A system with feed-liquid reaction and ultrafiltration

Abstract

The present invention discloses a system with liquid-feed reaction and ultrafiltration. The system includes a glass reactor, a TCU temperature control module, a weighing module, a stirring module, a peristaltic pump, a CIP circulation pump, a spray ball, a pH meter, an ultrafiltration fixture, and a conductivity meter. The present invention combines the functions of a biological reactor and an ultrafiltration system to provide an efficient and controllable equipment design for bacterial polysaccharide hydrolysis oxidation, derivatization, binding reaction and ultrafiltration. When the equipment is used to produce polysaccharide and protein conjugate vaccines, the process includes steps such as polysaccharide degradation, derivatization, binding reaction and ultrafiltration.

Description

Technical Field

[0001] The invention belongs to pharmaceutical equipment and relates to a composite use system for precise control of liquid-feed reaction and ultrafiltration in a biopharmaceutical process. Background Art

[0002] Bacterial polysaccharide-protein conjugate vaccines play a very important role in preventing invasive diseases caused by Haemophilus influenzae type b, meningococci and Streptococcus pneumoniae. These vaccines have a bacterial polysaccharide-protein conjugate reaction step in their production methods, and the preparation process of pneumococcal polysaccharide-protein conjugate vaccines often requires the degradation and derivatization of pneumococcal polysaccharides before the conjugation reaction step. In most processes, after the polysaccharide degradation, derivatization and conjugation reactions are completed, the reaction products are then subjected to ultrafiltration concentration and dialysis.

[0003] The process of polysaccharide degradation, derivatization and conjugation reaction requires a container, and the reaction process needs to control temperature, stirring, pH value and feeding speed. The traditional method is: put the solution into a glass container such as a beaker or reagent bottle, put it into a constant temperature water bath shaker, use a pH meter to detect the change of pH value, add the required reagents through a peristaltic pump to complete the conjugation reaction, and manually record various conditions such as reaction time, temperature, pH value, etc.

[0004] At present, as the requirements for GMP plants become more and more stringent, the demand for automation is also increasing. Some biopharmaceutical companies use reactors to control the processes of polysaccharide degradation, derivatization and conjugation reactions, and then use automated ultrafiltration systems for ultrafiltration concentration and dialysis.

[0005] The main components of the reactor and the main components of the automated ultrafiltration system are partially the same, as shown in the table below. The design of the present invention combines the two into one, forming an integrated device, which saves costs and is easy to operate.

[0006] Table 1. Comparison of the main components of the three types of equipment

[0007]

[0008] Summary of the invention

[0009] The object of the present invention is to provide a system with feed-liquid reaction and ultrafiltration effects.

[0010] When the system is used to produce polysaccharide and protein conjugate vaccines, it can achieve hydrolysis and oxidation, and has functions such as polysaccharide degradation, derivatization, conjugation reaction and ultrafiltration, and it is efficient and controllable.

[0011] The system of the present invention is mainly composed of a glass kettle, a respirator, a TCU temperature control module, a temperature probe, a weighing module, a stirring module, two peristaltic pumps, a circulation pump, a pH meter, and an ultrafiltration fixture, wherein a stainless steel cover is provided on the top of the glass kettle, 1. the stirring module, 2. the respirator, 3. the pH probe, 4. the temperature probe, 26. peristaltic pump 1, 28. peristaltic pump 2, and 14. the ultrafiltration fixture are respectively connected to the stainless steel cover of the glass kettle, 10. a weighing module is provided below the glass kettle, 11. a circulation pump is connected to the bottom of the glass kettle, and 2. the TCU temperature control module is respectively connected to 7. the TCU liquid inlet and 8. the TCU liquid outlet of the glass kettle.

[0012] Among them, when carrying out the feed liquid reaction step, 26. The outlet ends of peristaltic pump 1 and 28. peristaltic pump 2 are respectively connected to the stainless steel cover of the glass kettle for adding different feed liquids at the same time; 2. The respirator is connected to the stainless steel cover; 1. The stirring paddle of the stirring module is inserted into the glass kettle through the stainless steel cover to mix the feed liquid; 4. The temperature probe is inserted into the glass kettle through the stainless steel cover to monitor the temperature change; 3. The pH probe is inserted into the glass kettle through the stainless steel cover to monitor the pH change, and the weighing module is associated with the glass kettle to monitor the weight change of the feed liquid.

[0013] Among them, when performing the ultrafiltration step, the inlet end of the circulation pump 11 is connected to the liquid outlet at the bottom of the glass kettle, the outlet end of the circulation pump 11 is connected to the liquid inlet end of the ultrafiltration fixture 14, and the reflux end of the ultrafiltration fixture 14 is connected to the glass kettle through a stainless steel cover to form an ultrafiltration loop, and the ultrafiltration fixture discharges waste liquid through the end outlet.

[0014] Before CIP operation, fix the spray ball 5 on the inner side of the stainless steel cover of the glass kettle, connect the outlet of the circulation pump 11 to the liquid inlet of the ultrafiltration fixture 14, connect the reflux end of the ultrafiltration fixture 14 to the inside of the glass kettle 6 through the stainless steel cover, connect the inlet of the circulation pump 11 to the liquid outlet 23 at the bottom of the glass kettle 6 to form a CIP cleaning loop for CIP operation.

[0015] Specifically, the connection mode of each component in the system of the present invention is:

[0016] The system is mainly composed of a glass kettle, a respirator, a TCU temperature control module, a temperature probe, a weighing module, a stirring module, two peristaltic pumps, a circulation pump, a pH meter, and an ultrafiltration fixture.

[0017] Among them, the top of the glass kettle 6 is provided with a stainless steel cover, 1. a stirring module, 2. a respirator, 3. a pH probe, 4. a temperature probe, 26. a peristaltic pump 1, 28. a peristaltic pump 2, and an ultrafiltration 14. a clamp are respectively connected to the stainless steel cover of the glass kettle, a 10. weighing module is provided below the glass kettle, a 11. circulating pump is connected to the bottom of the glass kettle, and a 2. TCU temperature control module is respectively connected to the 7. TCU liquid inlet and 8. TCU liquid outlet of the glass kettle.

[0018] Among them, 6. A stainless steel cover is provided on the top of the glass kettle, 26. The outlet end of the peristaltic pump 1 and 28. The outlet end of the peristaltic pump 2 are respectively connected to the stainless steel cover of the glass kettle, 3. The pH meter probe is inserted into the glass kettle through the stainless steel cover; 2. The respirator is connected to the stainless steel cover; 1. The stirring paddle of the stirring module is inserted into the glass kettle through the stainless steel cover; 4. The temperature probe is inserted into the glass kettle through the stainless steel cover; 25. The TCU temperature control module is connected to the glass kettle; 10. The weighing module is set at the bottom of the glass kettle,

[0019] Among them, the inlet end of the 11th circulation pump is connected to the inlet pipe 23 at the bottom of the glass kettle, the outlet end of the 11th circulation pump is connected to the liquid inlet end of the ultrafiltration fixture 14, the reflux pipe 24 of the ultrafiltration fixture is connected to the glass kettle through a stainless steel cover to form an ultrafiltration loop, and the permeate outlet 22 of the ultrafiltration fixture is connected to the waste liquid drainage; the ultrafiltration fixture is provided with a 13th inlet end pressure sensor, a 16th reflux end pressure sensor and a 15th permeate end pressure sensor, the ultrafiltration fixture is also provided with a 18th reflux end flow sensor and a 19th permeate end flow sensor, and the 24th reflux pipe is provided with a 17th reflux valve, a 21st permeate valve, and a 20th conductivity meter,

[0020] Among them, 5. the spray ball is fixed on the inner side of the stainless steel cover of the glass kettle, and 24. the reflux pipe is connected to 5. the spray ball.

[0021] Furthermore, the TCU temperature control module is connected to the glass kettle, and precise temperature control is achieved through the TCU temperature control module according to the temperature changes monitored by the temperature probe.

[0022] Furthermore, the program is edited to set the required pH value range, and the monitored pH data is associated with the peristaltic pump, so that the peristaltic pump adds acid or alkali solution according to the set value to automatically adjust the pH value.

[0023] Furthermore, the program is edited to set the weight of the liquid to be added, and the weighing module and the peristaltic pump are associated so that the peristaltic pump automatically adds the liquid according to the set value.

[0024] Furthermore, the ultrafiltration fixture inlet, reflux end and permeate end are provided with pressure sensors, the reflux end and permeate end are provided with flow sensors, the reflux end loop and permeate end outlet are provided with solenoid valves, and the permeate end outlet is provided with a conductivity sensor.

[0025] Another object of the present invention is to provide a method for using the system.

[0026] Step 1, degradation reaction step: the outlet ends of the first peristaltic pump 26 and the second peristaltic pump 28 are respectively connected to the stainless steel cover of the glass kettle for adding different feed liquids at the same time; the respirator 2 is connected to the stainless steel cover; the stirring paddle of the stirring module 1 is inserted into the glass kettle through the stainless steel cover to mix the feed liquid; the temperature probe 4 is inserted into the glass kettle through the stainless steel cover to monitor temperature changes; the pH meter 3 is inserted into the glass kettle through the stainless steel cover to monitor pH changes, and the weighing module is associated with the glass kettle to monitor changes in feed liquid weight.

[0027] Step 2, when performing the ultrafiltration step, the inlet end of the circulation pump 11 is connected to the liquid outlet at the bottom of the glass kettle, the outlet end of the circulation pump 11 is connected to the liquid inlet end of the ultrafiltration fixture 14, and the reflux end of the ultrafiltration fixture 14 is connected to the glass kettle through a stainless steel cover to form an ultrafiltration loop, and the ultrafiltration fixture discharges waste liquid through the end outlet.

[0028] Step 3, cleaning step. Before CIP operation, fix the spray ball 5 on the inner side of the stainless steel cover of the glass kettle, connect the outlet end of the circulation pump 11 to the liquid inlet end of the ultrafiltration fixture 14, connect the reflux end of the ultrafiltration fixture 14 to the glass kettle 6 through the stainless steel cover, connect the inlet end of the circulation pump 11 to the 23. liquid outlet at the bottom of the glass kettle 6 to form a CIP cleaning loop and perform CIP operation.

[0029] Preferably, the method for using the system of the present invention comprises the following steps:

[0030] Among them, in the step 1 of the degradation reaction of pneumonia polysaccharide, the outlet end of 26. peristaltic pump 1 and the outlet end of 28. peristaltic pump 2 are respectively connected to the stainless steel cover of 6. glass kettle, 26. peristaltic pump 1 is used to add liquid, 28. peristaltic pump 2 is used to add acid / alkali solution, 3. pH meter is inserted into 6. glass kettle through the stainless steel cover to monitor pH changes, edit the program, set the required pH value range, associate the monitored pH data with 28. peristaltic pump 2, add acid / alkali solution according to the set value, and automatically adjust the pH value. ; 2. The respirator is connected to the stainless steel cover; the stirring paddle is inserted into the glass kettle through the stainless steel cover to mix the liquid; 4. The temperature probe is inserted into the glass kettle through the stainless steel cover to monitor the temperature change, and the 25. TCU temperature control module is connected to the jacket of the glass kettle, and the temperature is controlled by the TCU temperature control module according to the temperature change monitored by the temperature probe; 10. The weighing module is associated with the glass kettle to monitor the weight change of the liquid; after the reaction is completed, it needs to be stored at 2-8°C, and the temperature control is set to 4±1°C.

[0031] Among them, in the second step of ultrafiltration, the above connections do not need to be changed, 11. the inlet end of the circulation pump is connected to the liquid outlet at the bottom of the glass kettle, 11. the outlet end of the circulation pump is connected to 14. the liquid inlet end of the ultrafiltration fixture, and the reflux pipe of the ultrafiltration fixture 24 is connected to 6. the glass kettle through a stainless steel cover to form an ultrafiltration loop, and the outlet of the permeate end of the ultrafiltration fixture 22 is connected to the waste liquid drainage; pressure sensors are set at the inlet end, 16. the reflux end and 15. the permeate end of the ultrafiltration fixture, flow sensors are set at the reflux end and 19. the permeate end of the ultrafiltration fixture, and solenoid valves are set at the reflux end loop and 21. the permeate end outlet. The program is edited to complete the ultrafiltration and dialysis processes; 20. The permeate end outlet is provided with a conductivity sensor, and the end point of the ultrafiltration dialysis is judged by the permeate flow rate and conductivity.

[0032] Step 3: CIP operation. Fix the spray ball 5 on the inner side of the stainless steel cover of the glass kettle 6. Connect the reflux pipe 24 to the spray ball 5. Connect the inlet end of the circulation pump 11 to the inlet pipe 23 at the bottom of the glass kettle to form a CIP cleaning loop. Connect the reflux pipe 24 of the ultrafiltration fixture to the waste liquid drainage or the spray ball 5 according to the cleaning procedure. Connect the outlet 22 to the waste liquid drainage. Perform CIP cleaning operation according to the cleaning procedure.

[0033] The functions of the various components or modules of the system of the present invention are as follows:

[0034] 1. Stirring module: used to mix the liquid in the reactor;

[0035] 2. Respirator: connects the glass kettle to the outside air, keeps the pressure inside and outside the glass kettle consistent, and has the function of sterilizing and filtering the air;

[0036] 3. pH meter: monitor the pH value of the solution in the glass kettle;

[0037] 4. Temperature probe: monitor the temperature of the solution in the glass kettle;

[0038] 5. Spray ball: used to clean the inner wall of the glass kettle;

[0039] 6. Glass kettle: a container used for polysaccharide degradation, derivatization and conjugation reactions, and also a liquid storage container for ultrafiltration processes;

[0040] 7. Liquid inlet of glass kettle jacket: connected to TCU temperature control module, through which the liquid in TCU temperature control module enters the jacket to control the temperature of the liquid in the glass kettle;

[0041] 8. Liquid outlet of glass kettle jacket: connected to TCU temperature control module, through which the liquid in the jacket returns to the TCU temperature control module to control the temperature of the liquid in the glass kettle;

[0042] 9. Discharge bottom valve: After opening, the liquid in the glass kettle flows out from this valve;

[0043] 10. Weighing module: used to monitor the weight of the liquid in the reactor in real time;

[0044] 11. Circulation pump: used to pump the liquid in the glass kettle into the ultrafiltration fixture, or pump it out when the product needs to be recovered;

[0045] 12. Product recovery port: used for product recovery;

[0046] 13. Inlet pressure sensor: monitors the liquid pressure before entering the ultrafiltration fixture;

[0047] 14. Clamp: used to fix the ultrafiltration membrane package;

[0048] 15. Permeate end pressure sensor: monitors the liquid pressure at the permeate end of the ultrafiltration fixture;

[0049] 16. Reflux pressure sensor: monitors the liquid pressure at the reflux end of the ultrafiltration fixture;

[0050] 17. Reflux valve: controls the liquid flow at the reflux end;

[0051] 18. Reflux flow meter: monitors the liquid flow at the reflux end of the ultrafiltration fixture;

[0052] 19. Permeate flow meter: monitors the liquid flow at the permeate end of the ultrafiltration fixture;

[0053] 20. Conductivity meter: monitors the conductivity of the liquid at the permeate end of the ultrafiltration fixture;

[0054] 21. Permeate valve: controls the liquid flow rate at the permeate end;

[0055] 22. Permeate outlet: The permeate liquid is discharged from here;

[0056] 23. Inlet pipe: used to connect the discharge bottom valve and the circulation pump;

[0057] 24. Reflux pipe: used to connect the ultrafiltration fixture and the glass kettle;

[0058] 25. TCU temperature control module: controls the heat transfer liquid to flow into the jacket of the glass kettle for heat exchange and temperature control;

[0059] 26. Peristaltic pump 1: used to add liquid into the glass kettle;

[0060] 27. Liquid inlet: a pipeline used to add liquid into the glass kettle;

[0061] 28. Peristaltic pump 2: used to add acid / alkali into the glass kettle;

[0062] 29. Acid / alkali solution inlet: a pipeline used to add acid / alkali into the glass kettle;

[0063] a. Stirring port: The stirring paddle extends from this port into the bottom of the glass kettle;

[0064] b. Respirator installation port: used to install the respirator;

[0065] c. Temperature probe installation port: used to install the temperature probe;

[0066] d. pH meter installation port: used to install pH probe;

[0067] e. Feeding port: used to add feed liquid;

[0068] f. Spray ball installation port: used to install the spray ball;

[0069] g. Acid / base adding port: used to add acid / base solution;

[0070] h. Reflux pipe installation port: Connect the reflux pipe to form a loop for the ultrafiltration system.

[0071] Furthermore, the TCU temperature control module is connected to the glass kettle, and precise temperature control is achieved through the TCU temperature control module according to the temperature changes monitored by the temperature probe.

[0072] Furthermore, the program is edited to set the required pH value range, and the monitored pH data is associated with the peristaltic pump, so that the peristaltic pump adds acid or alkali solution according to the set value to automatically adjust the pH value.

[0073] Furthermore, the program is edited to set the weight of the liquid to be added, and the weighing module and the peristaltic pump are associated so that the peristaltic pump automatically adds the liquid according to the set value.

[0074] Furthermore, the ultrafiltration fixture inlet, reflux end and permeate end are provided with pressure sensors, the reflux end and permeate end are provided with flow sensors, the reflux end loop and permeate end outlet are provided with solenoid valves, and the permeate end outlet is provided with a conductivity sensor.

[0075] Most steps of bacterial polysaccharide-protein binding reaction include reaction and ultrafiltration steps. The existing equipment is a reactor for reaction and an ultrafiltration system for ultrafiltration, which are operated separately. The inventor has improved the existing technology. The beneficial effects of the present invention are:

[0076] 1. Effectively integrate polysaccharide degradation and subsequent ultrafiltration, reducing material transfer steps and improving work efficiency;

[0077] 2. Integrate the original reactor and ultrafiltration equipment, and share the same set of duplicate components of the two equipment, such as peristaltic pumps and liquid storage containers, thereby saving production costs;

[0078] 3. Reduce manual operation, higher degree of automation, and weighing module included in the design to better achieve data integrity;

[0079] 4. The reactor is equipped with a temperature control unit and a pH probe module. The ultrafiltration process can achieve precise temperature control and real-time monitoring of temperature and pH changes. It can comprehensively collect data on the reaction and ultrafiltration processes, which is conducive to product process improvement.

[0080] Explain and illustrate the technical terms that appear in the article

[0081] CIP (Clean in place): online cleaning.

[0082] TCU (Temperature Control Unit): Temperature control unit. BRIEF DESCRIPTION OF THE DRAWINGS

[0083] Figure 1 It is the structural diagram of the reaction-ultrafiltration system.

[0084] In the figure: 1, stirring module, 2, respirator, 3, pH meter, 4, temperature probe, 5, spray ball, 6, glass kettle, 7, glass kettle jacket liquid inlet, 8, glass kettle jacket liquid outlet, 9, discharge bottom valve, 10, weighing module, 11, circulation pump, 12, product recovery port, 13, inlet end pressure sensor, 14, fixture, 15, permeate end pressure sensor, 16, reflux end pressure sensor, 17, reflux valve, 18, reflux end flowmeter, 19, permeate end flowmeter, 20, conductivity meter, 21, permeate valve, 22, permeate end outlet, 23, inlet pipe, 24, reflux pipe, 25, TCU temperature control module, 26, peristaltic pump 1, 27, liquid inlet, 28, peristaltic pump 2, 29, acid / alkali solution inlet;

[0085] Figure 2 , Schematic diagram of stainless steel cover

[0086] In the figure: a, stirring port, b, respirator installation port, c, temperature probe installation port, d, pH meter installation port, e, feeding port, f, spray ball installation port, g, acid / alkali addition port, h, reflux pipe installation port. DETAILED DESCRIPTION

[0087] The present invention is further described by the following specific examples, but is not intended to be limiting of the present invention.

[0088] Example 1 Reaction-ultrafiltration system applied to the degradation of pneumonia polysaccharides, such as Figure 1 As shown,

[0089] The system comprises: 6. glass kettle, 2. respirator, 25. TCU temperature control module, 4. temperature probe, 10. weighing module, 1. stirring module, 26. peristaltic pump 1, 28. peristaltic pump 2, 11. circulation pump, 5. spray ball, 3. pH meter, 14. ultrafiltration fixture, 20. conductivity meter, 18. reflux end flow meter, 16. reflux end pressure sensor, 19. permeate end flow meter, 15. permeate end pressure sensor, the step of carrying out pneumonia polysaccharide degradation reaction, 26. the outlet end of the first peristaltic pump and 28. the outlet end of the second peristaltic pump are respectively connected to the stainless steel cover of the glass kettle, 3. the pH meter is inserted into the glass kettle through the stainless steel cover; 2. the respirator is connected to the stainless steel cover; the stirring paddle is inserted into the glass kettle through the stainless steel cover, 4. the temperature probe is inserted into the glass kettle through the stainless steel cover, 25. the TCU temperature control module is connected to the glass kettle, 10. the weighing module is arranged at the bottom of the glass kettle,

[0090] 11. The inlet end of the circulation pump is connected to the liquid outlet at the bottom of the glass kettle, and the outlet end of the circulation pump is connected to the liquid inlet end of the ultrafiltration fixture. The 24. reflux pipe of the ultrafiltration fixture is connected to the 6. glass kettle through a stainless steel cover to form an ultrafiltration loop. The 22. permeate end outlet of the ultrafiltration fixture is connected to the waste liquid drainage. The ultrafiltration fixture is provided with 13. an inlet end pressure sensor, 16. a reflux end pressure sensor and 15. a permeate end pressure sensor. The ultrafiltration fixture is also provided with 18. a reflux end flow sensor and 19. a permeate end flow sensor. The 24. reflux pipe is provided with 17 reflux valve, 21. a permeate valve, and 20. a conductivity meter.

[0091] 5. The spray ball is fixed on the inner side of the stainless steel cover of the 6. glass kettle, and the 24. reflux pipe is connected to the 5. spray ball. The 11. circulation pump inlet end is connected to the 23. inlet pipe at the bottom of the glass kettle, and the 22. outlet end is connected to the waste liquid drainage.

[0092] Example 2: Use of the reaction-ultrafiltration system for the degradation of pneumonia polysaccharides.

[0093] The system includes: 6. glass kettle, 2. respirator, 25. TCU temperature control module, 4. temperature probe, 10. weighing module, 1. stirring module, 26. first peristaltic pump, 28. second peristaltic pump, 11. circulation pump, 5. spray ball, 3. pH meter, 14. ultrafiltration fixture, 20. conductivity meter, 18. reflux end flow meter, 16. reflux end pressure sensor, 19. permeate end flow meter, 15. permeate end pressure sensor,

[0094] The step of carrying out the degradation reaction of pneumonia polysaccharide is as follows: 26. The outlet end of peristaltic pump 1 and 28. The outlet end of peristaltic pump 2 are respectively connected to the stainless steel cover of 6. glass kettle; 26. Peristaltic pump 1 is used to add feed liquid; 28. Peristaltic pump 2 is used to add acid / alkali solution; 3. pH meter is inserted into 6. glass kettle through the stainless steel cover to monitor pH changes, edit the program, set the required pH value range, associate the monitored pH data with 28. Peristaltic pump 2, add acid / alkali solution according to the set value, and automatically adjust the pH value. ; 2. The respirator is connected to the stainless steel cover; the stirring paddle is inserted into the glass kettle through the stainless steel cover to mix the feed liquid; 4. The temperature probe is inserted into the glass kettle through the stainless steel cover to monitor the temperature change, and 25. TCU temperature control module is connected to the glass kettle jacket, and the temperature is controlled by the TCU temperature control module according to the temperature change monitored by the temperature probe; 10. The weighing module is associated with the glass kettle to monitor the weight change of the feed liquid; after the reaction is completed, it needs to be stored at 2-8°C, and the temperature control is set to 4±1°C.

[0095] Ultrafiltration step, the above connections do not need to be changed, 11. the circulation pump inlet is connected to the liquid outlet at the bottom of the glass kettle, 11. the circulation pump outlet is connected to 14. the ultrafiltration fixture liquid inlet, the ultrafiltration fixture 24. the reflux pipe is connected to 6. the glass kettle through the stainless steel cover to form an ultrafiltration loop, the ultrafiltration fixture 22. the permeate outlet is connected to the waste liquid drainage; the ultrafiltration fixture 13. the inlet, 16. the reflux end and 15. the permeate end are equipped with pressure sensors, the ultrafiltration fixture 18. the reflux end and 19. the permeate end are equipped with flow sensors, 17. the reflux end loop and 21. the permeate outlet are equipped with solenoid valves, the program is edited to complete the ultrafiltration and dialysis processes; 20. the permeate outlet is equipped with a conductivity sensor, and the end point of the ultrafiltration dialysis is judged by the permeate flow and conductivity.

[0096] For CIP operation, fix the spray ball 5 on the inner side of the stainless steel cover of the glass kettle 6, connect the return pipe 24 to the spray ball 5, connect the inlet end of the circulation pump 11 to the inlet pipe 23 at the bottom of the glass kettle to form a CIP cleaning loop, connect the return pipe 24 of the ultrafiltration fixture to the waste liquid drainage or the spray ball 5 according to the cleaning procedure, and connect the outlet 22 to the waste liquid drainage, and perform CIP cleaning operation according to the cleaning procedure.

[0097] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical solutions and concepts of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A system with feed-liquid reaction and ultrafiltration, characterized in that: The system is mainly composed of a glass kettle, a respirator, a TCU temperature control module, a temperature probe, a weighing module, a stirring module, two peristaltic pumps, a circulation pump, a pH probe and an ultrafiltration fixture. A stainless steel cover is provided on the top of the glass kettle, and the stirring module, the respirator, the pH probe, the temperature probe, the first peristaltic pump, the second peristaltic pump and the ultrafiltration fixture are respectively connected to the stainless steel cover of the glass kettle. A weighing module is provided under the glass kettle, and the bottom of the glass kettle is connected to the circulation pump. The TCU temperature control module is respectively connected to the TCU liquid inlet and TCU liquid outlet of the glass kettle. The spray ball is fixed on the inner side of the stainless steel cover of the glass kettle, the outlet end of the circulation pump is connected to the liquid inlet end of the clamp, the reflux end of the clamp is connected to the glass kettle through the stainless steel cover, and the inlet end of the circulation pump is connected to the liquid outlet at the bottom of the glass kettle to form a cleaning loop; the outlet ends of the first peristaltic pump and the second peristaltic pump are respectively connected to the stainless steel cover of the glass kettle, the respirator is connected to the stainless steel cover, the stirring paddle of the stirring module is inserted into the glass kettle through the stainless steel cover, the temperature probe is inserted into the glass kettle through the stainless steel cover, and the pH probe is inserted into the glass kettle through the stainless steel cover.

2. The system of claim 1, when used to produce polysaccharide and protein conjugate vaccines, can achieve hydrolysis and oxidation, and has the steps of polysaccharide degradation, derivatization, conjugation reaction and ultrafiltration.

3. The method for using the system of claim 1, comprising the following steps: Step 1, degradation reaction step: the outlet ends of the first peristaltic pump and the second peristaltic pump are respectively connected to the stainless steel cover of the glass kettle for adding different feed liquids at the same time; the respirator is connected to the stainless steel cover; the stirring paddle of the stirring module is inserted into the glass kettle through the stainless steel cover to mix the feed liquid; the temperature probe is inserted into the glass kettle through the stainless steel cover to monitor the temperature change; the pH probe is inserted into the glass kettle through the stainless steel cover to monitor the pH change; the weighing module is associated with the glass kettle to monitor the weight change of the feed liquid, Step 2: During the ultrafiltration step, the inlet end of the circulation pump is connected to the liquid outlet at the bottom of the glass kettle, the outlet end of the circulation pump is connected to the liquid inlet end of the ultrafiltration fixture, and the reflux end of the ultrafiltration fixture is connected to the glass kettle through a stainless steel cover to form an ultrafiltration loop. The ultrafiltration fixture discharges waste liquid through the outlet end. Step 3, cleaning step. Before the CIP operation, fix the spray ball on the inner side of the stainless steel cover of the glass kettle, connect the outlet of the circulation pump to the spray ball, and connect the inlet of the circulation pump to the liquid outlet at the bottom of the glass kettle to form a CIP cleaning loop for CIP operation.

4. The method of use according to claim 3, characterized in that: In the degradation reaction step described in step 1, the outlet ends of the first peristaltic pump and the second peristaltic pump are respectively connected to the stainless steel cover of the glass kettle, the first peristaltic pump is used to add the feed liquid, the second peristaltic pump is used to add the acid / alkali solution, the pH probe is inserted into the glass kettle through the stainless steel cover to monitor the pH change, the program is edited, the required pH value range is set, the monitored pH data and the second peristaltic pump are associated, the acid / alkali solution is added according to the set value, and the pH value is automatically adjusted; the respirator is connected to the stainless steel cover; the stirring paddle is inserted into the glass kettle through the stainless steel cover to mix the feed liquid; the temperature probe is inserted into the glass kettle through the stainless steel cover to monitor the temperature change, the TCU temperature control module is connected to the glass kettle jacket, and the temperature is controlled by the TCU temperature control module according to the temperature change monitored by the temperature probe; the weighing module is associated with the glass kettle to monitor the weight change of the feed liquid; after the reaction is completed, it needs to be stored at 2 to 8°C, and the temperature control is set to 4±1°C.

5. The method of use according to claim 3, characterized in that: In the second step of ultrafiltration, the above connections do not need to be changed. The inlet of the circulation pump is connected to the liquid outlet at the bottom of the glass kettle, the outlet of the circulation pump is connected to the liquid inlet of the ultrafiltration fixture, the reflux pipe of the ultrafiltration fixture is connected to the glass kettle through a stainless steel cover to form an ultrafiltration loop, and the outlet of the ultrafiltration fixture through the permeate end is connected to the waste liquid drainage; pressure sensors are set at the inlet, reflux and permeate ends of the ultrafiltration fixture, flow sensors are set at the reflux and permeate ends of the ultrafiltration fixture, and electromagnetic valves are set at the reflux loop and the outlet of the permeate end. Edit the program to complete the ultrafiltration and dialysis processes; A conductivity sensor is provided at the outlet of the permeate port, and the end point of ultrafiltration dialysis is determined by the permeate flow rate and conductivity.

6. The method of use according to claim 3, characterized in that: The third step is CIP operation. Fix the spray ball on the inner side of the stainless steel cover of the glass kettle, connect the reflux pipe to the spray ball, connect the inlet end of the circulation pump to the inlet pipe at the bottom of the glass kettle to form a CIP cleaning loop. Connect the reflux pipe of the ultrafiltration fixture to the waste liquid drainage or the spray ball according to the cleaning procedure, and connect the waste liquid drainage through the end outlet. Perform CIP cleaning operation according to the cleaning procedure.

7. Use of the system according to claim 1 in the preparation and production of vaccines.

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