NL2007929C2

NL2007929C2 - Dmb medication cassette.

Info

Publication number: NL2007929C2
Application number: NL2007929A
Authority: NL
Inventors: Renatus Antonius Kanters; Theodorus Joannes Maria Hodes; Aruna Rosita Banwarie; Petrus Leonardus Antonius Smeenk
Original assignee: Tiofarma B V
Priority date: 2011-12-07
Filing date: 2011-12-07
Publication date: 2013-06-10

Description

DMB MEDICATION CASSETTE FIELD OF THE INVENTION

The present invention relates to the field of fluid delivery medication cassettes.

5 More in particular, the present invention relates to sterile fluid delivery cassettes and to sterile fluid delivery cassettes filled with sterile parenteral formulations, meant to deliver parenteral formulations via ambulatory infusion systems to patients, and methods to provide those fluid delivery cassettes.

10 BACKGROUND OF THE INVENTION

Ambulatory medical infusion pumps are a commercial success and popular medical instruments. The pumps allow for a continuous and calibrated parenteral delivery of a variety of therapeutic fluids, including but not limited to antibiotics, pain relieving drugs, chemotherapy drugs, and saline solutions.

15 Microbiological purity or sterility of the fluid to be administered parenterally to patients is of utmost importance since the risk of exposure of patients to potential pathogens is to be minimized. The sterility of the fluid that is administered parenterally to a patient depends on the microbiological purity of the fluid in its original packaging, on the sterility of the equipment that is used to administer the fluid, and on the sterility 20 of the environment in which administering is performed.

One conventional method for assuring the sterility of a product is aseptic manufacturing. Aseptic manufacturing relies on the process of avoiding contamination with microorganism as much as possible. Aseptic processing is performed with sterile products in a sterile environment but it cannot avoid all microbiological contamination. 25 The demands of maintaining a sterile environment throughout the manufacturing process are time-consuming, laborious and expensive. In case the manufacturing process comprises a complex series of steps, the risk of contamination with microorganisms increases with every subsequent step.

Conventional filling of fluid delivery medication cassettes used with ambulatory 30 infusion systems at pharmacies and hospitals, for example Deltec CADD™ medication cassettes, is performed aseptically. These medication cassettes comprise an outer housing having a single opening. The outer housing encloses an inner reservoir. The inner reservoir, which is a flexible bag, is meant to contain the fluid to be administered.

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It has one opening that is connected to a delivery conduit emerging from the cassette through said single opening. A female Luer-taper connection is attached to the other end of the delivery conduit. The Luer taper is a standardized system, generally known by those skilled in the art, of small-scale fluid fittings used for making leak-free 5 connections between a male-taper fitting and the corresponding female part on medical and laboratory instruments. When the cassette is not in use, a clamp that is attached to the delivery conduit prevents fluid and/or air to enter or leave the cassette. Furthermore, a protective cap is placed on the Luer-taper connection that is attached to the delivery conduit.

10 The conventional aseptic process to fill a sterilized Deltec CADD® medication cassette comprises the following steps. The sterile cassette is unwrapped and placed in a sterile work area. The cassette cover is removed and the fluid to be loaded into the cassette reservoir is collected in a syringe with a male Luer connection tip. The protective cap is removed from the female Luer connection attached to the conduit 15 emerging from the cassette. The clamp on the delivery conduit is removed to open the flow path to the reservoir. The fluid is slowly injected into the reservoir to prevent the formation of microbubbles. The clamp on the delivery conduit is closed. The reservoir is gently squeezed to accumulate smaller air bubbles into one single air bubble in the upper portion of the reservoir near the connection to the conduit. The clamp on the 20 conduit is opened and all air is removed from the reservoir using the syringe. The syringe is removed from the conduit and the Luer connection on the delivery conduit is closed with a cap. Last, the cassette cover is closed. This process is time-consuming and though performed in a sterile environment is prone to microbiological contamination since the cassette is not always closed during the process and the sterile 25 fluid comes into contact with the environment during a number of process steps. Generally, cassettes filled with this conventional aseptic process have, when kept under low-temperature storage conditions, a microbiological shelf-life of 14 day at a maximum. Such a short shelf-life is often insufficient.

US 2002/0172615 A1 describes a process for the production of sterile prefilled 30 containers, for example prefilled syringe bodies, said process comprising the steps of sterilizing a container, for example using electron-beam radiation, transferring the sterilized container to a sterile environment and introducing a sterile medical solution 3 into the sterilized container. The container is optionally sealed after the medical solution has been transferred thereto.

US 5,881,534 describes a process for sterilization of containers for medical use made of polymeric material using gamma irradiation, in which process said containers 5 are enclosed in a gas impermeable bag together with an oxygen scavenger and water, for a time sufficient to consume substantially all the oxygen. Subsequently the enclosed container is subjected to a sterilizing dose of gamma-radiation. The enclosed container may be sterilized as such or may be filled with a parenterally administrable preparation prior to subjecting it to gamma irradiation. This patent also describes a sealed gamma-10 radiation sterilized medical article made of polymeric material and a sealed gamma-radiation sterilized medical article made of polymeric material containing a parenterally administrable preparation.

WO 2005/058377 describes sterilization of prefilled medical devices, like vials, cartridges, bottles, containers and syringes. The medium prefilled within the container 15 may be a saline solution, or may be a drug for parenteral administration to the body. Desirably, the container is sealed after being filled with the medium and prior to radiation treatment. The container may further be enclosed within packaging, such as a blister package, prior to irradiation treatment.

A disadvantage of above methods in which pre-sterilized containers, cartridges, 20 et cetera, are filled with fluid is that the reservoir of the sterilized containers will be microbiologically contaminated directly after unwrapping the sealed container in case the container is already open, or will be contaminated when it is opened to deliver the fluid to the reservoir. This reduces the microbiological shelf-life of the filled containers considerably.

25 A disadvantage of those methods described above in which containers pre-filled with fluid are sterilized is that many therapeutic fluids are not particularly stable when subjected to ionizing radiation, resulting in undesired degradation of the therapeutic fluids.

A further disadvantage of above methods resulting in prefilled medical devices 30 is that containers, cartridges, et cetera, filled with a variety of fluids and having a short microbiological shelf-life, have to be kept in stock so as to meet the uncertain prospective demands of patients.

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Thus, a simplified process is needed in which a sterile fluid is transferred to a sterile cassette adapted for parenterally administering said fluid to a patient. Also a longer microbiological shelf-life of the filled cassettes is needed.

5 SUMMARY OF THE INVENTION

The inventors have found that above objects can be realized by first sterilizing a microbiologically-closed fluid delivery cassette having a sterility barrier that is penetrable by fluid but not by microorganisms and subsequently filling the sterilized microbiologically-closed fluid delivery cassette with a sterile fluid, preferably under 10 aseptic conditions.

One aspect of the invention relates to a microbiologically-closed fluid delivery cassette comprising a housing having a transfer opening, a reservoir located within the housing, the reservoir comprising a flexible bag having a delivery opening, a delivery conduit comprising a first and a second end, wherein the first end is coupled to said 15 delivery opening of the flexible bag, said delivery conduit protruding through the transfer opening of the housing, a connector that connects the second end of the delivery conduit to a sterilizing filter, and a sterilizing filter.

A second aspect of the invention relates to a method for sterilizing one or more microbiologically-closed fluid delivery cassettes and aseptically filling them with a 20 sterile fluid, said method comprising a) providing one or more of said microbiologically-closed fluid delivery cassettes comprising a housing having a transfer opening, a reservoir located within the housing, the reservoir comprising a flexible bag having a delivery opening, a delivery conduit comprising a first and a second end, wherein the first end is coupled to said delivery opening of the flexible 25 bag, said delivery conduit protruding through the transfer opening of the housing, a connector that connects the second end of the delivery conduit to a sterilizing filter, and a sterilizing filter, b) sterilizing one or more microbiologically-closed fluid delivery cassettes with a sterilant chosen from the group consisting of steam, ethyleneoxide, a dose of gamma radiation, electron beam radiation, X-rays, or a combination thereof, 30 and c) introducing the sterile fluid into the reservoir via the sterilizing filter.

Another aspect of the invention concerns an aseptically filled microbiologically-closed fluid delivery cartridge that is obtained via the method described above.

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The inventors have found that the process of filling, preferably aseptically filling, the sterilized microbiologically-closed fluid delivery cassettes with sterile fluid is more user-friendly compared to conventional aseptic filling processes. A further advantage of the method of the present invention is that microbiological shelf-life and 5 chemical stability of the filled microbiologically-closed fluid delivery cassettes is remarkably better than for conventionally filled fluid delivery cassettes. Other advantages of the various embodiments of the present invention will become apparent from the detailed description below and the appending examples.

10 DETAILED DESCRIPTION OF THE INVENTION

Accordingly, one aspect of the invention relates to a microbiologically-closed fluid delivery cassette comprising a housing having a transfer opening, a reservoir located within the housing, the reservoir comprising a flexible bag having a delivery opening, a delivery conduit comprising a first and a second end, wherein the first end is 15 coupled to said delivery opening of the flexible bag, said delivery conduit protruding through the transfer opening of the housing, a connector that connects the second end of the delivery conduit to a sterilizing filter, and a sterilizing filter. An example of a microbiologically-closed fluid delivery cassette is presented in the Figure.

In this document and in its claims, the verb ‘to comprise’ and its conjugations 20 are used in their non-limiting sense to mean that items following the word are included, without excluding items not specifically mentioned. In addition, reference to an element by the indefinite article ‘a’ or ‘an’ does not exclude the possibility that more than one of the element is present, unless the context clearly requires that there be one and only one of the elements. The indefinite article ‘a’ or ‘an’ thus usually means ‘at 25 least one’.

The term ‘microbiologically-closed system’ as used herein refers to a system having one or more openings, each opening being sealed from the environment so that it is not penetrable by microorganisms, said system being hermetically mechanically closed otherwise.

30 The term ‘fluid delivery cassette’ as used herein can refer to any container or reservoir that can hold fluid and has at least one opening to remove and or add air and/or fluid. Non-limiting examples of fluid delivery cassettes in the context of the present invention are cassettes that can be used in ambulatory infusion systems for 6 parenteral administration of fluids, such as Deltec CADD® medication cassettes. The fluid delivery cassettes as used in the present invention typically have a fluid capacity of between 10 and 500 ml, more preferably between 20 and 250 ml.

The microbiologically-closed fluid delivery cassettes of the present invention 5 preferably have been adapted to be compatible with infusion pumps that are currently used in ambulatory infusion systems such as Deltec CADD® pumps or Graseby 9000 pumps.

The delivery conduit typically is made of silicone. The housing typically is made of polycarbonate.

10 The connector connecting the delivery conduit and the sterilizing filter should be mechanically as well as microbiologically closed to avoid any bacterial ingress into the fluid reservoir. Nevertheless, the sterilizing filter must be easily removable from the delivery conduit. These requirements can for example be met by using Luer-taper connections, which are generally used in medical and laboratory instruments. The Luer-15 taper is a standardized system of small-scale fluid fittings used for making leak-free connections between a male-taper fitting and its mating female part. Key features of Luer-taper connectors are defined in the ISO 594 standards. There are two varieties of Luer-taper connections: Luer-Lok and Luer-Slip. Luer-Lok fittings are securely joined by means of a tabbed hub on the female fitting which screws into threads in a sleeve on 20 the male fitting. Luer-Slip fittings simply conform to Luer taper dimensions and are pressed together and held by friction. In a preferred embodiment, the delivery conduit emerging at one side from the opening of the cassette has a male or female Luer fitting on the other side. The sterilizing filter has a male or female Luer fitting at its inlet and outlet, with the provision that the outlet of the sterilizing filter can be Luer connected to 25 the Luer fitting on the conduit.

The sterilizing filter must be penetrable by fluids but not by microorganisms, and must be sterilizable and preferably removable from the microbiologically-closed fluid delivery cassette. Furthermore, the sterilizing filter must be able to at least filtrate a fluid volume equal to the fluid capacity of the reservoir. The choice of filter may also 30 depend on the polarity of the fluid that needs to be transferred across the filter, as is generally known by those skilled in the art.

A filter with a pore size of 0.22 pm or smaller will effectively remove bacteria. The filters themselves may be purchased as pre-sterilized disposable units in sealed 7 packaging, or may be sterilized by the user, generally by autoclaving at a temperature that does not damage the fragile filter membranes. Since terminal sterilization of the microbiologically-closed fluid delivery cassette as a whole is performed the filters themselves do not necessarily need to be pre-sterilized.

5 The sterilizing filters as described herein can be made of a variety of materials.

It is an important aspect of the invention that the sterilizing filter is resistant to the method of terminal sterilization of the microbiologically-closed fluid delivery cassette. Most commercially available sterilizing filters are made of medical grade polymeric materials that are not sensitive to steam and/or ethylene oxide (EtO). Most medical 10 grade polymeric materials further have a radiation-dose tolerance level of 100 kGy or higher.

Hence, sterilizing filters that can advantageously be used in the present invention have Luer fittings on both sides of the filter, have a pore size of 0.22 pm or smaller, have a process volume of at least the volume of the reservoir to be loaded, and 15 are made of materials that are resistant to EtO, steam, and ionizing radiation with a dose of less than 50 kGy. Non-limiting examples of such sterilizing filters are Millex® Durapore (polyvinylidenefluoride membrane), Millipore Express (polyethersulfone membrane) filters from Merck Millipore and Mini sart high flow filters from Sartorius Stedim Biotech.

20 The sterilizing filter preferably is removable from the microbiologically-closed fluid delivery cassette to check its integrity without leaving the fluid delivery cassette open. In a preferred embodiment of the invention, the Luer connector that connects on one side to the conduit and on the other side to the sterilizing filter comprises a valve that opens up the flow path for fluids when it is connected to the sterilizing filter and 25 automatically and immediately closes when the sterilizing filter is removed. A nonlimiting example of such connectors is the Safeflow valve of B. Braun Melsungen AG, Germany, which opens when pressure is applied on the valve and is closed otherwise.

The terms ‘aseptic manufacture’, ‘aseptic process’, ‘aseptically filling’ or ‘asepsis’ as used herein refer to processes that are performed with sterile components in 30 a sterile environment. Aseptic manufacture relies on the process of avoiding contamination with microorganisms as much as possible. Aseptic manufacture of a microbiologically-closed fluid delivery cassette starting from sterile parts generally results in a microbiologically contaminated system, since asepsis cannot avoid all 8 contamination. An alternative to aseptic manufacturing is sterilization of premanufactured products at the end of the manufacturing process. This alternative is called terminal sterilization. Terminal sterilization relies on the lethal treatment of microorganisms. Once terminally sterilized, the inner part of the microbiologically-5 closed fluid delivery cassette will remain sterile. In terminal sterilization it is not necessary that pre-sterilized parts are used in the manufacturing process, since the assembly constructed from the separate parts is sterilized as a whole.

In an embodiment of the invention, a microbiologically-closed fluid delivery cassette as defined in the foregoing is provided, packed into a microbiologically 10 impermeable bag or pouch. The packaging functions as a sterile barrier system to maintain the sterile state obtained after terminal sterilization unchanged during transport and storage. The terms bag, plastic bag, polybag, or pouch as used herein are used interchangeably and stand for a type of packaging made of thin, flexible, plastic film, nonwoven fabric, or plastic textile. The term ‘microbiologically impermeable 15 packaging’ as used herein means that the packaging material is impermeable for particles of the size of microorganisms.

In a preferred embodiment of the invention a microbiologically-closed fluid delivery cassette as defined in the foregoing is provided of which at least the interior is sterile, especially microbiologically sterile. It is particularly preferred that the 20 microbiologically-closed fluid delivery cassettes of the present invention are assembled first and subsequently terminally sterilized.

Hence, a second aspect of the invention relates to a method for sterilizing microbiologically-closed fluid delivery cassettes of the present invention, comprising a) providing one or more microbiologically-closed fluid delivery cassettes comprising a 25 housing having a transfer opening, a reservoir located within the housing, the reservoir comprising a flexible bag having a delivery opening, a delivery conduit comprising a first and a second end, wherein the first end is coupled to said delivery opening of the flexible bag, said delivery conduit protruding through the transfer opening of the housing, a connector that connects the second end of the delivery conduit to a 30 sterilizing filter, and a sterilizing filter, and b) sterilizing one or more microbiologically-closed fluid delivery cassettes with a sterilant chosen from the group consisting of steam, ethyleneoxide, a dose of gamma radiation, electron beam radiation, X-rays, or a combination thereof.

9 A particularly preferred aspect of the invention relates to a method for sterilizing one or more microbiologically-closed fluid delivery cassettes of the present invention and aseptically filling them with a sterile fluid, said method comprising a) providing one or more of said microbiologically-closed fluid delivery cassettes, b) 5 sterilizing one or more microbiologically-closed fluid delivery cassettes with a sterilant chosen from the group consisting of steam, ethyleneoxide, a dose of gamma radiation, electron beam radiation, X-rays, or a combination thereof, and c) introducing the sterile fluid into the reservoir via the sterilizing filter.

In a preferred embodiment, the reservoir is evacuated via the sterilizing filter 10 prior to step c). This can advantageously be carried out using a syringe or electric pump. Step c) can also be carried out using a syringe or electric pump.

The term ‘sterilizing’ as used herein refers to a process that eliminates, removes, or kills all forms of microbial contamination, including transmissible agents such as fungi, bacteria, viruses, and spore forms, present on a surface, contained in a fluid, or in 15 medication. Sterilization can be achieved by applying the proper combinations of heat, chemicals, irradiation, high pressure, and filtration.

Sterilizing processes may be a compromise between the degradation effect on the materials and destruction of microorganisms. A sterilization process that destroys all microorganisms, but renders the item being sterilized unfit for use is of no value.

20 Various methods of sterilization of medical devices and tools are known in the art. Each method has its specific advantages and disadvantages. Sterilization methods that can advantageously be used in the present invention are heat treatment with steam, treatment with ionizing radiation, chemical treatment, and combinations thereof.

Steam sterilization is typically performed in an autoclave wherein all air has 25 been replaced by steam. Typical sterilization conditions are a steam temperature of 121-134 °C with a holding time of at least 15 minutes at 121 °C up to 3 minutes at 134 °C. For effective sterilization, steam needs to penetrate the autoclave load uniformly, so an autoclave must not be overcrowded, and the inner part of bottles and containers must be accessible and/or penetrable by steam. Indicators may be placed in the most difficult 30 places for the steam to reach to ensure that steam actually penetrates there. These indicators will change colour when the appropriate sterilization conditions have been met. These indicators are commercially available and are well known to the person skilled in the art.

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Although heating provides a reliable way to rid objects of all transmissible agents, it is not always appropriate, because it may damage heat-sensitive materials. Alternatively, chemicals can be advantageously used for sterilization. Low temperature gas sterilizers function by exposing the articles to be sterilized to high concentrations 5 (typically 5 - 10% v/v) of very reactive gases such as alkylating agents like ethylene oxide (EtO), and oxidizing agents such as ozone. Liquid sterilants and high disinfectants typically include oxidizing agents such as hydrogen peroxide and peracetic acid and aldehydes such as glutaraldehyde and o-phthalaldehyde. While the use of gas and liquid chemical sterilants avoids the problem of heat damage, the article 10 to be sterilized should be chemically resistant to the sterilant being used.

EtO gas is commonly used to sterilize objects sensitive to temperatures greater than 60 °C and / or radiation. EtO treatment is generally carried out between 30 °C and 60 °C with a relative humidity above 30% and a gas concentration between 200 and 800 mg/1, and typically lasts for at least three hours. Ethylene oxide penetrates well, 15 moving through paper, cloth, and some plastic films and is highly effective. EtO can kill all known viruses, bacteria and fungi, including bacterial spores and is compatible with most materials, even when repeatedly applied.

A typical EtO sterilization process consists of a preconditioning phase, the actual sterilization run and a period of post-sterilization aeration to remove toxic 20 residues, such as ethylene oxide residues and by-products such as ethylene glycol and ethylene chlorohydrine.

EtO sterilization requires evacuation of air from the sterilization chamber, the introduction of moisture allowing the EtO to penetrate more effectively, the introduction of the EtO gas (either in the pure state or as a mixture with an inert gas), 25 and keeping the internal pressure of the chamber lower than one atmosphere to prevent leakage of the EtO into the atmosphere. After the specified exposure time, the EtO is purged and the chamber is flooded with filtered sterile air to remove any residual EtO. As with steam sterilization, indicators may be placed in the places most difficult to reach for the EtO to ensure that EtO actually penetrates there. Indicators that change 30 colour upon EtO treatment are commercially available and are well known to the person skilled in the art.

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Sterilization methods using ionizing radiation are also well known in the art. The ionizing radiation can for example exist of electron beams, X-rays and gamma rays, or combinations thereof

Gamma rays are commonly used for sterilization of disposable medical 5 equipment, such as syringes, needles and cannulas. Sterilization by irradiation with gamma rays may however in some cases affect material properties. Electron-beam irradiation is also commonly used for medical device sterilization. Electron beams provide a much higher dosing rate than gamma or X-rays. Due to the higher dose rate, less exposure time is needed and thereby potential degradation to polymers is reduced. 10 A limitation is that electron beams are less penetrating than either gamma or X-rays. X-rays and high-energy X-rays (Bremsstrahlung) are a form of ionizing energy allowing to irradiate large packages and pallet loads of medical devices. Their penetration is sufficient to treat multiple pallet loads of low-density packages with very good dose uniformity ratios.

15 In a preferred embodiment, terminal sterilization of the microbiologically- closed fluid delivery cassettes is performed with ionizing radiation. The ionizing radiation may comprise gamma radiation, electron-beam radiation, X-ray radiation, or combinations thereof, preferably gamma radiation.

The irradiation may be conducted at any dosage useful to provide effective 20 sterilization without degrading the microbiologically-closed medication cassette, i.e. the cassette including inter alia conduit, Safeflow valve, and sterilizing filter. The radiation dose required for terminal sterilization is readily determined by a person skilled in the art. The radiation dose according to the present invention is provided in a range from 10 kGy to 50 kGy, more preferably in a range between 20 kGy and 45 kGy. 25 In an even more preferred embodiment, terminal sterilization of the microbiologically-closed fluid delivery cassette is performed with gamma radiation in a range from 10 kGy to 50 kGy, more preferably in a range between 20 kGy and 45 kGy.

The inside of the sterilized fluid delivery cassette will remain free of microbiological contamination during storage, since the cassette is microbiologically 30 closed. However, during transport and storage, there is always a risk that the outer part of the sterilized cassette is contaminated, since it is exposed to the environment which is predominantly non-sterile.

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To further reduce the risk of microbiological contamination during storage of the microbiologically-closed fluid delivery cassette, it can be packed prior to sterilization. Hence, in another preferred embodiment of the invention, a method is provided as defined in the foregoing in which one or more cassettes are packed into a 5 first microbiologically impermeable bag or pouch prior to sterilization. Hence, the packaging functions as a sterile barrier system to maintain the sterile state unchanged during transport and storage. The terms bag, plastic bag, polybag, or pouch as used herein are used interchangeably and stand for a type of packaging made of thin, flexible, plastic film, nonwoven fabric, or plastic textile. The term ‘microbiologically 10 impermeable packaging’ as used herein means that the packaging material is impermeable for particles of the size of microorganisms.

As will be clear to those skilled in the art, the process of sterilizing a packed microbiologically-closed fluid delivery cassette requires the sterilant to be able to pass the microbiologically impermeable bag or pouch. Requirements for packaging of 15 terminally sterilized medical devices are commonly known by those skilled in the art and have been laid down in international standards (see for example ISO 11607-1:200).

Steam sterilization requires a temperature between 121°C and 134°C. Hence, in embodiments in which steam sterilization is used, the material the bag or pouch is made of is able to withstand these temperatures. Steam sterilization is based on the energy 20 given off by the hot steam. Therefore, the materials used allow the steam to penetrate at least part of the packaging, i.e. the packaging has a breathable section. Furthermore, the breathable material typically is sufficiently permeable to allow fast evacuation of the steam during the process.

Suitable materials for packing the microbiologically-closed fluid delivery 25 cassette when using steam as the sterilant are for example porous materials such as medical-grade paper and non-woven materials of polyolefin such as high-density polyethylene (HOPE), wet laid non-wovens (pulp and plastic fibres), and SMS-type non-wovens (polypropylene). Non-limiting examples are for example Dupont Tyvek®, and Steriking ESP, PAP, PPP and PPAP flexible films as provided by WIPAK B.V., 30 Netherlands.

EtO sterilization does not normally involve high temperatures and this fact allows a fairly wide choice of suitable packaging materials. The breathable section of the packaging film typically is also permeable to water vapor and air. As with steam 13 sterilization, the packaging acts like a filter in that it allows sterilizing EtO, water and air to pass through and simultaneously prevents microorganisms from penetrating the packaging. Suitable materials for packaging the microbiologically-closed fluid delivery cassette when using EtO gas sterilization are for example porous materials such as 5 medical grade paper and non-woven materials of polyolefin such as HDPE, wet laid non-wovens (pulp and plastic fibres), and SMS-type non-wovens (polypropylene). Non-limiting examples are Dupont Tyvek® and Steriking ML P/ML E, PE C, MW, MW EL and ML flexible films as provided by WIPAK B.V., Netherlands.

Sterilization by irradiation can affect certain polymers in a detrimental way. 10 Suitable materials for packaging the microbiologically-closed fluid delivery cassette when sterilizing using irradiation are for example porous materials such as medical-grade paper and non-woven materials of polyolefin such as HDPE, PA-film, PE-film, PET-film, PET/PE-film, wet laid non-wovens (pulp and plastic fibres). Non-limiting examples are Dupont Tyvek®, Steriking MW, ML E, MW EL and PAE-laminated 15 flexible films as provided by WIPAK B.V., Netherlands.

Preferred packaging materials which can advantageously be used in the sterilization methods of the invention are HDPE such as Dupont Tyvek® and medical grade paper.

In another embodiment of the invention, one or more of the first 20 microbiologically impermeable bags comprising one or more microbiologically-closed fluid delivery cassettes are packed in a second bag or pouch prior to sterilization (step b). This second bag or pouch can be made of identical materials as the first bag or pouch. In case the sterilized microbiologically-closed fluid delivery cassette is packed into a first and second microbiologically impermeable bag, the microbiologically-25 closed fluid delivery cassette is removed from these bags prior to step c).

As will be clear to those skilled in the art, sterilization of microbiologically-closed fluid delivery cassettes as such or within packaging results in sterile microbiologically-closed fluid delivery cassettes.

In yet another embodiment of the invention the first and/or second bags or 30 pouches can be heat sealed. In still yet another embodiment the pouches or packaging materials are made of non-forming films and can be used either in combination with formable films to make a peelable or non-peelable ‘all-film’ pack. In yet another embodiment, the bags or pouches are heat-sealed in an oxygen-depleted atmosphere in 14 the presence of nitrogen or another suitable inert gas. In still another embodiment of the invention, a self-adhesive label is applied onto the first and/or second bags or pouches prior to sterilization, said label changing colour upon sterilization. Such labels are commercially available for the sterilization methods of the invention and are commonly 5 known to those skilled in the art.

The sterile fluid may be a therapeutic fluid or a non-therapeutic fluid, including materials such as flush solutions, contrast agents, pharmaceutical agents and vaccines. Desirably, the sterile fluid is provided for parenteral administration to the human body. Preferred examples are saline water and pharmaceutical drug formulations. Preferred 10 examples of pharmaceutical drug formulations are analgesics and antibiotics. Especially preferred products are fluids for parenteral administration that need to be stored after production. These examples, however, are by no means intended to limit the scope of the invention.

Aseptically filling of microbiologically-closed fluid delivery cassettes is 15 preferably performed in a Laminar Air Flow (LAF) cabin Class A placed in a clean room (Class B or Class A). Prior to filling, the experimental devices within the LAF-cabin and the cabin itself should be disinfected.

In case the sterilizing filter has a pore size that is to big to prevent the microorganisms to pass the sterility barrier, or if the sterilizing filter malfunctions in 20 some other way, the filled fluid delivery cassette may suffer from contamination with microorganisms. Such contaminated cartridges can not be used for parenteral administration. Hence, in a preferred embodiment of the invention a method according to the foregoing is provided in which the sterilizing filter is removed after filling the cassette and is immediately replaced by a sterile closing cap in a sterile environment, 25 said method further comprising testing the integrity of the contaminated sterilizing filter. As is generally known by those skilled in the art, the integrity of sterilizing filters can be tested using a Bubble Point test. As stated above, in a preferred embodiment the connector linking the sterilizing filter and the delivery conduit emerging from the cassette automatically closes upon removal of the sterilizing filter. Hence, after removal 30 of the sterilizing filter the system is still microbiologically closed. The bubble point of the sterilizing filters according to the present invention can be determined using a Sartocheck 3Plus integrity tester along with a Midisart Test Manifold lOx, both devices obtained from Sartorius Stedim Biotech GmbH, Germany. When the measured bubble 15 point exceeds a certain reference value corresponding to the relevant type of sterilizing filter, the sterility of the filtrate is guaranteed.

Still another aspect of the invention concerns an aseptically filled sterilized microbiologically-closed fluid delivery cartridge that is obtained via the method as 5 described in any of the foregoing. As will be clear from the examples, the aseptically filled sterilized microbiologically-closed fluid delivery cartridges typically are microbiological stable for at least 6 months at 25 C°, more preferably at least 12 months, most preferably at least 24 months.

The following examples are meant to further illustrate the invention and some 10 of its preferred embodiments without intending to limit its scope. Further examples and embodiments will be easily derived from the description, optionally combined with general technical knowledge, particularly in combination with known sterilization principles and principles of aseptic work.

15 EXAMPLES

Example 1: microbiologically-closed medication cassettes, assembling and sterilization 20 This example describes the assembling and sterilization of microbiologically- closed medication cassettes (assembled by pharmacy De Magistrale Bereider [DMB]). All parts that can be obtained presterilised are used as such. The filter is used non-sterilised in this example.

A Deltec medication cassette with a fluid delivery reservoir having a capacity of 25 100 ml is provided. This cassette can be used in ambulatory infusion systems in combination with a Deltec CADD pump or a Graseby 9000 pump. The inner reservoir is connected to one side of a conduit made of silicone emerging through the transfer opening of the Deltec medication cassette. The Deltec medication cassette has a female Luer fitting attached to the other end of the conduit which can be connected to standard 30 infusion lines. A plastic clamp is placed on the conduit. This clamp can be used to open or close the fluid delivery path to the reservoir.

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The female Luer fitting attached to the conduit is connected with the male Luer side on a Safeflow valve from B. Braun Melsungen AG, Germany. This Safeflow valve has a female Luer connection on the opposite side. The female Luer connection on the Safeflow valve is attached to the male Luer connection of a 0.22 pm Minisart High 5 Flow sterilizing filter from Sartorius Stedim Biotech GmbH, Germany. The resulting fluid delivery path comprising the conduit and fluid reservoir is now microbiologically closed. Nevertheless, it may still contain living microorganisms.

To realize a sterile system, the microbiologically-closed medication cassette as a 10 whole is sterilized. A male Luer closing cap is mounted on the female Luer connection of the sterilizing filter. The microbiologically-closed medication cassette is packed per 6 in a polyethylene bag having a gamma indicator self-adhesive label attached thereto. This label changes from yellow to red after exposure to gamma radiation. One set of packed microbiologically-closed medication cassettes are packed in a second 15 polyethylene bag and exposed to gamma irradiation at a dose of >25 kGy.

Example 2: aseptic filling of microbiologically-closed medication cassettes with sterile medication solution 20 Filling of microbiologically-closed medication cartridges is performed in a

Laminar Air Flow (LAF) cabin, Class A, placed in a clean room (Class B or A). Prior to filling, the experimental devices within the LAF-cabin and the cabin were disinfected with sterile 70% v/v isopropyl alcohol in deionised water.

The required number of packed sterilized microbiologically-closed medication 25 cassettes, having a reservoir capacity of 100 ml, as described in Example 1, is unwrapped by removing the first polyethylene bag. Only those packed microbiologically-closed medication cassettes carrying a red (sufficiently irradiated) sterilization indicator self-adhesive label are used in the filling procedure.

30 When the sterilization indicator is red, the second polyethylene bag is removed from the microbiologically-closed medication cassette. The closing cap connected to the 0.22 pm sterilizing filter on the medication cassette is removed and the connection between the conduit emerging from the cassette, the Safeflow valve and the sterilizing 17 filter is tested by applying moderate force onto it. Cassettes having a sterilizing filter and conduit that are not securely connected potentially result in contaminated systems and are excluded from the filling procedure. Immediately following the removal of the closing cap, one side of a sterile Luer-Lock three-way valve is connected to the Luer 5 Lock connection of the sterilizing filter. A second opening of the thee-way valve is connected to a sterile silicone conduit attached to a vacuum pump capable of reaching a pressure of < 0,05 bar, which is used to evacuate the reservoir of the medication cassette, and a third opening is connected to a sterile silicone conduit attached to a peristaltic pump, which is used to fill the reservoir of the medication cassette with 10 medication fluid. The three-way valve is constructed in such a way that either the fluid path between the vacuum pump and the reservoir or the fluid path between the peristaltic pump and the reservoir is open. The two fluid paths can not be open simultaneously.

15 First, the three-way valve is positioned in such a way so as to open the fluid path between vacuum pump and reservoir. The vacuum pump is turned on until the pressure in the reservoir of the medication cassette is reduced to < 0.05 bar. Afterwards, the peristaltic pump is preset to deliver the required amount of medication solution (between 95.0 and 102.0 g). This step is critical since overfilling may demolish the 20 reservoir. Subsequently, the three-way valve is positioned in such a way so as to open the fluid path between peristaltic pump and the reservoir. When about 100 g of medication solution has been added to the reservoir the peristaltic pumps is turned off, the three-way valve is removed and the closing cap is repositioned on the sterilizing filter.

25

The filled cassette reservoir is checked for air bubbles. Cassettes comprising air bubbles in the reservoir can not be used for parenteral administration. In case no air bubbles are present in the reservoir a clamp is placed on the conduit connecting the reservoir and the sterilizing filter to close the fluid delivery path.

30

The integrity of every sterilizing filter connected via a Safeflow valve to the conduit of a filled medication cassette is to be tested. For this purpose, the sterilizing filter is removed from the Safeflow valve. The Safeflow valve automatically closes 18 upon removal of the sterilizing filter. The ‘open side’ of Safeflow valve is disinfected with sterile 70% v/v ethanol in WFI immediately after removing the sterilizing filter and is closed with a new sterile cap with Luer connection. The aseptically filled microbiologically-closed medication cassette is now ready for use or storage.

5

The integrity test is performed with a Bubble Point test in water using a Sartocheck 3Plus integrity tester along with a Midisart Test Manifold lOx, both devices obtained from Sartorius Stedim Biotech GmbH, Germany.

The contaminated side of the filter to be tested (up to 10 filters a time) is 10 connected to the Sartocheck 3Plus integrity tester whereas the other side of the filter is submerged in water. The bubble point of a filter is defined as the test pressure at which the liquid inside the pore structure of its wetted membrane is actively removed by overcoming the capillary forces. The pressure on the contaminated side of the filter is steadily increased using the Sartocheck 3Plus integrity tester up to a pressure at which 15 bubbles are noted in the water. This pressure is called the Bubble Point. Only when the Bubble Point equals or exceeds 3.2 bar, the filter passes the integrity test, which guarantees the sterility of the filtrate. Medication cassettes having a filter that does not pass the integrity test can not be used for parenteral administration.

20 Example 3: validation of aseptic conditions during filling procedure and sterility of filled cassette

Tryptic Soy Broth (TSB) is commonly used for the cultivation of a wide variety of microorganisms. Thus, in comparison with most medication solutions, an aqueous 25 solution comprising TBS is a very good culture medium for potential microbiological contamination. Filling sterilized microbiologically-closed medication cartridges with TSB-containing fluid is a worst-case test for the microbiological stability obtained via the aseptic filling procedure of the present invention (as described in Example 2).

The microbiological stability obtained using the filling procedure according to 30 the present invention was validated by filling batches consisting of at least 20 medication cassettes per batch with sterile solution comprising 3 wt% TSB in water for injection (WFI). This procedure is repeated for three separately produced sterile TSB-solutions.

19

Sterility of TSB-containing fluid in filled medication cassettes is evaluated by visually inspecting the permeability of light through the cassettes after an incubation time of 1 week at 20°C-25°C and subsequently 1 week at 30°C-35°C. If the TSB-containing fluid is clear after the incubation time, it is sterile, if the TSB-containing 5 fluid is turbid, it is microbiologically contaminated.

Every batch comprises as a positive control one medication cassette that is microbiologically contaminated by removing the filter from the medication cartridge and blowing air through the conduit into the reservoir of the medication cassette. Since the reservoir of this positive control is contaminated prior to filling the cassette with 10 sterile TSB-containing fluid, the TSB-containing fluid must be turbid after the incubation time of 1 week at 20°C-25°C and subsequently 1 week at 30°C-35°C. Experimental results for three different batches are given in Table 1.

Table 1: sterility of microbiologically-closed medication cassettes filled with TSB-15 containing fluid after incubation

Batch number 26032010 15042010 16042010

Number of filled medication cassettes 20 22 20 (Requirement: >20)

Number of turbid (contaminated) cassettes 0 0 0 (Requirement: 0)

Positive control turbid?

Yes Yes Yes (Requirement: Yes)

Conclusion

No anomalies have been observed during and after the filling procedure. The performed sterility test meets the required criteria. On the basis of this observation, it is 20 concluded that aseptically filling of sterilized microbiologically-closed medication cassettes according to the method of the present invention results in filled medication cassettes that meet the required sterility conditions.

20

Example 4; microbiological and chemical shelf-life of filled sterilized microbiologically-closed medication cassettes

Microbiological and chemical shelf life of filled sterilized microbiologically-5 closed medication cassettes is determined by sampling medication fluid of medication cassettes stored at different incubation times and temperatures. Physical properties that are indicative for development of microbiological activity and or chemical instability are appearance (colour, turbidity), osmolarity, pH and in some cases also the amount of the medicinal component in the medication solution.

10

Isotonic aqueous solutions of morphine hydrochloride trihydrate (morphine HCL 3aq, CAS [6055-06-7]) are prepared by adding water for injection (WFI), sodium chloride and morphine HCL 3aq in the desired quantities to a mixing beaker. The resulting mixture is mechanically agitated until a clear solution is obtained. The pH is 15 adjusted to 4.1-4.3 using 0.5 M hydrochloric acid. The resulting mixture is mechanically agitated for an additional 15 minutes. The closed beaker with the aqueous solution of morphine HCL 3aq is degassed in an ultrasonic bath for 10 minutes.

Microbiologically-closed sterilized medication cassettes according to Example 1 are aseptically filled with different batches of aqueous solutions comprising morphine 20 HCL 3aq, CAS [6055-06-7], using the procedure as described in Example 2.

Samples are taken from the fluid of ‘fresh’ aseptically filled microbiologically-closed medication cassettes and from the fluid of medication cassettes being held at certain incubation time and temperature. The osmolarity, pH, morphine HCL 3aq content, and appearance (colour, turbidity) are determined for every sample. The results 25 are given in Table 2.

The amount of morphine HCL 3aq in the medication solution is determined via HPLC. The osmolarity and the pH of the solution are determined using suitable equipment commonly known to those skilled in the art.

30 21

Table 2; physical properties of fresh and incubated medication solution sampled from aseptically filled microbiologically-closed medication cassettes S' ^ i ö 6- . 2 1 S „ £8 | id= § , ! 8-¾ S ir)=.S = 1¾¾

2 i—( ÜÜ CSöÖ H [ ) H -H . HH C-l , ^ ,J >H I _2 .¾ C^5 2 2 O W

5 § o jp *9 *1 § Ji ° cl ^ g Ph öp -o g lo S ^ S v.

I ill §Ö1 I ais 1 I Hi?. §£go §15 S gf - £ <“"• I t I ° I! “ 20100504 Ï5 Ö - Yes Ï97 100.4% 287 - 20100504 25 L5 25 Yes Ï76 99.6% 286 - 20100504 25 3 25 Yes Ï66 99.6% 284 20100504 25 6 25 Yes Ï63 100.0% 289 1.44% 20100504 25 Ï2 25 Yes Ï52 101.2% 289 0.44% 20100503 20 Ö - Yes 44)9 99.6% 283 - 20100503 20 L5 25 Yes Ï8Ö 98.2% 28l - 20100503 20 3 25 Yes 3^65 98.4% 283 0.7% 20100503 20 6 25 Yes Ï57 99.0% 288 1.5% 20100503 20 Ï2 25 Yes 3^42 98.9% 285 0.54% 5 Conclusion

From the experimental results given in Table 2, it is concluded that aseptically filling of sterilized microbiologically-closed medication cassettes according to the method of the present invention results in medication cassettes comprising medication solution with a microbiological and chemical shelf-life of at least 12 months at 25°C.

10

FIGURE LEGEND

Microbiologically-closed fluid delivery cassette comprising a housing (1) having a transfer opening (2), a reservoir (3) located within the housing, the reservoir comprising a flexible bag (4) having a delivery opening (5), a delivery conduit (6) 15 comprising a first (7) and a second end (8), wherein the first end is coupled to said delivery opening of the flexible bag, said delivery conduit protruding through the transfer opening of the housing, a connector (9) that connects the second end of the delivery conduit to a sterilizing filter (10), and a sterilizing filter (10).

Claims

Microbiologically sealed cassette for administering liquid, which comprises: • a housing (1) which has a transport opening (2); 5. a reservoir (3) positioned within the housing, which reservoir comprises a flexible bag (4) with a passage opening (5); • a feed-through hose (6) which comprises a first (7) and a second end (8), wherein the first end is coupled to said feed-through opening of the flexible bag, said feed-through hose protruding through the feed opening 10 from the housing; • a connecting piece (9) which connects the second end of the transport hose to a sterilizing filter (10); and a sterilizing filter (10), in which at least the inner part of the microbiologically sealed cassette 15 is sterile.

A microbiologically sealed fluid delivery cassette according to claim 1, wherein the connector includes a valve that closes automatically when the sterilizing filter is removed. 20

A microbiologically sealed fluid delivery cassette according to claim 1 or 2, wherein the sterilizing filter has a pore size of 0.22 µm or less.

4. Method for sterilizing and aseptically filling with a sterile liquid one or more microbiologically closed cassettes for administering liquid, wherein a microbiologically closed cassette for administering liquid comprises: • a housing (1) which has a transport opening (2) ; 30. a reservoir (3) positioned within the housing, which reservoir comprises a flexible bag (4) with a passage opening (5); • a feed-through hose (6) comprising a first (7) and a second end (8), wherein the first end is coupled to said feed-through opening of the flexible bag, said feed-through hose protruding from the housing through the feed opening; • a connecting piece (9) which connects the second end of the transport hose to a sterilizing filter (10); and a sterilizing filter (10), the method comprising: a) providing one or more of said microbiologically sealed cassettes for administering liquid; b) sterilizing one or more microbiologically sealed cassettes for administering liquid with a sterilizing agent selected from the group consisting of steam, ethylene oxide, a dose of gamma radiation, electron beam radiation, x-ray radiation, or a combination thereof, preferably ionizing radiation , more preferably gamma radiation; and c) introducing the sterile fluid into the reservoir via the sterilizing filter.

5. Method as claimed in claim 4, wherein one or more microbiologically sealed cassettes for administering liquid before step b) are packaged in a first microbiologically impermeable bag and wherein the first microbiologically impermeable bag is removed before step c).

6. Method as claimed in claim 5, wherein one or more of the microbiologically impermeable bags comprising one or more microbiologically sealed cassettes for administering liquid are packaged in a second microbiologically impermeable bag prior to sterilization and wherein the first and second microbiologically impermeable bags be removed before step c).

7. Method according to claim 5 or 6, wherein a self-adhesive label, which changes color during sterilization, is applied to the microbiologically impermeable bag.

The method of claim 4, wherein the reservoir is evacuated via the sterilizing filter prior to step c).

The method of any one of claims 5-7, wherein the first and / or second microbiologically impermeable bag are made from high density polyethylene or medical grade paper. 5

Method according to claim 4, wherein the microbiologically sealed cassette for administering liquid is sterilized with a radiation dose between 10 and 50 kGy, preferably with a radiation dose between 20 and 45 kGy.

The method of claim 4, wherein the sterile fluid is selected from the group consisting of pharmaceutical drug formulations, which preferably comprise an analgesic or an antibiotic, and saline.

12. Method as claimed in claim 4, wherein after step c) the integrity of the sterilizing filter is tested by means of a Bubble point test.

The method of any one of claims 4-12, wherein the connector includes a valve that closes automatically when the sterilizing filter is removed.

The method of any one of claims 4-13, wherein the sterilizing filter has a pore size of 0.22 µm or less.

Aseptically filled microbiologically sealed cassette for administering liquid obtained by the method according to one of claims 4-14. 25