall and stirring dress
Sealing part is put, is cleaned with pure water emphasis, rushes residue and raffinate to the greatest extent.Check each packing ring, apron whether aged deterioration, and in time more
Change.The connection of each conduit component is finished, and electrode is connected with central controller by electrode wires, to pH value electrode, dissolved oxygen electricity
Pole carries out Zero calibration and slope demarcation.Air pressurize is passed through, checks the air-tightness of reactor.
(iii) digester sterilization phase：121 DEG C of empty elimination bacterium 30min.Insert pH value electrode and dissolved oxygen electrode, digester
Built with 7L pure water, 121 DEG C of real elimination bacterium 30min.
(iv) the digester debugging stage：After sterilizing, start-up temperature control assembly, design temperature is 37 DEG C, and system is led to
Circulation is crossed to cool to design temperature；PID control heater heats and circulating water, temperature are maintained at 37 DEG C.
(v) wash phase is digested：Discharge valve is opened, pure water is discharged out of tank body.Digestive juice dump valve is closed, is opened
Cleaning fluid enters valve, adds cleaning fluid 5L by pressure differential method, rinses tank body 30min；Cleaning fluid dump valve is opened, drains cleaning
Liquid.Clean 1-3 times repeatedly, until noresidue is verified in cleaning.The nutrient solution of the muptiple-use bioreactor cultures of 10L is settled, transferred
Clear liquid, sedimentation liquid is transferred in the muptiple-use digesters of 10L by tank body bottom valve.Cleaning fluid 5L is added to clear again in digester
Wash, settle.During cleaning, design temperature is 37 DEG C, rotating speed 50rpm.After cleaning, stop stirring, emptied after settling clear
Washing lotion.
(vi) incipient stage is digested：After stage to be cleaned terminates, open digestive juice and enter valve, 0.6L digestive juices are pumped to
In digester, design temperature is 37 DEG C, rotating speed 25rpm, pH 7.0.Free cell number is measured by sampling every 10min, when
When cell number is not further added by, it is considered as digestion process completion, closes stirring, pH, open digestive juice dump valve, emptying digestive juice.
(vii) termination phase is digested：After to the end of digestion, open culture medium and enter valve, 5L culture mediums are pumped to and disappeared
Change in device, design temperature is 37 DEG C, rotating speed 100rpm.Every 10min, free cell number is measured by sampling, works as cell number
It is not further added by or cytoactive declines, is considered as digestion and terminates.
(viii) cell transition phase：After digestion terminates, cell transfer valve is opened, is transferred to cell by pressure differential method
In the muptiple-use bioreactors of 50L.It is 0.3 × 10 that free cell number, which is measured by sampling,6Cells/mL, cell attachment after 14 hours
To new carrier, loss cell rate is 41.56%.
Muptiple-use digester in comparative example 1 needs installation and debugging repeatedly, it is necessary to carry out disinfection and clean online, thus wave
Time-consuming and manpower, and the loss cell rate of muptiple-use intelligent digester is up to 41.56%, and it is provided by the utility model once
Property digester eliminates SIP (sterilization system on line) and CIP (on-line cleaning), the equipment step such as installation and debugging repeatedly, simplifies operation
Flow, save material resources, human cost；And disposable digester loss late minimum reachable 2%, greatly reduce cell dissociation
Loss late.
Above-mentioned embodiment, only illustrate technical concept and architectural feature of the present utility model, it is therefore intended that allow ripe
Knowing the stakeholder of technique can implement according to this, but above said content is not intended to limit the scope of protection of the utility model,
Every any equivalent change or modification made according to Spirit Essence of the present utility model, all should fall into protection of the present utility model
Within the scope of.
Claims (27)
- A kind of 1. disposable intelligent digester systems for animal cell culture, it is characterised in that：Including disposable digester Unit and intelligent control unit, the disposable digester unit include at least can be used for fluid and the digestion of accommodating culture cell The sterile closed chamber of liquid, at least charging aperture connected with the closed chamber, an at least gas outlet, an at least air inlet, An at least digestive juice entrance, an at least filter washing water inlet, an at least culture medium entrance, an at least cleaning fluid and digestive juice outlet with And an at least sample tap, and retention component and mixing component are at least additionally provided with the closed chamber, the retention component is extremely It is few in the closed chamber by the carrier in fluid retain and make zooblast by, the mixing component at least to By the material mixing in the closed chamber.
- 2. the disposable intelligent digester systems according to claim 1 for animal cell culture, it is characterised in that：Bag Closed bag is included, the inner chamber of the closed bag forms the closed chamber, the charging aperture, outlet are provided with the closed bag Mouth, air inlet, digestive juice entrance, filter washing water inlet, culture medium entrance, while the closed bag bottom is additionally provided with the cleaning fluid With digestive juice outlet and sample tap.
- 3. the disposable intelligent digester systems according to claim 2 for animal cell culture, it is characterised in that：Institute State retention component and be located at the closed bag inner chamber bottom, and be tightly connected with the closed bag inner wall surrounding, on the closed bag It is additionally provided with least an acid solution entrance and at least an alkali liquor inlet.
- 4. the disposable intelligent digester systems according to claim 2 for animal cell culture, it is characterised in that：Institute State and an at least cell switching access and at least cell switching outlet are additionally provided with closed bag.
- 5. the disposable intelligent digester systems according to claim 2 for animal cell culture, it is characterised in that：Institute State at the top of closed bag and sidepiece forms multiple ports, described multiple ports are used separately as the charging aperture, gas outlet, air inlet Mouth, digestive juice import, cleaning fluid import, culture medium import, cleaning fluid and digestive juice outlet and sample tap.
- 6. the disposable intelligent digester systems according to claim 5 for animal cell culture, it is characterised in that：Institute State port at least through any of cap, female Luer, hose barb joint, check valve, sampler, sterilizing filter with External environment is isolated.
- 7. the disposable intelligent digester systems according to claim 2 for animal cell culture, it is characterised in that：Extremely A few air inlet pipe inserts the closed chamber by the air inlet, and the air inlet pipe lower end connects with air sparger, described Air sparger is located at below the fluid level in the closed chamber, and an at least escape pipe passes through described in the insertion of the gas outlet Closed chamber.
- 8. the disposable intelligent digester systems according to claim 7 for animal cell culture, it is characterised in that：Institute Stating air sparger includes ventilation ring, a plurality of passages is evenly distributed with the ventilation ring, the aperture of the passage is small In the diameter of carrier.
- 9. the disposable intelligent digester systems according to claim 7 for animal cell culture, it is characterised in that：Institute State and flowmeter and filter are also connected with air inlet pipe, pressure gauge or pressure sensor and pressure control are also associated with the escape pipe Valve processed, the pressure in the closed chamber are maintained between 0.01-0.05Mpa.
- 10. the disposable intelligent digester systems according to claim 2 for animal cell culture, it is characterised in that： The material of the closed bag includes rigid, semi-rigid or flexible plastics.
- 11. the disposable intelligent digester systems according to claim 2 for animal cell culture, it is characterised in that： The disposable digester unit includes supporting construction, and the supporting construction is at least used to support the closed bag.
- 12. the disposable intelligent digester systems according to claim 11 for animal cell culture, it is characterised in that： The supporting construction is included in the fixed card buckle that the closed bag upper and lower part stretches out.
- 13. the disposable intelligent digester systems according to claim 11 for animal cell culture, it is characterised in that： The supporting construction includes the support frame being located at outside the closed bag, and the closed bag is arranged on support frame as described above or described In support frame, support frame as described above is fixing support rack or removable support frame.
- 14. the disposable intelligent digester systems according to claim 11 for animal cell culture, it is characterised in that： The supporting construction includes the support frame in the closed bag.
- 15. the disposable intelligent digester systems according to claim 11 for animal cell culture, it is characterised in that： Any one of the supporting construction at least in metal drum, Plastic Drum, wooden barrel or glass tank.
- 16. the disposable intelligent digester systems according to claim 11 for animal cell culture, it is characterised in that： The mixing component is connected with drive mechanism, and the drive mechanism is connected with the supporting construction, and is arranged on described close Close outside bag or inside, the drive mechanism include motor.
- 17. the disposable intelligent digester systems according to claim 16 for animal cell culture, it is characterised in that： The mixing component includes mechanical agitation mechanism and/or magnetic agitation mechanism.
- 18. the disposable intelligent digester systems according to claim 17 for animal cell culture, it is characterised in that： The mixing component includes agitating shaft and agitating paddle, and the agitating paddle is fixedly connected with one end of the mixing shaft and is located at the closing chamber Interior, the other end of the agitating shaft is located at outside the closed chamber and is connected with drive mechanism, and the agitating shaft Also it is tightly connected with the joint of the closed chamber locular wall through more than one sealing ring.
- 19. the disposable intelligent digester systems according to claim 18 for animal cell culture, it is characterised in that： Any one in the agitating paddle at least straight oar selected from single or multiple lift, arrow leaf oar, curved leaf oar, propeller.
- 20. the disposable intelligent digester systems according to claim 1 for animal cell culture, it is characterised in that： The retention component includes at least a sieve plate or filter screen, and the aperture of the sieve plate or filter screen is more than the diameter of zooblast and is less than The diameter of microcarrier.
- 21. the disposable intelligent digester systems according to claim 2 for animal cell culture, it is characterised in that： The intelligent control unit includes：Temperature-controlling module, at least controlling the temperature in the closed chamber；And/or pH control assemblies, at least monitoring the pH value of the fluid in the closed chamber；And/or dissolved oxygen component, at least change to detect the dissolved oxygen in the closed chamber；And/or online living cells sensor cluster, at least change to monitor the number of viable cells wandered about as a refugee in digestion process；And/or weigh assembly, at least to on-line monitoring fluid inlet；And/or central controller, at least controlling the running status of each component；The temperature-controlling module, pH control assemblies, dissolved oxygen component, online living cells sensor cluster and weigh assembly are and institute State central controller and closed chamber connection.
- 22. the disposable intelligent digester systems according to claim 21 for animal cell culture, it is characterised in that： The temperature-controlling module, pH control assemblies, dissolved oxygen component, online living cells sensor cluster and weigh assembly are disposable Component.
- 23. the disposable intelligent digester systems according to claim 21 for animal cell culture, it is characterised in that： The intelligent control unit also includes：Carbon dioxide sensing component, at least change to detect the carbon dioxide in the closed chamber；And/or mixing rate sensory package, at least detecting the troubled water of the fluid in the closed chamber；And/or photoelectric sensing component, at least detecting the turbidity of the fluid in the closed chamber；The carbon dioxide sensing component, mixing rate sensory package and photoelectric sensing component connect with the central controller Connect.
- 24. the disposable intelligent digester systems according to claim 21 for animal cell culture, it is characterised in that： The temperature-controlling module includes heater, chuck circulation and plug-in type or non-insertion temperature electrode；And/or The pH control assemblies include pH value electrode；And/or the dissolved oxygen component includes dissolved oxygen electrode；It is and/or described online living thin Born of the same parents' sensor cluster is as a plug or non-insertion mode is installed on the closed chamber sidepiece, and the online living cells sensing Device assembly is close to the retention component；And/or the weigh assembly includes one of the supporting disposable digester unit Above Weighing module and terminal box, the Weighing module electrically connect with terminal box.
- 25. the disposable intelligent digester systems according to claim 24 for animal cell culture, it is characterised in that： The weigh assembly includes being installed on 3-4 Weighing module at the leg of the disposable digester unit.
- 26. the disposable intelligent digester systems according to claim 21 for animal cell culture, it is characterised in that： The intelligent control unit also includes liquid pumping component, and the liquid pumping component includes cleaning liquid pump, digestion liquid pump, culture In base pump, sour pump, alkali pump, cleaning fluid excavationg pump, digestive juice excavationg pump and cell shifting pump any one or it is two or more Combination, it is described cleaning liquid pump, digestion liquid pump, culture medium pump, sour pump, alkali pump, cleaning fluid excavationg pump, digestive juice excavationg pump and Cell shifting pump is connected with the central controller respectively.
- 27. the disposable intelligent digester systems according to claim 21 for animal cell culture, it is characterised in that： The central controller also includes wireless communication module, the central controller through the wireless communication module and remote terminal without Line connects.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201720348413.8U CN206814791U (en) | 2017-04-05 | 2017-04-05 | Disposable intelligent digester systems for animal cell culture |
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|---|---|---|---|
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106754366A (en) * | 2017-04-05 | 2017-05-31 | 苏州迪欧益生物科技有限公司 | For the disposable intelligent digester systems of animal cell culture |
| CN108315259A (en) * | 2018-05-09 | 2018-07-24 | 武汉赛科成科技有限公司 | A kind of disposable film device of fluid bed cell culture of filling chip carrier |
-
2017
- 2017-04-05 CN CN201720348413.8U patent/CN206814791U/en active Active
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106754366A (en) * | 2017-04-05 | 2017-05-31 | 苏州迪欧益生物科技有限公司 | For the disposable intelligent digester systems of animal cell culture |
| CN108315259A (en) * | 2018-05-09 | 2018-07-24 | 武汉赛科成科技有限公司 | A kind of disposable film device of fluid bed cell culture of filling chip carrier |
| CN108315259B (en) * | 2018-05-09 | 2024-01-23 | 武汉赛科成科技有限公司 | Fluidized bed cell culture disposable membrane device filled with sheet-shaped carrier |
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