CN113129671A - Laboratory model system and method for formulation product filling process development and characterization - Google Patents
Laboratory model system and method for formulation product filling process development and characterization Download PDFInfo
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- CN113129671A CN113129671A CN201911423434.1A CN201911423434A CN113129671A CN 113129671 A CN113129671 A CN 113129671A CN 201911423434 A CN201911423434 A CN 201911423434A CN 113129671 A CN113129671 A CN 113129671A
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- 238000000034 method Methods 0.000 title claims abstract description 18
- 238000011161 development Methods 0.000 title claims abstract description 15
- 238000005429 filling process Methods 0.000 title claims abstract description 15
- 238000013064 process characterization Methods 0.000 title claims abstract description 12
- 238000009472 formulation Methods 0.000 title abstract description 5
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- 238000004891 communication Methods 0.000 claims abstract description 6
- 230000002572 peristaltic effect Effects 0.000 claims description 71
- 238000004519 manufacturing process Methods 0.000 claims description 64
- 239000007788 liquid Substances 0.000 claims description 48
- 239000000243 solution Substances 0.000 claims description 33
- 229920001296 polysiloxane Polymers 0.000 claims description 26
- 230000001133 acceleration Effects 0.000 claims description 22
- 229940079593 drug Drugs 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 8
- 238000004088 simulation Methods 0.000 claims description 3
- 239000011550 stock solution Substances 0.000 claims description 3
- 239000000611 antibody drug conjugate Substances 0.000 claims description 2
- 229940049595 antibody-drug conjugate Drugs 0.000 claims description 2
- 230000001413 cellular effect Effects 0.000 claims description 2
- 108020001507 fusion proteins Proteins 0.000 claims description 2
- 102000037865 fusion proteins Human genes 0.000 claims description 2
- 230000002068 genetic effect Effects 0.000 claims description 2
- 238000012806 monitoring device Methods 0.000 claims description 2
- 229940126586 small molecule drug Drugs 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 229960005486 vaccine Drugs 0.000 claims description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 30
- 229940098773 bovine serum albumin Drugs 0.000 description 30
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 24
- 239000004033 plastic Substances 0.000 description 13
- 239000004793 Polystyrene Substances 0.000 description 12
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 12
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- 230000000694 effects Effects 0.000 description 4
- 238000011165 process development Methods 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000005094 computer simulation Methods 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 230000037452 priming Effects 0.000 description 2
- 238000010925 quality by design Methods 0.000 description 2
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- G—PHYSICS
- G09—EDUCATION; CRYPTOGRAPHY; DISPLAY; ADVERTISING; SEALS
- G09B—EDUCATIONAL OR DEMONSTRATION APPLIANCES; APPLIANCES FOR TEACHING, OR COMMUNICATING WITH, THE BLIND, DEAF OR MUTE; MODELS; PLANETARIA; GLOBES; MAPS; DIAGRAMS
- G09B9/00—Simulators for teaching or training purposes
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- G—PHYSICS
- G09—EDUCATION; CRYPTOGRAPHY; DISPLAY; ADVERTISING; SEALS
- G09B—EDUCATIONAL OR DEMONSTRATION APPLIANCES; APPLIANCES FOR TEACHING, OR COMMUNICATING WITH, THE BLIND, DEAF OR MUTE; MODELS; PLANETARIA; GLOBES; MAPS; DIAGRAMS
- G09B25/00—Models for purposes not provided for in G09B23/00, e.g. full-sized devices for demonstration purposes
- G09B25/02—Models for purposes not provided for in G09B23/00, e.g. full-sized devices for demonstration purposes of industrial processes; of machinery
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- Engineering & Computer Science (AREA)
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- Infusion, Injection, And Reservoir Apparatuses (AREA)
Abstract
Laboratory model systems and methods for formulation product filling process development and characterization are disclosed. The mold system includes a filling fluid supply device, a dosing filling pump, a filling device and a conduit connecting the filling fluid supply device, dosing filling pump and filling device in fluid communication with each other, and a timing device.
Description
Technical Field
The present application relates to laboratory model systems and methods for formulation product filling process development and characterization. The model and the method improve the precision of process research, realize the simulation of production process conditions and reduce the research and development cost of enterprises.
Background
The drug solution can expose the components in the solution to various physical stress conditions during the filling process, such as high temperature and high shear stress (Elias, C.B., Joshi, J.B., 1998.Role of hydraulic seal on activity and structure of proteins, adv.biochem. Eng.59, 47-71.), simultaneous high shear stress accompanying the gas-liquid interface generated by the foam, and the like (Maa, Y. -F., Hsu, C.C., 1997.Protein condensation b. Biotechnol. Bioeng.54, 503 + 512.). The physical stress can affect the stability of active components or other auxiliary materials in the medicinal solution, for example, the protein medicinal solution is easy to degrade, aggregate and precipitate in the filling process. Therefore, it is necessary to study the influence of the process on the stability of the drug and determine the appropriate process parameters and ranges during the development of the drug production process. For example, factors such as temperature, high shear stress effects, etc. affect stability, and parameters that can be set in actual equipment and model systems are related to these stability-affecting factors, such as peristaltic pump speed, acceleration, filling line internal diameter/length, etc.
The production and filling equipment for pharmaceutical solutions generally consists of a set of control systems and several metering pumps, and the equipment is complex and expensive. Therefore, the development and characterization of the production equipment used for the production process would result in a significant waste of equipment resources. Meanwhile, more drug stock solution is needed for production equipment, and development cost is increased. Laboratory models corresponding to production equipment typically use the same peristaltic pump Model, and such laboratory scale-down models for process development and characterization are desirable choices for pharmaceutical research and development companies (Paul Kroll, Model-based methods in the biopharmaceutical process life cycle, Pharm Res (2017) 34: 2596-. On the other hand, some filling devices used in the production process, such as the filling workstation of Bosch, germany, do not have a corresponding reduced model, and other types of metering pumps are required for process development and characterization, which results in a large difference between the laboratory model and the production device, for example, different liquid filling speeds under the same peristaltic pump parameters, which results in different effects such as shear stress, and the like. At this time, how to use metering pumps of different models to develop and characterize the production filling process is very important.
There are many reports on the Development principles of laboratory Scale-down models, the main principle being to reproduce the shear stress and the duration of action experienced by the fluid during production based on the properties of the tubing fluid (Feroz Jameel, Quality by Design for biomedical Drug Product Development, Chapter 13: Application of QbD Elements in the Development and Scale-up of Commercial Filling Process). Currently, few reports are made at home and abroad about laboratory models and methods for researching filling processes of preparation products by using different filling pumps. In 2009, the development of a filling process computer dynamic simulation system (new army, the development of a filling process computer dynamic simulation system, computer and applied chemistry, 2009, 26(8), 1067-. The simulation software does not mention the investigation and evaluation of the shear stress in liquid filling, is only a theoretical simulation, and has no corresponding test model for evaluating the influence of the process on the product stability.
Clearly, there is still a need in the art to find a model system for process development and characterization with high accuracy using a formulation product filling production facility when the latter is not used in a laboratory facility.
Disclosure of Invention
To solve the above technical problem, one aspect of the present application provides a laboratory model system for pharmaceutical production filling process development and characterization, comprising a filling liquid supply device, a dosing filling pump, a filling device in fluid communication with each other, and a pipeline connecting the filling liquid supply device, the dosing filling pump and the filling device in fluid communication, and a timing device.
Another aspect of the present application provides a laboratory modeling method for pharmaceutical manufacturing filling process development and characterization, comprising: a) constructing a laboratory model system comprising a filling liquid supply, a dosing filling pump, a filling device in fluid communication with each other and a conduit connecting the filling device, dosing filling pump and filling device in fluid communication with each other; b) setting filling quantity and other filling parameters; c) operating the model system and determining the filling time; wherein the filling amount differs by no more than 10% from the filling amount of a production filling line; and the actual production process conditions are simulated by adjusting the settings of other filling parameters.
In one embodiment of the present application, the laboratory model system has at least 1 filling liquid supply device. In one embodiment of the present application, the number of filling liquid supplies used in the laboratory model system is the same as the number of filling liquid supplies used in the production filling line. In a preferred embodiment of the present application, the laboratory model system has 1 filling liquid supply device. In one embodiment of the application, the filling liquid supply device comprises a storage container. In one embodiment of the present application, the storage container comprises a fluid reservoir, a fluid bottle, a fluid bag, or other suitable container. In a preferred embodiment of the present application, the filling liquid supply device further comprises a filling liquid.
In one embodiment of the present application, the laboratory model system has at least 1 dosing pump. In one embodiment of the present application, the number of dosing pumps used in the laboratory model system is the same as the number of dosing pumps used in the production dosing line. In a preferred embodiment of the present application, the laboratory model system has 1 dosing pump. In one embodiment of the present application, the dosing pump is a dosing peristaltic pump. In a preferred embodiment of the present application, the metering peristaltic pump is a two-channel peristaltic pump. In one embodiment of the present application, the dosing pump used in the laboratory model system is the same type of dosing pump used in the production dosing line. In another embodiment of the present application, the dosing pump used in the laboratory model system is a different model than the dosing pump used in the production filling line.
In one embodiment of the present application, the laboratory model system has at least 1 filling device. In one embodiment of the present application, the number of filling devices used in the laboratory model system is the same as the number of filling devices used in the production filling line. In a preferred embodiment of the present application, the laboratory model system has 1 filling device. In one embodiment of the present application, the filling device comprises a filling needle. In one embodiment of the present application, the inside diameter of the filling needle used in the laboratory model system is the same as the inside diameter of the filling needle used in the production filling line. In another embodiment of the present application, the inside diameter of the filling needle used in the laboratory model system is different from the inside diameter of the filling needle used in the production filling line.
In one embodiment of the present application, a pipeline includes one or more pipe segments. In one embodiment of the present application, the number of tube segments in the laboratory model system is the same as the number of tube segments in the production filling line. In a preferred embodiment of the present application, the laboratory model system comprises 3 pipe sections. In one embodiment of the present application, a pipeline includes one or more interfaces connecting segments of the pipeline. In a preferred embodiment of the present application, the tubing comprises 2 ports. In a preferred embodiment of the present application, the interface is a branch pipe interface, e.g. a Y-interface.
In one embodiment of the present application, the laboratory modeling system further comprises a receiving container. In one embodiment of the present application, the receiving container may comprise a plastic bottle, ampoule, flask, beaker, bag, tub, jar, syringe, or the like.
In one embodiment of the present application, the laboratory model system further comprises a timing device. In one embodiment of the application, a timing device is used to measure and/or control the filling time. In one embodiment of the present application, the timing device is a stopwatch or an automatic timer.
In one embodiment of the present application, the laboratory model system further comprises a filling parameter monitoring device and/or a filling parameter control device. In a preferred embodiment of the present application, the filling parameter monitoring means and/or the filling parameter control means are comprised in a dosing filling pump. In one embodiment of the present application, the filling parameters are selected from: filling amount, pump speed, acceleration, time delay, suck-back parameters, pipeline inner diameter, pipeline length and filling liquid viscosity.
In one embodiment of the present application, the filling amount is 0.1mL to 10L, such as 0.5mL to 1L, 1mL to 100mL, or 2mL to 20 mL. In one embodiment of the present application, the filling amount in the laboratory model system differs from the filling amount of the production filling line by no more than 10%, preferably by no more than 5%, more preferably by the same filling amount as the production filling line.
In one embodiment of the present application, the pump speed is 10rpm to 1000rpm, such as 50rpm to 500rpm, or 100rpm to 400 rpm. In one embodiment of the present application, the pump speed used in the laboratory model system is the same as the pump speed used in the production filling line. In another embodiment of the present application, the pump speed used in the laboratory model system is different from the pump speed used in the production filling line.
In one embodiment of the present application, acceleration is expressed in rpm/s or percent or other units. In one embodiment of the present application, the acceleration is 10 to 1000rpm/s, such as 50 to 200rpm/s, or about 100 rpm/s. In one embodiment of the present application, the range of acceleration is dependent on the dosing pump. In one embodiment of the present application, the acceleration used in the laboratory model system is the same as the acceleration used in the production filling line. In another embodiment of the present application, the acceleration used in the laboratory model system is different from the acceleration used in the production filling line.
In one embodiment of the application, the delay is 0.1s to 10s, for example 0.5s to 5s, 1s to 3s, or about 1 s. In one embodiment of the present application, the time delay used in the laboratory model system is the same as the time delay used in the production filling line. In another embodiment of the present application, the time delay used in the laboratory model system is different from the time delay used in the production filling line.
In one embodiment of the present application, the suckback parameter is expressed in time or radians or other units. In one embodiment of the present application, the suck back parameter is from 1 to 15, such as from 5 to 10, or about 7. In one embodiment of the present application, the range of suck-back parameters depends on the dosing pump. In one embodiment of the present application, the suckback parameters used in the laboratory model system are the same as those used in the production filling line. In another embodiment of the present application, the suckback parameters used in the laboratory model system are different from the suckback parameters used in the production filling line.
In one embodiment of the present application, the viscosity of the filling fluid is less than 1300 cp. In one embodiment of the present application, the priming liquid is a newtonian fluid. In another embodiment of the present application, the priming liquid is a non-newtonian fluid. In one embodiment of the present application, the viscosity of the filling liquid used in the laboratory model system is the same as the viscosity of the filling liquid used in the production filling line. In another embodiment of the present application, the viscosity of the filling fluid used in the laboratory model system is different from the viscosity of the filling fluid used in the production filling line.
In one embodiment of the present application, the filling time is from 100ms to 50000ms, for example from 500ms to 10000ms, or from 1000ms to 5000 ms. In one embodiment of the present application, the filling time used in the laboratory model system is the same as the filling time used in the production filling line. In another embodiment of the present application, the filling time used in the laboratory model system is different from the filling time used in the production filling line. In another embodiment of the present application, the filling time used in the laboratory model system is less than the filling time used in the production filling line.
In one embodiment of the present application, the pipeline length of one or more pipe sections is from 2cm to 15m, for example from 20cm to 1.5 m. In one embodiment of the present application, the ratio of the line length of one or more of the tube sections to the line length of the corresponding tube section in the production filling line is each from 1: 10 to 10: 1, such as from 1: 5 to 5: 1, from 1: 3 to 3: 1, or the same as the line length of the corresponding tube section in the production filling line. For example, in a laboratory model for process development or characterization, it may be repeated 10 times, which means that the liquid has traveled the same pipe 10 times, equivalent to 10 times the length. Therefore, the representation and the production are consistent by repeating the 1/10 pipeline for 10 times, and the 1/10 pipeline can be used for one time, or the 1/10 pipeline can be used for one time by 10 times the length of the pipeline.
In one embodiment of the present application, one or more of the following features of one or more of the tube segments are the same as the corresponding tube segments in the production filling line: material, inner diameter, and wall thickness. In one embodiment of the present application, the internal pipe diameter of the one or more pipe sections is each from 0.1mm to 50mm, for example from 1mm to 10mm, or from 1.6mm to 4.8 mm. In one embodiment of the present application, the inner pipe diameter of one or more pipe sections is the same as the inner pipe diameter of the corresponding pipe section in the production filling line. In another embodiment of the present application, the one or more tube sections have a different inner tube diameter than the corresponding tube sections in the production filling line. In a preferred embodiment of the present application, the material of the one or more tube sections is silicone. In one embodiment of the present application, the material of one or more tube sections is the same as the material of the corresponding tube section in the production filling line. In another embodiment of the present application, the material of one or more of the tube sections is different from the material of the corresponding tube section in the production filling line. In one embodiment of the present application, the wall thickness of the one or more tube sections is each 0.5mm to 5mm, such as 1mm to 3mm, or 1.6 mm. In one embodiment of the present application, the wall thickness of one or more tube sections is the same as the wall thickness of the corresponding tube section in the production filling line. In another embodiment of the present application, the wall thickness of one or more tube sections is different from the wall thickness of the corresponding tube section in the production filling line.
In one embodiment of the present application, the filling liquid is the same pharmaceutical stock liquid or a simulant liquid as the actual production. In a preferred embodiment of the present application, the filling liquid is the same stock pharmaceutical liquid as the actual production. In another preferred embodiment of the present application, the filling liquid is a simulant liquid. In one embodiment of the present application, the drug stock solution or the simulant solution comprises a biological drug, a chemical small molecule drug, or both. In one embodiment of the present application, the biological agent is selected from the group consisting of a monoclonal antibody, a diabody, an antibody drug conjugate, a fusion protein, a vaccine, a cellular drug, a genetic drug, or any combination thereof.
Compared with the prior art, the laboratory model system and the laboratory model method can directly reproduce the influence of factors such as the shearing force and the filling time of the filling liquid under the production condition on the stability of the product. By adjusting the filling parameters, the laboratory model system of the present application can be brought into association with a production filling line, i.e. the same or shorter filling time, when filling the same volume.
Drawings
The present application is described in more detail below with reference to the attached drawing figures, wherein:
FIG. 1 is a schematic view of one embodiment of a product filling module system of the present application. Wherein the filling model system comprises: the filling liquid supply device 6, the metering filling pump 1, the filling device 7, the receiving container 5 and a pipeline connecting the above elements, wherein the pipeline comprises a pipe section 4, a connector 3, a pipe section 2, a connector 3' and a pipe section 8.
Fig. 2 is a graph of process model fill volume versus time showing the fill volume versus time at pump speeds of 100rpm, 200rpm, 300rpm, or 400rpm, respectively.
Detailed Description
Definition of
In the present application, the "filling liquid supply device" refers to a device for supplying filling liquid to a filling system, such as a storage container, e.g., a liquid storage tank, a liquid storage bottle, etc. Alternatively, the filling liquid supply device comprises the filling liquid itself, for example a filling liquid contained in a storage container.
In the present application, "dosing filling pump" includes various types of filling pumps known in the art having a dosing function, such as dosing peristaltic pumps. Dosing filling pumps are common devices in pharmaceutical filling, the selection of the type and the determination of the number being within the routine skill of a person skilled in the art.
In the present application, a "filling device" is a device for filling a receiving container with a filling liquid, for example a filling needle. In some embodiments, the filling mold system described herein may also be used without the addition of a filling needle, in which case the end of the line forms the filling device.
In this application, "line" refers to a fluid flow path line formed by piping that fluidly connects various devices in the system, such as a filling liquid supply device, a dosing filling pump, and a filling device. Optionally, a flow directing device such as a port (e.g., a branch port) and a flow rate or flow control device such as a control valve may be included in the conduit. In this application, "tube section" refers to a section of tubing defined as an end point by any two devices in a production filling line and a model filling system. The term "corresponding line section in the production filling line" refers to a line section defined by two devices of the model filling system corresponding to the filling line, for example, a line section from the filling liquid supply device to the inlet of the metering filling pump in the model filling system and a line section from the filling liquid supply device to the inlet of the metering filling pump in the production filling line are in corresponding relationship.
In one embodiment of the present invention, as shown in fig. 1, the filling model system uses a dual-channel peristaltic pump as the metering filling pump 1, the tube segment 2 is a dual-channel tube passing through the dual-channel peristaltic pump, and the dual-channel tube is connected at two ends thereof to the tube segment 4 and the tube segment 8 through the connectors 3 and 3'. In operation, filling liquid from the filling liquid supply device 6 enters the pipe section 2 through the pipe section 4 via the connector 3, passes through the metering filling pump 1 via the pipe section 2 and then enters the pipe section 8 via the connector 3', and finally is filled into the receiving container 5 via the filling device 8.
The technical solutions of the present application will be described in detail and fully with reference to the accompanying drawings, and it should be understood that the described embodiments are only some embodiments of the present application, but not all embodiments. All other embodiments obtained by a person of ordinary skill in the art based on the embodiments in the present application without any inventive step are within the scope of protection of the present application.
Example 1
A peristaltic pump PF6 model manufactured by Watson-Marlow company is used as a metering filling pump 1, silicone tubes with the lengths of two ends of 50cm, the inner diameters of 4.8mm and the wall thicknesses of 1.6mm are cut out to be used as a tube section 4 and a tube section 8 in a graph 1, two sections of silicone tubes with the lengths of 25cm, the inner diameters of 3.2mm and the wall thicknesses of 1.6mm are used as a tube section 2 in the graph 1, and proper Y-shaped connectors 3 and 3' are selected to be connected. The connected pipeline is fixed on a peristaltic pump head, a Bosch filling needle with the inner diameter of 3.5mm is connected to one side of a solution outlet, and a polystyrene plastic bottle is placed below the filling needle to serve as a receiving container 5. Bovine Serum Albumin (BSA) solution (viscosity of about 1cp, histidine buffer, pH 6.0, sodium chloride 150mM, BSA concentration 15mg/mL) was selected as the mimetic.
The filling volume of the peristaltic pump is set to be 2.00mL, the pump speed is 100rpm, the acceleration is 100rpm/s, the delay time is 1s, and the suck-back parameter is 7. And starting a peristaltic pump to empty, adjusting the filling amount, and determining the actual filling weight of 1.9902 g. The peristaltic pump was started, the time required after a certain number of fills was measured, and the time required for each fill was calculated to be 948.8 milliseconds.
Example 2
A peristaltic pump PF6 model manufactured by Watson-Marlow company is used as a metering filling pump 1, silicone tubes with the lengths of two ends being 45cm, the inner diameters being 4.8mm and the wall thicknesses being 1.6mm are cut out to be used as a tube section 4 and a tube section 8 in a graph 1, two sections of silicone tubes with the lengths of 10cm, the inner diameters being 3.2mm and the wall thicknesses being 1.6mm are used as a tube section 2 in the graph 1, and proper Y-shaped connectors 3 and 3' are selected to be connected. The connected pipeline is fixed on a peristaltic pump head, a Bosch filling needle with the inner diameter of 3.5mm is connected to one side of a solution outlet, and a polystyrene plastic bottle is placed below the filling needle to serve as a receiving container 5. Bovine Serum Albumin (BSA) solution (viscosity of about 1cp, histidine buffer, pH 6.0, sodium chloride 150mM, BSA concentration 15mg/mL) was selected as the mimetic.
The filling volume of the peristaltic pump is set to be 20.00mL, the pump speed is 400rpm, the acceleration is 100rpm/s, and the delay time is 1 s. And starting a peristaltic pump to empty, adjusting the filling amount, and determining the actual filling weight of 20.0236 g. The peristaltic pump was started, the time required after a certain number of fills was measured, and the time required for each fill was calculated to be 1776.8 milliseconds.
Example 3
A peristaltic pump PF6 model manufactured by Watson-Marlow company is used as a metering filling pump 1, silicone tubes with the lengths of two ends of 150cm, the inner diameters of 4.8mm and the wall thicknesses of 1.6mm are cut out to be used as a tube section 4 and a tube section 8 in a graph 1, two sections of silicone tubes with the lengths of 20cm, the inner diameters of 3.2mm and the wall thicknesses of 1.6mm are used as a tube section 2 in the graph 1, and proper Y-shaped connectors 3 and 3' are selected to be connected. The connected pipeline is fixed on a peristaltic pump head, a Bosch filling needle with the inner diameter of 3.5mm is connected to one side of a solution outlet, and a polystyrene plastic bottle is placed below the filling needle to serve as a receiving container 5. Bovine Serum Albumin (BSA) solution (viscosity of about 1cp, histidine buffer, pH 6.0, sodium chloride 150mM, BSA concentration 15mg/mL) was selected as the mimetic.
The filling volume of the peristaltic pump is set to be 2.00mL, the pump speed is 100rpm, the acceleration is 10rpm/s, and the delay time is 1 s. And starting a peristaltic pump to empty, adjusting the filling amount, and determining the actual filling weight to be 2.0096 g. The peristaltic pump was started, the time required after a certain number of fills was measured, and the time required for each fill was calculated to be 1536.4 milliseconds.
Example 4
A peristaltic pump PF6 model manufactured by Watson-Marlow company is used as a metering filling pump 1, silicone tubes with the lengths of both ends of 70cm, the inner diameters of 4.8mm and the wall thicknesses of 1.6mm are cut out to be used as a tube section 4 and a tube section 8 in a graph 1, two sections of silicone tubes with the lengths of 15cm, the inner diameters of 3.2mm and the wall thicknesses of 1.6mm are used as a tube section 2 in the graph 1, and proper Y-shaped connectors 3 and 3' are selected to be connected. The connected pipeline is fixed on a peristaltic pump head, a Bosch filling needle with the inner diameter of 3.5mm is connected to one side of a solution outlet, and a polystyrene plastic bottle is placed below the filling needle to serve as a receiving container 5. A0.8% methylcellulose solution (1270 cp in 20mM histidine buffer, pH 6.0, 150mM NaCl) was selected as the simulant.
The filling volume of the peristaltic pump is set to be 2.00mL, the pump speed is 100rpm, the acceleration is 100rpm/s, and the delay time is 1 s. And starting a peristaltic pump to empty, adjusting the filling amount, and determining the actual filling weight of 2.0037 g. The peristaltic pump was started, the time required after a certain number of fills was measured, and the time required for each fill was calculated to be 948.4 milliseconds.
Example 5
A peristaltic pump PF6 model manufactured by Watson-Marlow company is used as a metering filling pump 1, silicone tubes with the lengths of two ends of 60cm, the inner diameters of 3.2mm and the wall thicknesses of 1.6mm are cut out to be used as a tube section 4 and a tube section 8 in the graph 1, two sections of silicone tubes with the lengths of 25cm, the inner diameters of 2.4mm and the wall thicknesses of 1.6mm are used as a tube section 2 in the graph 1, and proper Y-shaped connectors 3 and 3' are selected to be connected. The connected pipeline is fixed on a peristaltic pump head, a Bosch filling needle with the inner diameter of 2.1mm is connected to one side of a solution outlet, and a polystyrene plastic bottle is placed below the filling needle to serve as a receiving container 5. Bovine Serum Albumin (BSA) solution (viscosity of about 1cp, histidine buffer, pH 6.0, sodium chloride 150mM, BSA concentration 15mg/mL) was selected as the mimetic.
The filling volume of the peristaltic pump is set to be 2.00mL, the pump speed is 400rpm, the acceleration is 100rpm/s, and the delay time is 1 s. And starting a peristaltic pump to empty, adjusting the filling amount, and determining the actual filling weight of 2.0136 g. The peristaltic pump was started, the time required after a certain number of fills was measured, and the time required for each fill was calculated to be 627.1 milliseconds.
Example 6 filling time study under different filling line lengths
Group 1:
a peristaltic pump PF6 model manufactured by Watson-Marlow company is used as a metering filling pump 1, silicone tubes with the lengths of two ends of 150cm, the inner diameters of 4.8mm and the wall thicknesses of 1.6mm are cut out to be used as a tube section 4 and a tube section 8 in a graph 1, two sections of silicone tubes with the lengths of 20cm, the inner diameters of 3.2mm and the wall thicknesses of 1.6mm are used as a tube section 2 in the graph 1, and proper Y-shaped connectors 3 and 3' are selected to be connected. The connected pipeline is fixed on a peristaltic pump head, a Bosch filling needle with the inner diameter of 3.5mm is connected to one side of a solution outlet, and a polystyrene plastic bottle is placed below the filling needle to serve as a receiving container 5. Bovine Serum Albumin (BSA) solution (viscosity of about 1cp, histidine buffer, pH 6.0, sodium chloride 150mM, BSA concentration 15mg/mL) was selected as the mimetic.
The filling volume of the peristaltic pump is set to be 2.00mL, 3.00mL, 5.00mL, 8.00mL, 10.00mL or 20.00mL respectively, the pump speed is 100rpm or 400rpm, the acceleration is 100rpm/s, and the delay time is 1 s. And starting the peristaltic pump to empty, adjusting the filling amount, and determining the actual filling weight. And starting the peristaltic pump, measuring the time required after filling for a certain number of times, and further calculating the time required by each filling. The fill volume and/or pump speed is then adjusted for the next measurement.
Group 2:
a peristaltic pump PF6 model manufactured by Watson-Marlow company is used as a metering filling pump 1, silicone tubes with the lengths of two ends of 50cm, the inner diameters of 4.8mm and the wall thicknesses of 1.6mm are cut out to be used as a tube section 4 and a tube section 8 in a graph 1, two sections of silicone tubes with the lengths of 20cm, the inner diameters of 3.2mm and the wall thicknesses of 1.6mm are used as a tube section 2 in the graph 1, and proper Y-shaped connectors 3 and 3' are selected to be connected. The connected pipeline is fixed on a peristaltic pump head, a Bosch filling needle with the inner diameter of 3.5mm is connected to one side of a solution outlet, and a polystyrene plastic bottle is placed below the filling needle to serve as a receiving container 5. Bovine Serum Albumin (BSA) solution (viscosity of about 1cp, histidine buffer, pH 6.0, sodium chloride 150mM, BSA concentration 15mg/mL) was selected as the mimetic.
The filling volume of the peristaltic pump is set to be 2.00mL, 3.00mL, 5.00mL, 8.00mL, 10.00mL or 20.00mL respectively, the pump speed is 100rpm or 400rpm, the acceleration is 100rpm/s, and the delay time is 1 s. And starting the peristaltic pump to empty, adjusting the filling amount, and determining the actual filling weight. And starting the peristaltic pump, measuring the time required after filling for a certain number of times, and further calculating the time required by each filling. The fill volume and/or pump speed is then adjusted for the next measurement.
Specific results are shown in table 1 below.
TABLE 1 filling time study under different filling line length conditions
As can be seen from the above, the length of the tubing had no significant effect on the filling time.
EXAMPLE 7 filling time study at different liquid viscosities
Group 1:
a peristaltic pump PF6 model manufactured by Watson-Marlow company is used as a metering filling pump 1, silicone tubes with the lengths of two ends of 50cm, the inner diameters of 4.8mm and the wall thicknesses of 1.6mm are cut out to be used as a tube section 4 and a tube section 8 in a graph 1, two sections of silicone tubes with the lengths of 20cm, the inner diameters of 3.2mm and the wall thicknesses of 1.6mm are used as a tube section 2 in the graph 1, and proper Y-shaped connectors 3 and 3' are selected to be connected. The connected pipeline is fixed on a peristaltic pump head, a Bosch filling needle with the inner diameter of 3.5mm is connected to one side of a solution outlet, and a polystyrene plastic bottle is placed below the filling needle to serve as a receiving container 5. Bovine Serum Albumin (BSA) solution (viscosity of about 1cp, histidine buffer, pH 6.0, sodium chloride 150mM, BSA concentration 15mg/mL) was selected as the mimetic.
The filling volume of the peristaltic pump is set to be 2.00mL, 3.00mL, 5.00mL, 8.00mL, 10.00mL or 20.00mL respectively, the pump speed is 100rpm or 400rpm, the acceleration is 100rpm/s, and the delay time is 1 s. And starting the peristaltic pump to empty, adjusting the filling amount, and determining the actual filling weight. Starting the peristaltic pump, measuring the time required after filling for a certain number of times, further calculating the time required for each filling, and then adjusting the filling volume and/or the pump speed to carry out the next measurement.
Group 2:
a peristaltic pump PF6 model manufactured by Watson-Marlow company is used as a metering filling pump 1, silicone tubes with the lengths of two ends of 50cm, the inner diameters of 4.8mm and the wall thicknesses of 1.6mm are cut out to be used as a tube section 4 and a tube section 8 in a graph 1, two sections of silicone tubes with the lengths of 20cm, the inner diameters of 3.2mm and the wall thicknesses of 1.6mm are used as a tube section 2 in the graph 1, and proper Y-shaped connectors 3 and 3' are selected to be connected. The connected pipeline is fixed on a peristaltic pump head, a Bosch filling needle with the inner diameter of 3.5mm is connected to one side of a solution outlet, and a polystyrene plastic bottle is placed below the filling needle to serve as a receiving container 5. A0.8% methylcellulose solution (1270 cp in 20mM histidine buffer, pH 6.0, 150mM NaCl) was selected as the simulant.
The filling volume of the peristaltic pump is set to be 2.00mL, 3.00mL, 5.00mL, 8.00mL, 10.00mL or 20.00mL respectively, the pump speed is 100rpm or 400rpm, the acceleration is 100rpm/s, and the delay time is 1 s. And starting the peristaltic pump to empty, adjusting the filling amount, and determining the actual filling weight. Starting the peristaltic pump, measuring the time required after filling for a certain number of times, further calculating the time required for each filling, and then adjusting the filling volume and/or the pump speed to carry out the next measurement.
The specific results are shown in Table 2 below.
TABLE 2 filling time study at different liquid viscosities
EXAMPLE 8 study of the relationship between filling volume and time for different inner diameters of pipelines
Group 1:
a peristaltic pump PF6 model manufactured by Watson-Marlow company is used as a metering filling pump 1, silicone tubes with the lengths of two ends of 50cm, the inner diameters of 4.8mm and the wall thicknesses of 1.6mm are cut out to be used as a tube section 4 and a tube section 8 in a graph 1, two sections of silicone tubes with the lengths of 20cm, the inner diameters of 3.2mm and the wall thicknesses of 1.6mm are used as a tube section 2 in the graph 1, and proper Y-shaped connectors 3 and 3' are selected to be connected. The connected pipeline is fixed on a peristaltic pump head, a Bosch filling needle with the inner diameter of 3.5mm is connected to one side of a solution outlet, and a polystyrene plastic bottle is placed below the filling needle to serve as a receiving container 5. Bovine Serum Albumin (BSA) solution (viscosity of about 1cp, histidine buffer, pH 6.0, sodium chloride 150mM, BSA concentration 15mg/mL) was selected as the mimetic.
The filling volume of the peristaltic pump is set to be 2.00mL or 3.00mL respectively, the pump speed is 100rpm or 400rpm, the acceleration is 100rpm/s, and the delay time is 1 s. And starting the peristaltic pump to empty, adjusting the filling amount, and determining the actual filling weight. Starting the peristaltic pump, measuring the time required after filling for a certain number of times, further calculating the time required for each filling, and then adjusting the filling volume and/or the pump speed to carry out the next measurement.
Group 2:
a peristaltic pump PF6 model manufactured by Watson-Marlow company is used as a metering filling pump 1, silicone tubes with the lengths of two ends of 50cm, the inner diameters of 3.2mm and the wall thicknesses of 1.6mm are cut out to be used as a tube section 4 and a tube section 8 in the graph 1, two sections of silicone tubes with the lengths of 20cm, the inner diameters of 1.6mm and the wall thicknesses of 1.6mm are used as a tube section 2 in the graph 1, and proper Y-shaped connectors 3 and 3' are selected to be connected. The connected pipeline is fixed on a peristaltic pump head, a Bosch filling needle with the inner diameter of 2.1mm is connected to one side of a solution outlet, and a polystyrene plastic bottle is placed below the filling needle to serve as a receiving container 5. Bovine Serum Albumin (BSA) solution (viscosity of about 1cp, histidine buffer, pH 6.0, sodium chloride 150mM, BSA concentration 15mg/mL) was selected as the mimetic.
The filling volume of the peristaltic pump is set to be 2.00mL or 3.00mL respectively, the pump speed is 100rpm or 400rpm, the acceleration is 100rpm/s, and the delay time is 1 s. And starting the peristaltic pump to empty, adjusting the filling amount, and determining the actual filling weight. Starting the peristaltic pump, measuring the time required after filling for a certain number of times, further calculating the time required for each filling, and then adjusting the filling volume and/or the pump speed to carry out the next measurement.
The specific results are shown in Table 3 below.
TABLE 3 study of the relationship between filling volume and time for different inner diameters of pipelines
As can be seen from the above, the filling time is inversely related to the inner diameter of the pipeline, and the adjustment of the filling time can be realized by adjusting the pipe diameter of the pipeline.
Example 9 study of Process model fill volume and time relationship
A peristaltic pump PF6 model manufactured by Watson-Marlow company is used as a metering filling pump 1, silicone tubes with the lengths of two ends of 50cm, the inner diameters of 4.8mm and the wall thicknesses of 1.6mm are cut out to be used as a tube section 4 and a tube section 8 in a graph 1, two sections of silicone tubes with the lengths of 20cm, the inner diameters of 3.2mm and the wall thicknesses of 1.6mm are used as a tube section 2 in the graph 1, and proper Y-shaped connectors 3 and 3' are selected to be connected. The connected pipeline is fixed on a peristaltic pump head, a Bosch filling needle with the inner diameter of 3.5mm is connected to one side of a solution outlet, and a polystyrene plastic bottle is placed below the filling needle to serve as a receiving container 5. Bovine Serum Albumin (BSA) solution (histidine buffer, pH 6.0, sodium chloride 150mM, BSA concentration 15mg/mL) was selected as the mock solution.
The filling volume of the peristaltic pump is set to be 2.00mL, 3.00mL, 5.00mL, 8.00mL, 10.00mL or 20.00mL respectively, the pump speed is 100rpm, 200rpm, 300rpm or 400rpm, the acceleration is 100rpm/s, and the delay time is 1 s. And starting the peristaltic pump to empty, adjusting the filling amount, and determining the actual filling weight. And starting the peristaltic pump, measuring the time required after filling for a certain number of times, and further calculating the time required by each filling. The next measurement is then made by adjusting the fill volume and/or pump speed, the results of which are shown in figure 2.
The above are only examples of the present application, and do not limit the scope of the present application. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. All embodiments need not be described or illustrated herein. The technical solutions like this formed by equivalent transformation or equivalent substitution fall within the protection scope of the present application.
Claims (10)
1. A laboratory model system for pharmaceutical production filling process development and characterization includes a filling fluid supply means, a dosing filling pump, a filling device and a tubing connecting the filling fluid supply means, dosing filling pump and filling device in fluid communication with each other, and a timing device.
2. The mold system of claim 1 wherein the filling device comprises a filling needle; preferably, the inner diameter of the filling needle is the same as the inner diameter of a filling needle used in a production filling line.
3. The modeling system of claim 1, further comprising a filling parameter monitoring device and/or a filling parameter control device; for example, the filling parameters are selected from: filling amount, pump speed, acceleration, time delay, suck-back parameters, pipeline inner diameter, pipeline length and filling liquid viscosity.
4. The modeling system of claim 1, wherein the ratio of the length of the pipeline of one or more pipe segments to the length of the pipeline of the corresponding pipe segment in the production filling line is from 1: 10 to 10: 1, respectively.
5. The modeling system of claim 1, wherein one or more of the following characteristics of one or more of the segments are the same as the corresponding segments in the production filling line: material, inner diameter, and wall thickness.
6. The mold system of claim 1 wherein the tubing is silicone tubing.
7. The modeling system of claim 1, wherein the dosing filling pump is a different model than a dosing filling pump used in a production filling line.
8. The model system of claim 1, the dosing filling pump being a peristaltic pump, such as a two-channel peristaltic pump.
9. A laboratory modeling method for pharmaceutical manufacturing filling process development and characterization, comprising:
a) constructing the laboratory model system of any one of claims 1-8;
b) setting filling quantity and other filling parameters;
c) operating the model system and determining the filling time;
wherein the filling amount differs by no more than 10%, preferably no more than 5%, more preferably the same as the filling amount of the production filling line; and, the actual production process conditions are simulated by adjusting the settings of other filling parameters.
10. The modeling method of claim 9, the fill liquid having at least one of the following characteristics:
i) the filling liquid is a drug stock solution or a simulation solution which is the same as the actual production;
ii) the viscosity of the filling liquid is lower than 1300 cp; or
iii) the filling liquid comprises a biological drug, a chemical small molecule drug or both, wherein preferably the biological drug is selected from the group consisting of a monoclonal antibody, a diabody, an antibody drug conjugate, a fusion protein, a vaccine, a cellular drug, a genetic drug or any combination thereof.
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