A blow-molded pipe fitting

Abstract

This application provides a blow-molded disposable valve and fitting, and its clamping half-mold, for constructing a high-flow or medium-high pressure disposable separation and purification system for downstream biopharmaceutical applications. The system is characterized by comprising: a disposable elbow formed by injection blow molding, and a clamping half-mold with elbow grooves; disposable tees and crosses formed by injection blow molding, and clamping half-molds with tees and crosses grooves; a disposable valve cavity formed by injection blow molding, and a clamping half-mold with valve cavity grooves; a valve diaphragm die-cast onto the disposable valve cavity; and a valve actuator connected to two closed valve cavity clamping half-molds to form a complete disposable valve. The disposable valve, elbow, tee, and cross, along with existing disposable pumps and instruments, can be assembled and combined at extremely low material costs to form a large-scale or medium-high pressure disposable separation and purification system for downstream biopharmaceutical applications, including chromatography systems, ultrafiltration systems, and other systems.

Description

Technical Field

[0001] This specification relates to the field of downstream purification and separation technology in biopharmaceuticals, specifically to a blow-molded valve and fitting for downstream purification processes, suitable for low-cost production and particularly suitable for high-flow or medium-high pressure process environments. Background Technology

[0002] In the biopharmaceutical industry, downstream processing plays a crucial role in refining therapeutic products, including monoclonal antibodies, recombinant proteins, and advanced therapies such as viral vectors used in gene therapy. Therefore, biopharmaceuticals are an essential component of modern medicine, providing advanced treatments for a wide range of diseases. However, producing these drugs involves complex challenges. Typically, the process begins by culturing host cells in a bioreactor to generate the desired active pharmaceutical ingredient (API), followed by multiple purification steps. Downstream operations, such as chromatography, ultrafiltration, and sterile filtration, are essential for the separation and purification of biological agents. With the increasing demand for high-volume production of drugs such as monoclonal antibodies as intermediates for therapeutics, such as the production of ADCs, which require monoclonal antibodies as a raw material, large-capacity systems have had a significant impact on drug production. These systems typically operate on a tens-of-tonnes scale, using large-diameter pipes and valves to process bioactive products.

[0003] In a given separation and purification process, the isolation of live cells or components is crucial, as contamination can render the product unusable. To reduce the risk of contamination and the need for cleaning agents and rinsing / cleaning validation in the bioprocessing industry, the concept of single-use, disposable products is increasingly being adopted. Because single-use valves and fittings require validation of the finished material to comply with regulations such as USP CLASS VI, high-quality, high-purity plastics are typically used.

[0004] Currently, disposable equipment used in the pharmaceutical industry is based on stainless steel systems. For example, valves are manufactured by replacing stainless steel with various types of plastic materials and using similar structures and processing methods, such as forming flow channels and valve chambers within plastic sheets. Similarly, various clamp valves directly use complex flexible hoses to form flow channels. For fittings required along the flow path, flexible hoses are used for connection, thus avoiding the use of elbows, or plastic elbows are used to connect the hoses to form the pipeline route; plastic tees are used to connect the hoses to form tee routes.

[0005] Because the system needs to withstand a certain operating pressure, even low-pressure systems use a considerable amount of high-quality plastics. For example, hoses typically require 3-4 bar to withstand pressure, necessitating a certain wall thickness. Furthermore, due to the complexity of processing and the need for machining, these consumables remain a significant source of pharmaceutical production costs for single-use systems.

[0006] Furthermore, the strength of plastics is far lower than that of stainless steel, so they cannot be used in medium- and high-pressure production processes. Moreover, there are not many types of plastics that simultaneously possess certain mechanical properties and chemical compatibility; most of them result in high-cost plastic products.

[0007] For flexible tubing, due to the stretchability of materials such as silicone, the tubing expands and deforms under production conditions due to internal fluid pressure. This results in dead angles at the joint where the tubing connects to the pagoda-shaped connector. This could potentially adversely affect the quality of the bioproducts.

[0008] At the same time, due to pressure resistance, these disposable products can only be made into small-diameter specifications. For large-scale production, the cost of materials and processing methods required may be higher than that of stainless steel, and they may even be impossible to process with current manufacturing equipment or processes. Therefore, large systems above the pilot stage can only be made of stainless steel at present.

[0009] In addition, certain design methods, such as forming flow channels and valve chambers within the plastic sheet, can result in a valve resistance drop of at least twice that of similar stainless steel valves. For large systems, it may even be impossible to find a pump with the corresponding capacity, making it impossible to build such a disposable production system.

[0010] Therefore, there is a desire and a need to address these challenges by developing disposable, large-bore valves and fittings specifically designed for drug purification and separation in large-volume systems. Disposable technologies are increasingly favored in the biopharmaceutical industry because they reduce the risk of cross-contamination, eliminate cleaning requirements, and streamline production processes. Specifically, disposable consumables used in large systems require minimal raw material consumption, can withstand medium to high pressure conditions, have no dead zones, and their resistance drop for individual valves is no higher than that of equivalent stainless steel valves. They are also easy to install and readily available. Summary of the Invention

[0011] To address the problems mentioned in the background art, embodiments of this specification provide a blow-molded valve and fitting for constructing a drug purification and separation system under high flow or medium-high pressure conditions in downstream purification processes of biopharmaceuticals. The valve includes: a disposable elbow formed by injection molding and blow molding processes. The elbow is typically formed into a preform through injection molding, and then the preform is blow-molded to form the final finished elbow. This elbow has a thickened port, which typically uses a chuck connection interface. The elbow wall is formed into a thin wall through blow molding. A clamping half-mold with a groove in the shape of the elbow is used to tightly fit the outer wall of the disposable elbow. Two clamping half-molds are joined together to accommodate the disposable elbow and form a complete elbow fitting. This fitting is suitable for forming reinforced connections with other fittings or valves. One-piece tees and crosses are formed using injection molding and blow molding processes. The tees and crosses are typically formed into blanks through injection molding, and then the blanks are blow molded to form the final finished tees and crosses. The tees and crosses have thickened ports, which are usually connected by chucks. The walls of the tees and crosses are formed into thin walls through blow molding. Clamping half-molds with grooves in the shape of tees and crosses can fit tightly to the outer walls of the one-piece tees and crosses. Two clamping half-molds are joined together to form a complete tee and cross fitting. This fitting is suitable for forming a reinforced connection with other fittings or valves. It features a disposable valve cavity formed by injection molding and blow molding processes. The valve cavity uses the same flow channel structure as stainless steel valves to maintain the same valve pressure drop. The valve cavity is usually formed into a preform through injection molding, and then the preform is blow molded to form the final finished valve cavity. The valve cavity has a thickened port, which usually adopts a chuck connection interface. The valve cavity wall is formed into a thin wall through blow molding. The clamping half mold has a groove in the shape of the valve cavity, which can fit tightly to the outer wall of the disposable valve cavity. The two clamping half molds are spliced ​​together to form a complete valve flow channel structure. This valve flow channel structure is suitable for forming a reinforced connection with other pipe fittings or valves. The valve diaphragm is die-cast onto a disposable valve cavity, forming a closed valve cavity flow channel, and the valve is opened and closed under the action of the actuator; the valve actuator is connected to two closed valve cavity clamping half molds to form a complete disposable valve. The connection between the actuator and the valve adopts a quick snap-fit ​​port, so that it can be quickly connected; the disposable valve, elbow, tee, four-way valve, and existing disposable pumps and instruments can be assembled and combined to form a downstream disposable separation and purification system for biopharmaceuticals, including a chromatography system, an ultrafiltration system, and a sterilization filtration or virus removal filtration system.

[0012] Preferably, the clamping half-molds for elbows, tees, crosses, and valves have connection ports of the same specifications to facilitate the connection between different components when building the system. The port method of quick chuck connection is usually selected, but flange connection can also be selected to strengthen the connection.

[0013] Preferably, the valve diaphragm has a double-layer kneading structure. The double-layer diaphragm reduces the risk of leakage on the one hand, and on the other hand, it can be made of materials with different properties to deal with the fluid side and the non-fluid side respectively.

[0014] Preferably, the diaphragm layer that does not contact the fluid is made of a magnetic flexible material. The magnetic diaphragm can automatically adhere to the actuator when the actuator is open and open with the actuator, thereby counteracting the influence of negative pressure. It can be used at the inlet end of the pump. In addition, the valve assembly is easy to install, and the diaphragm structure that is not connected to the actuator is easy to manufacture.

[0015] Preferably, the actuator stem and diaphragm of the valve have no fixed connection, which makes installation very convenient and the structure of the diaphragm can be greatly simplified.

[0016] Preferably, the clamping half-mold of the elbow, tee, and cross has a rectangular shape, which is suitable for external connection of instruments, such as ultrasonic flow meters.

[0017] Almost all thermoplastics can be used for blow molding, such as polyethylene, polyvinyl chloride, polypropylene, polystyrene, linear polyester, polycarbonate, polyamide, cellulose acetate and polyacetal resins.

[0018] Compared with the prior art, the beneficial effects that at least one technical solution adopted in the embodiments of this specification can achieve include at least:

[0019] Disposable valve cavities and fittings manufactured using injection and blow molding methods require minimal materials, keeping both consumable costs and manufacturing costs within acceptable limits, thereby reducing the production cost per batch of medicines. The blow molding process allows for one-piece molding of valves and fittings, eliminating internal dead corners. The same flow channel structure as stainless steel valves keeps valve pressure drop within a reasonable range. The clamping half-mold closure structure can withstand medium to high pressure production conditions, and the consistent design of the clamping half-mold port connections makes installation extremely convenient and quick. Large-diameter disposable valves and fittings enable the construction of disposable large-diameter systems, effectively supporting large-scale production. Attached Figure Description

[0020] To more clearly illustrate the technical solutions of the embodiments of this application, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0021] Figure 1 An injection mold for a disposable elbow preform according to the present invention is shown;

[0022] Figure 2 A disposable elbow blow molding die according to the present invention is shown;

[0023] Figure 3This illustrates a disposable elbow clamping half-die according to the present invention;

[0024] Figure 4 This illustrates a disposable elbow clamping product according to the present invention;

[0025] Figure 5 An injection mold for a disposable valve cavity preform according to the present invention is shown;

[0026] Figure 6 A disposable valve cavity blow molding die according to the present invention is shown;

[0027] Figure 7 The finished product of a disposable valve assembly according to the present invention is shown;

[0028] Figure 8 The present invention illustrates a combination of a disposable valve, a clamping half-mold, and an actuator;

[0029] Figure 9 This illustrates a disposable three-way preform injection mold according to the present invention;

[0030] Figure 10 This illustrates a disposable tee blow molding die according to the present invention;

[0031] Figure 11 This illustrates a disposable three-way clamping half-mold according to the present invention;

[0032] Figure 12 The finished product of a disposable tee assembly according to the present invention is shown;

[0033] Figure 13 This shows a disposable four-way assembly product according to the present invention;

[0034] Figure 14 This illustrates a typical chromatography process according to the present invention;

[0035] Figure 15 This illustrates a typical ultrafiltration process according to the present invention;

[0036] Figure 16 A perspective view of a typical tomography system assembly according to the present invention is shown;

[0037] Figure 17 A front view of a typical tomography system assembly according to the present invention is shown;

[0038] Figure 18 A partial perspective view of a typical chromatography system according to the present invention is shown;

[0039] Figure 19 A perspective view of a typical ultrafiltration system assembly according to the present invention is shown;

[0040] Figure 20 A front view of a typical ultrafiltration system assembly according to the present invention is shown;

[0041] Figure 21 A partial perspective view of a typical ultrafiltration system according to the present invention is shown; Detailed Implementation

[0042] The embodiments of this application will now be described in detail with reference to the accompanying drawings.

[0043] The following specific examples illustrate the implementation of this application. Those skilled in the art can easily understand other advantages and effects of this application from the content disclosed in this specification. Obviously, the described embodiments are only a part of the embodiments of this application, and not all of them. This application can also be implemented or applied through other different specific embodiments, and the details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of this application. It should be noted that, in the absence of conflict, the following embodiments and features in the embodiments can be combined with each other. Based on the embodiments in this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0044] It should be noted that various aspects of embodiments within the scope of the appended claims are described below. It will be apparent that the aspects described herein can be embodied in a wide variety of forms, and any particular structure and / or function described herein is merely illustrative. Based on this application, those skilled in the art will understand that one aspect described herein can be implemented independently of any other aspect, and two or more of these aspects can be combined in various ways. For example, any number and aspects set forth herein can be used to implement the device and / or practice the method. Additionally, this device and / or method can be implemented using structures and / or functionalities other than one or more of the aspects set forth herein.

[0045] It should also be noted that the illustrations provided in the following embodiments are only schematic representations of the basic concept of this application. The drawings only show the components related to this application and are not drawn according to the actual number, shape and size of the components in the actual implementation. In the actual implementation, the form, quantity and proportion of each component can be arbitrarily changed, and the layout of the components may also be more complex.

[0046] Furthermore, specific details are provided in the following description to facilitate a thorough understanding of the examples. However, those skilled in the art will understand that the described aspects can be practiced without these specific details.

[0047] Currently, single-use products are widely used in the pharmaceutical and biotechnology industries because they do not require cleaning or cleaning validation. The main problems with the application of single-use purification equipment in downstream biopharmaceutical applications are as follows:

[0048] Existing downstream purification systems in biopharmaceuticals can only utilize disposable products suitable for small to medium-scale applications. Furthermore, since the design of these disposable products is largely derived from stainless steel, their pressure resistance is inferior, limiting their use to low-pressure processes. Moreover, the current design and manufacturing methods for disposable products cannot be directly extended to large-diameter systems. Additionally, the current development approach for disposable products prioritizes preventing cross-contamination, remaining energy-intensive and costly in terms of cost savings. The products are becoming increasingly complex, with any plastic material considered disposable, deviating from the original intention of using disposable materials to replace stainless steel and save costs.

[0049] Through extensive and in-depth research, the inventors have provided a blow-molded disposable valve and fitting, as well as a clamping half-mold. The disposable valve, elbow, tee, and cross are assembled with the clamping half-mold structure and existing disposable pumps and instruments to form a disposable separation and purification system for downstream biopharmaceutical applications, including chromatography systems, ultrafiltration systems, and other systems.

[0050] The technical problem solved by this invention is to provide an optional disposable system for the large-scale purification and production of biopharmaceuticals downstream, and to greatly reduce the cost of consumables.

[0051] More specifically, the solution adopted in this invention includes: using blow-molded disposable valves and fittings and their clamping half-molds to build a high-flow or medium-high pressure disposable separation and purification system for downstream biopharmaceutical applications, and effectively reducing the cost of consumables.

[0052] The technical solutions provided by the various embodiments of this application are described below with reference to the accompanying drawings.

[0053] Figure 1 The manufacturing process of the elbow injection preform is given. 101 and 103 are two molds, and 102 is an injection mandrel. They are combined together to form an injection mold.

[0054] Figure 2 The mold for blow molding of the elbow injection preform is given. 106 and 107 are blow molding molds, and 104 is the injection preform including the mandrel.

[0055] Figure 3The diagram shows an exploded view of the blow-molded elbow held in two half-molds. 111 and 114 are the two holding half-molds. The connection port 112 of the holding half-molds adopts a quick-connect chuck, but other forms such as flange connection can also be used. The specifications of the chuck connection are fixed to facilitate the connection between different components. 113 is the finished one-time blow-molded elbow.

[0056] Figure 4 The appearance of the assembled elbow 100 is shown. The exterior has a rectangular structure, which is conducive to the installation of various accessories on the outer surface, such as the generator and receiver of an ultrasonic flow meter.

[0057] Figure 5 The mold for injection molding of the valve cavity preform is shown. 201 is one half of the mold, and 202 is the injection mandrel.

[0058] Figure 6 The image shows the state of the injection valve cavity preform 203, including the mandrel 202, being blow molded in blow molds 204 and 205.

[0059] Figure 7 The appearance of the complete valve 200 assembly is shown.

[0060] Figure 8 The various components of valve 200 are shown, including a disposable valve chamber 206 placed between valve clamping half molds 208 and 211. The valve chamber is controlled by a double-layer diaphragm 210 to open and close the valve. After the clamping half molds are assembled, they are connected to the actuator 212 through the same connection structure. If a quick-clamping structure is used, the actuator valve stem 213 has an elliptical valve plate. When the valve plate moves to close, it presses the diaphragm 210 and then presses it against the valve chamber sealing surface to form the valve closed. When the valve plate 213 is in the open position, the diaphragm 210 is magnetic, so the diaphragm is attracted to the valve plate and opens the valve chamber seal as the valve plate opens.

[0061] Figure 9 The injection molds 301 and 303 for the T-shaped injection preform and the mandrel 302 are shown.

[0062] Figure 10 The blow molding dies 304 and 305 are shown, as well as the injection preform 306 with a mandrel 302.

[0063] Figure 11 The image shows the blow-molded tee 307 being held in tee half-molds 308 and 309, with the half-molds having port connections 310 of a universal structure and size.

[0064] Figure 12 The image shows the complete 300 tee fitting after assembly. Tee fittings are mainly used for connecting pipeline branches and instruments.

[0065] Figure 13 The image shows the complete four-way mounting kit 350 after assembly. Four-way mounting kits are mainly used for the integrated connection of pipeline branches or instruments.

[0066] Figure 14 It demonstrates a typical downstream chromatography separation process with multiple liquid inlets, dual pumps, bubble traps for degassing, instruments for pre-column conductivity and pressure, column position valves, instruments for post-column conductivity, pH, UV, etc., and multiple liquid outlets.

[0067] Figure 15 It shows a typical downstream ultrafiltration separation process with multiple liquid inlets, a membrane holder, a control valve, various instruments upstream and downstream of the membrane such as flow meters, pressure and conductivity meters, etc., and multiple liquid outlets.

[0068] Figure 16 The diagram shows a perspective view of an apparatus constructed using the valves and insights described in this invention according to a typical chromatography process. The disposable apparatus is easy to install as a consumable, and typically all components are arranged in a single plane.

[0069] Figure 17 The front view of the equipment built according to a typical chromatography process is shown, including: control cabinet 401, operation panel 402, pump 409, post-pump electrical conduction 408, pressure 407, various connecting tees, elbows, and valves, such as tee 406, elbow 404, and valve 405 for bubble trap bypass connection, and also includes bubble trap 403.

[0070] Figure 18 The image shows partial perspective details of the equipment built according to a typical chromatography process, including valve chamber 206, disposable elbow 113, valve clamping half mold 208, and elbow clamping half mold 114.

[0071] Figure 19 The diagram shows a perspective view of the equipment built according to a typical ultrafiltration process, including pressure 509 and conductivity 508 connected to the tee.

[0072] Figure 20 The diagram shows a front view of an equipment built according to a typical ultrafiltration process, including inlet valves such as 506, pump 505, membrane holder 507, ultrasonic flow meter generator 504 and receiver 503 connected to the outer wall of the tee, and electrical control cabinet 501 and control panel 502.

[0073] Figure 21 The diagram shows a partial perspective view of an apparatus built according to a typical ultrafiltration process, including features such as elbow clamping half-mold 114, disposable elbow 113, valve chamber 206, and valve clamping half-mold 208.

[0074] The aforementioned disposable valve chambers, tees, four-way valves, and elbows can be made of any suitable material that can withstand the chemical corrosivity associated with the solvents used in the separation / purification methods. For pharmaceutical and biotechnology applications, it is best to use materials suitable for GMP, such as polymers conforming to Federal Regulation 177 (CFR 177) and United States Pharmacopeia VI (USP VI). Suitable polymers, which are also flammable, are typically made of suitable elastomers or rubber materials (such as polyethylene, polyvinyl chloride, polypropylene, polystyrene, linear polyester, polycarbonate, polyamide, cellulose acetate, and polyacetal resins). The advantage of using flammable materials is that they can be easily disposed of by incineration.

[0075] Suitable polymers are preferably composed of materials that can be sterilized by gamma irradiation and / or other means (e.g., chemical sterilization or autoclaving), because minimizing microbial contamination is important when handling biofluids and / or pharmaceutical / biotechnology products.

[0076] Using the above design, disposable valve chambers and fittings can be quickly replaced when producing different batches of products, thereby meeting the cleanliness verification requirements for cross-contamination.

[0077] The blow-molded valves and fittings of this invention are used to construct high-flow or medium-to-high-pressure single-pass separation and purification systems for downstream biopharmaceutical applications. They are particularly useful in the large-scale manufacturing of pharmaceutical and biotechnology products, and can be used for the separation and purification of large volumes of biological fluids. Typical examples of such biological fluids include bioprocess solutions and / or suspensions, blood, plasma, fermentation products, and cell culture products. Examples of interesting chemical and biological compounds that may be present in such fluids include proteins, peptides, antibodies, vaccines, glycoproteins, lectins, pharmaceuticals, carbohydrates, lipids, and chemical intermediates.

[0078] The various embodiments in this specification are described in a progressive manner. Similar or identical parts between embodiments can be referred to interchangeably. Each embodiment focuses on describing the differences from other embodiments. In particular, the method embodiments described later are relatively simple in description because they correspond to the system; relevant parts can be referred to the descriptions in the system embodiments.

[0079] The above description is merely a specific embodiment of this application, but the scope of protection of this application is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in this application should be included within the scope of protection of this application. Therefore, the scope of protection of this application should be determined by the scope of the claims.

Claims

1. A blow-molded tubular fitting for constructing a high-flow-rate or medium-to-high-pressure single-stage separation and purification system for downstream biopharmaceutical applications, characterized in that... include: A disposable elbow formed by injection molding and blow molding processes, and a clamping half mold with elbow grooves; The system comprises disposable tees and crosses formed by injection and blow molding processes, and clamping half-molds with grooves for the tees and crosses; disposable valve cavities formed by injection and blow molding processes, and clamping half-molds with grooves for the valve cavities; a valve diaphragm die-cast onto the disposable valve cavity; and a valve actuator connected to two closed clamping half-molds of the valve cavity to form a complete disposable valve. The disposable valves, elbows, tees, crosses, and existing disposable pumps and instruments can be assembled into a disposable separation and purification system for downstream biopharmaceutical applications, including a chromatography system, an ultrafiltration system, and a sterilization or virus removal filtration system.

2. The blow-molded pipe fitting according to claim 1, characterized in that, The clamping semi-molds for elbows, tees, crosses, and valves have connection ports of the same specifications.

3. The blow-molded pipe fitting according to claim 1, characterized in that, The valve diaphragm has a double-layer kneading structure.

4. A blow-molded pipe fitting according to claim 3, characterized in that, The layer of the double-layer diaphragm that does not come into contact with the fluid is made of a flexible material with magnetic properties.

5. A blow-molded pipe fitting according to claim 1, characterized in that, The valve actuator stem and diaphragm are in contact without a fixed connection.

6. A blow-molded pipe fitting according to claim 1, characterized in that, The clamping semi-molds for elbows, tees, and crosses have a rectangular shape.

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