Patent Application
20110198066
The present invention concerns a device incorporating a single use heat exchanger that is sterilized prior to use in the pharmaceutical, biopharmaceutical, biotechnology or related fields.
Biotechnology, pharmaceutical and related industries have historically used stainless steel, or otherwise reusable, processes and devices. Re-useable processes must be cleaned and sterilized between batches. The cleaning and sterilization usually requires the use of steam and/or chemicals to accomplish the task. Additionally, for regulated products such as pharmaceuticals, the sterilization process has to be validated to show that it could repeatedly sterilize the device. The cleaning and sterilization processes and the validation are time consuming and expensive and cannot be varied without a new validation. Re-useable processes also have significantly higher startup costs in material and installation, and often require a much larger footprint.
As a result, in recent years these industries are increasingly moving towards the use of single use (disposable) containers, tubing, flow path components and ancillary equipment in their research, manufacturing and processing of sterile fluids. The use of disposable devices eliminates or minimizes the need for cleaning and sterilizing equipment between batches.
Heat exchangers of various types are used in the biotechnology and pharmaceutical markets to heat or cool fluid streams during processing.
Re-usable equipment and technologies require cleaning and sterilization, increased start-up costs and costly validations. They also create difficulties for technology transfer and can limit both scalability and reproducibility.
The present invention advantageously brings the benefits of single use devices to heat exchange applications to allow the user to safely process a fluid and/or biopharmaceutical product without the risk of contamination and thereby also reducing the cleaning and/or validation costs associated with conventional methods. Technology transfer, the process of moving, transferring or duplicating processes in different locations, is also made significantly easier through the use of such a device
a shows the plates used to create a plate exchanger, with
With reference to the figures, a single use device comprising a heat exchanger 1, 14, 22 and necessary tubing 9, fluid flow components 8, 23 and/or connectors 2, 10, 15 that is sterilized prior to use in the biotechnology, pharmaceutical or biopharmaceutical industries and is used for the heating or cooling of a fluid while maintaining the sterility of a fluid, process or container is described.
The heat exchanger will have at least two fluid steams. The product stream 6, 7 is the fluid which is to be heated or cooled. The utility stream 3, 4 is the fluid used to heat or cool the product stream. In most embodiments of the invention, sterility is maintained on the product stream and is not a concern for the utility stream. Flexible polymeric tubing 9, tubing components 8, 21 or connectors, including those considered to be sterile or aseptic connectors, 2, 10, 15 are used on the product stream inlet and/or outlet to connect the device to a container or process.
There are other, less common, fluid configurations such as when one product stream is used for heat transfer to or from another product stream, or such as when the product stream is used for heat transfer to the same stream (itself) at a different point in the process. In these configurations it may be required to maintain the sterility of both fluid streams. Most embodiments of the invention involve only two fluids, the product stream and the utility stream, although it may be possible to have more than one of either the utility or product streams depending on the application.
Currently, industry generally uses heat exchangers formed of a metallic composition such as stainless steel or aluminum. This is both for the heat transfer capabilities of metals and also for the longevity and clean-ability of the exchanger. As the present invention is designed for a single use, longevity and clean-ability are not required traits of the present invention. Although commonly thought of as poor conductors of heat transfer, plastics and polymers are well suited to heat transfer, especially in low volume fluid applications as often the case in pharmaceutical and related applications. The thermal conductivity of a material is a small factor when considering the overall heat transfer coefficient. Polymers and plastics are desirable materials for single use heat exchangers.
The device of the present invention is preferably formed in its entirety of a polymeric composition such as polypropylene (PP); polyamide (PA); polyethylene terephthalate (PET); polysulfone (PS); polyethersulfone (PES); polyvinyl chloride (PVC), polycarbonate (PC), polyvinylidene fluoride (PVDF), polyetheretherketone (PEEK), polytetrafluoroethylene (PTFE), polyurethane (PU); polyethylene (including ultrahigh molecular weight polyethylene, linear low density polyethylene, ultralow, low or medium density polyethylene); ethylene vinyl alcohol (EVOH); polyvinyl acetate (PVA); ethylene vinyl acetate (EVA); ethylene vinyl acetate copolymers; films and multilayered laminates of different thermoplastics; as well as other polymers and plastics (including thermoplastic polymers, thermoplastic elastomers, homopolymers, copolymers, block copolymers, graft copolymers, random copolymers, alternative copolymers, terpolymers, metallocene polymers) and derivatives or mixtures thereof. Such materials are available from a wide range of chemical manufacturers. Metals, including stainless steel and aluminum, may also be used to form all or a part of the invention.
Plate heat exchangers 14 are one of the most common exchangers used in biopharmaceutical, pharmaceutical, biotechnology and related fields. When the embodiment of the invention is of a plate exchanger type the device is formed by molding the face plate 11, end plate 13 and a plurality of middle plates 12. The plates are welded or sealed together. The number and size of middle plates is determined by the characteristics of the process including flow rate, fluid type, plate area and thickness, fluid temperatures and so forth. There are at least two inlet 3, 6 and two outlet 4, 7 connections that are most commonly molded into the front plate 11.
Shell and tube 1 and tubular heat exchangers are common formats to the biopharmaceutical, pharmaceutical, biotechnology and related fields. Shell and tube exchangers are comprised of an outer shell and a plurality of inner tubes 5. The product stream is usually that within the tubes. The utility stream generally flows through the outer shell. Tubular exchangers are formed much the same, except in that they only posses one, usually larger, tube within the shell. The preferred embodiment of the present invention uses molded rigid plastics and polymers to create both the tubes and the outer shell. In another embodiment of the invention, flexible polymeric films or containers 20, common to pharmaceutical and related industries for a variety of applications, may be used as the outer shell while flexible polymeric tubing 5, 9 may be used as the inner tube or tubes. Polymeric films or bag containers and tubing may be used in combination with a rigid plastic shell and/or rigid plastic tubes such that a flexible bag container shell may be used with rigid molded tubes or flexible polymeric tubes may be used with a rigid molded shell.
A condenser is an alternative name for a heat exchanger used to condense a gas into its liquid form. Graham 22 or Leibig type condensers are the most common and are essentially variations of tubular heat exchangers and may be constructed in the same fashion. The present invention may be used as a condenser type heat exchanger. Spiral exchangers are a format of heat exchanger where two tubular flow paths are wrapped together. The flow paths share an adjoining wall where the heat transfer takes place.
In the preferred embodiment of the present invention the heat exchanger is incorporated with or used in conjunction with sterile (aseptic) connectors 2, 10, 15 such that the device may be attached to a process or container without risk of contamination or use of a special area or procedure, such as under a hood in a clean room. Sterile connectors are increasingly used within industry to connect containers 17, 24, filters 16, sections of a process and so forth. Sterile connectors are available from a variety of suppliers to the pharmaceutical and biotechnology industries including Sartorius Stedim Biotech SA of France; Colder Products Company of St. Paul Minn.; Millipore Corp. of Billerica, Mass.; Pall Corp. of Port Washington, N.Y. and GE Healthcare of Fairfield, Conn. The heat exchanger may directly incorporate sterile connectors as its inlet and outlet, as shown in
The preferred embodiment of the present invention uses sterile connectors 2, 10, 15 that are initially a closed system to allow for device unpackaging and attachment while remaining sterile. Such connectors include the Lynx Connector from Millipore Corp., the Opta Connector from Sartorius Stedim Biotech SA, the ReadyMate Connector from GE Healthcare, the Kleenpak Connector from Pall Corp. and so forth. These connectors are of a design such that the disconnected ends are initially a sterile barrier. There are two matching pieces of the connector with one being attached to the process and the other being attached to the item desired to be connected to the process, in this case the invention. Upon combining the two ends of the connector the flow path is generally opened by way of some mechanism such as actuation, use of a membrane barrier and so forth. The fluid flow path is not exposed and therefore remains sterile.
The present invention is most commonly sterilized by exposure to irradiation. The two forms of irradiation most commonly used in the pharmaceutical and biotechnology industries for sterilization are exposure to gamma rays and cathode rays, also called electron beams or e-beams. X-rays and ultraviolet (UV) light are other sources of radiation that may also be used in some instances. Exposure to ethylene oxide (ETO) and autoclaving may also be used for sterilization. The present invention may be sterilized through a combination of techniques. For example, an irradiated heat exchanger may be coupled with autoclaved connectors under a hood. The preferred embodiment of the invention is that in which the heat exchanger is assembled with sterile connectors, tubing and/or flow path components prior to the entire device being sterilized, usually by gamma irradiation.
Materials have different levels of compatibility with respect to exposure to irradiation. Many materials turn brittle, discolor or crack following exposure to irradiation used for sterilization. Materials may be altered or blended to increase the contact dosage able to be applied. An irradiation compatible material is one that is able to perform its intended function following sterilization by irradiation. As the intended function may differ, a material may be considered compatible for one application of the device, while not compatible for another application. Furthermore, some materials may be more or less affected by one form of irradiation used for sterilization than another.
The device should be manufactured or assembled in a clean room or otherwise sterile environment so as to minimize contaminants and particulates that may be introduced.
In addition to being a unique device connected to a process, another embodiment of the present invention is a single use heat exchanger pre-connected to a piece of the process, such as a container or bioreactor, by way of tubing, flow path components or connectors. The entire section of the process including the container, the present invention and other ancillary components such as filters 16, additional tubing, sensors and the like are sterilized together through a method such as irradiation. A sterile connector may not be required in this embodiment as the heat exchanger is already connected to the process prior to sterilization. This embodiment is most applicable when using an entirely disposable polymeric flow path. Flexible single use containers in such processes are often located within stainless steel or plastic bins or totes 18. These are not sterilized with the single use portions of the process as they are not in fluid contact and therefore not a critical component of the process.
There are many adaptations of heat exchangers designed to increase or affect the heat transfer of the device that are known to prior art. These adaptations include baffles, cross-current or co-current flow, various tube shapes and configurations, flow pitch, plate chevrons and so forth. The present invention may incorporate these adaptations as required by the process or application. During use, flow through the device is normally provided by way of a pump 19.
The invention may be wirelessly enabled. The wireless communications device may be a RFID tag having a communication and storage or memory component or other wireless devices such as Bluetooth or Zigbee wireless enabled communications devices. By wirelessly enabling the device one can track the device history or important information, such as manufacture date, lot number, shelf life, sterilization date and the like.
The invention may be assembled either entirely or partially by either a vendor, the final end-user of the device, a contract manufacturing organization, a third party sterilizer or other company providing a service related to the invention.
