WO2026008541A1

WO2026008541A1 - Filling lance device, container system and methods for contamination-free filling of a container with a substance and concepts of handling and drying, specifically lyophilization of the substance

Info

Publication number: WO2026008541A1
Application number: PCT/EP2025/068478
Authority: WO
Inventors: Ruediger Bauer; Sebstian BRANDL; Florian EYBEL; Stefan FAUL; Simon LEX; Tu Hoang NGUYEN; Maria MESSMER; Karin MOSER-WEICHART; Alvir MUJCINOVIC; Dirk SCHEFFAUER
Original assignee: Roche Diagnostics GmbH
Current assignee: Roche Diagnostics GmbH
Priority date: 2024-07-03
Filing date: 2025-06-30
Publication date: 2026-01-08
Anticipated expiration: 2027-01-03

Abstract

A filling lance device (40) configured for contamination-free filling of a container (20) with a substance (1), the filling lance device (40) comprising: a tubular filling lance (41) and a lance housing (46) enclosing at least partially the tubular filling lance (41), wherein the tubular filling lance (41) and the lance housing (46) are movably arranged relative to each other between at least one filling configuration (A) and at least one de-contamination configuration (B, C, D), wherein the lance housing (46) comprises a channel system (48) being fluidically connectable to an external suction pump (7) and wherein the at least one de-contamination configuration (B, C, D) corresponds to a configuration in which the channel system (48) is in fluidic connection with the tubular filling lance (41).

Description

Filling lance device, container system and methods for contamination-free filling of a container with a substance and concepts of handling and drying, specifically lyophilization of the substance

Field of the Invention

The present invention relates to a filling lance device, a container system comprising the filling lance device and methods for contamination-free filling of a container with a substance as well as concepts of handling and drying, specifically lyophilization and/or vacuum distillation and/or collapse drying of the substance in the field of chemical, biochemical and/or pharmaceutical engineering, specifically in production, processing and handling of chemicals, biochemical substances and/or pharmaceuticals. Further, the present disclosure relates to a container for monitoring a temperature of a substance therein and method of drying the substance in the field of chemical, biochemical and/or pharmaceutical engineering, specifically in production, processing and handling of chemicals, biochemical substances and/or pharmaceuticals.

Background of the Invention

Production, processing and/or handling of harmful, toxic, instable and/or sensitive substances typically requires work areas in which workers are shielded and/or protected from the contamination with such substances and/or in some cases, the substances need to be protected from external influences such as contamination, oxidation, exposure to light, air, room temperature or the like. Such work areas may for example comprise glove boxes, in which the barrier for protecting workers and/or the barrier against surroundings, the temperature, the atmosphere, i.e. the pressure and/or gas environment, and/or the light exposure can be well defined. Such work environments are however difficult and expensive in realization and working in such an environment can be cumbersome.

Typically, during and/or after production of a substance, the substance needs to be handled and/or processed which may comprise filling and/transferring the substance in a container, preparing the substance for storage, such as drying, lyophilization, collapse drying and/or vacuum distillation and/or re-solubilization of the substance and taking out at least a portion of the substance from a container.

Different concepts for filling containers and/or bags are already available. For example, a port fixed in a membrane of a container may serve to fill liquids into the container via a hose, wherein the container may be a container for drying specifically lyophilization of the substance. There is however no concept of how to ensure a contamination-free transferral of a liquid into a container, specifically from the outer side of the container when removing the hose via which the liquid is filled into the container. Concepts including drip- free filling and self-closing coupling systems are available however cannot completely exclude contaminations when transferring liquids. In all cases, it appears that surfaces, which are exposed to the substance and/or the liquid, cannot be cleaned and/or de-contaminated in a targeted and reproducible manner and/or without exposure to the environment and/or surroundings.

Further, concepts are still required to not only fill but also extract and/or take out the substance from the container in a contamination-free manner, i.e. unloading the container at least partially by taking out at least a portion of the substance contained therein. Moreover, concepts are still required to dry the substance inside the container in a controlled and contamination-free manner.

A specific example in the field of biochemical and/or biological engineering is provided to demonstrate the situation, as follows. Substances, such as dusts which contain certain enzymes are classified as hazardous to health. The open handling of enzyme -containing lyophilisates (lyophilisates equals lyophilized susbtances) and/or dried substances is therefore typically not permitted in order to dry enzyme suspensions. Protection and safety devices currently make the harvesting of the lyophilisate possible but are still cumbersome to handle. Presently, three different concepts are used to provide a high degree of safety in the work area:

The first known concept relates to providing a closed/isolated working area, equipped with air condition and exhaust purification and a lock concept for personal and material on the harvest side, which is completely cleanable and thus de-contaminable. The production worker in the room is therefore adequately protected by personal protective equipment (PPE). After the open harvest of the product and portioning and transfer of the product into the container, which may be considered a storage container, all surfaces in the room are cleaned using a spray gun. The production worker and/or material can then exit the room without contaminating the outer environment.

The second known concept involves the use of isolator technology. The production worker is therefore spatially separated and can only intervene in the harvesting process at defined positions via rubber gloves, for example using glove boxes, depending on the degree of automation.

The third known concept relates to providing a closed containment such as GORE ©LYOGUARD® Freeze-Drying Trays. The GORE ®LYOGUARD® Freeze-Drying Trays is provided with a membrane surface that is permeable for vapour/steam but impermeable for liquids and solids. Therefore, the GORE ®LYOGUARD® Freeze-Drying Trays can be handled with less PPE compared to an open harvest as mentioned in the first concept, in terms of filling and capping for the drying process and the removal of the closed tray from the drying plant.

All described options are expensive and cumbersome to handle critical substances at a high degree of safety concerning contaminations. Furthermore, the third described concept is limited because of the lack of temperature control while drying and lack of guaranteed dripless filling. Therefore, concepts are still missing to isolate a substance during handling and/or processing from the environment replacing complex work areas, such as clean rooms and/or glove box-like workbenches.

Summary of the Invention

It is therefore desirable to provide simple and safe concepts and means for contamination-free handling of critical substances to protect workers from contamination when handling such substances. Specifically, it is desirable to provide methods and/or filling instruments and/or tools and/or systems comprising such filling instruments to fill a container with a substance in a contamination-free manner. Further, it may be desirable to provide methods and/or systems for extracting and/or taking out the substance from the container. Moreover, it may be desirable to provide methods and/or systems to dry the substance inside the container in a controlled and contamination-free manner.

Moreover, it is also desirable to provide methods and/or filling instruments and/or tools and/or systems for contamination-free monitoring of substances inside a container, specifically regarding the temperature of the substance. Further, it is desirable to reduce waste and/or cleaning procedures.

At least one of these objects is overcome by the subject matter of the independent claims. Further embodiments with optional features are subjected to the dependent claims. The invention to aspects and related embodiments thereof are described as follows, in more detail.

According to an aspect, a filling lance device is configured for contamination-free filling of a container with a substance and comprises: a tubular filling lance and a lance housing enclosing at least partially the tubular filling lance, wherein the tubular filling lance and the lance housing are movably arranged relative to each other between at least one filling configuration and at least one de -contamination configuration, wherein the lance housing comprises a channel system being fluidically connectable to an external suction pump and wherein the at least one de-contamination configuration corresponds to a configuration in which the channel system is in fluidic connection with the tubular filling lance or at least a portion of the tubular filling lance which is to be de -contaminated.

The filling lance device may provide a simple and safe instrument for contamination-free handling and transferal of critical substances into a container to protect workers from contamination when handling such substances. The filling lance device may be at least a part of a concept that helps replacing the known concepts, which are based on extensive de-contamination and cleaning procedures and/or expensive and complex isolating technologies.

Unlike open tray systems, the filling lance device and/or a container system comprising the filling lance device allows for a drip- and dust-free process. Further, the processes such as filling and/or drying (such as lyophilisation, vacuum distillation and/or collapse drying and/or other forms of drying) can be performed in a much more time -efficient manner as cleaning steps and/or cumbersome handling using complicated lab systems, such as glove boxes can be avoided. Moreover, the invention provides a more cost efficient solution for contamination-free handling and transferal of critical substances into a container to protect workers from contamination when handling such substances. Dust retention capacities of less than 60 ng/m³ may be achieved in some cases. When containments fulfil dust retention capacities of less than 60 ng/m³, neither PPEs nor isolators may become required during the product unloading process.

“Contamination-free filling” as described herein may help protecting workers who manage a filling process, a processing, a handling and/or a shipping of a substance from contamination with the substance that may be harmful and that is to be filled in the container, stored and/or shipped. In this entire disclosure, the term “contamination-free” may refer in the context of the filling process to a state and/or condition in which a person, a space and/or an environment around a substance is substantially, quasi or completely free from any unwanted leakage and/or escape of the substance. In this entire disclosure, the term “contamination-free” may in some cases also refer to a state and/or condition where something, such as the substance itself, a product, environment, and/or process, is substantially, quasi or completely free from any unwanted and/or harmful substances, particles, and/or microorganisms. In various industries, including healthcare, manufacturing, and research, maintaining a contamination-free environment is crucial to ensure the safety, quality, and reliability of products and processes. This involves implementing strict protocols, such as proper cleaning, sterilization, and handling procedures, to prevent the introduction and/or spread of contaminants. In this entire disclosure, the term “contamination-free” may specifically refer to a process that is quasi-dust-free, i.e. contaminations are reduced and/or held under 60ng/m³. Therefore, in some cases the term “contamination-free” may be considered “quasi-contamination- firee”.

A substance (also denoted “product” in some cases) may correspond to a solubilized substance in some cases or a dried substance in other cases. The substance may for example be in a solubilized form when being transferred and/or filled into the container. The substance may adopt a dried form, specifically the substance may be dried, e.g. lyophilized and/or vacuum distilled inside the container. The substance may be stored and/or shipped in a dried form. The substance may be re-solubilized when needed and when taken out of the container. The substance may comprise at least one of: a chemical, a pharmaceutical, a biochemical substance, a polymer, a biopolymer, a hormone, a protein, a peptide, specifically an enzyme and/or a co-enzyme, a lipid, a monoclonal antibody, a polyclonal antibody, ADI (active diagnostic ingredient), API (active pharmaceutical ingredient).

In this entire disclosure, the term “solubilized” and/or “re-solubilized” may refer to a process of substantially dissolving the substance and/or making it soluble in a liquid, often in water and/or other solvents. When a substance is solubilized, it means that it has been effectively dispersed and/or dissolved into the liquid to substantially form a homogeneous mixture. This process often involves using solubilizing agents and/or techniques to enhance the solubility of a substance that may be inherently insoluble or poorly soluble in the chosen solvent. Solubilization is commonly used in various applications, such as pharmaceutical formulations, chemical reactions, and analytical techniques, to ensure that substances are fully dissolved and evenly distributed in the liquid medium.

In this entire disclosure, the term “drying” may comprise different concepts of drying the substance comprising for example one of: lyopilization, vacuum distillation, collapse drying, drying by exposure to a gas (e.g. air, a stream of argon and/or the like), elevating the temperature, decreasing the pressure.

In this entire disclosure, the term “lyophilization” may be considered as freeze-drying and/or sublimation and may refer to a process used to remove water and/or other solvent from a substance and/or a product while preserving its structure and integrity. It is commonly used in the pharmaceutical, biotechnology, and food industries for the preservation of sensitive substances. The lyophilization process may comprise the steps: freezing, primary drying, and specifically secondary drying. First, the substance may be frozen to a very low temperature, typically below its eutectic point, to solidify the water and/or solvent within it. Then, in the primary drying phase, the pressure may be reduced, and heat may be applied to cause sublimation (may refer to the exposure to the room temperature), where the frozen water and/or solvent directly converts from a solid to a vapor without passing through a liquid phase. Optionally, in the secondary drying phase, the residual moisture may be removed by raising the temperature slightly to desorb any remaining water and/or solvent molecules. Lyophilization is advantageous for preserving heat-sensitive substances, such as proteins, enzymes, and pharmaceutical drugs, as it allows for long-term stability and easy reconstitution. The resulting lyophilized substance and/or product is typically in a dry, solid state, which can be stored at room temperature and re-hydrated and/or re -solubilized when needed by adding a suitable solvent.

In this entire disclosure, the term “collapse drying” may be considered a special type of distillation and lyophilization. During the collapse drying, a part of the frozen material melts and evaporates instead of sublimation. The collapse drying temperature is typically over the eutectic temperature of the solution.

In this entire disclosure, the term “vacuum distillation” may be considered a type of distillation process that is carried out under reduced pressure, typically below atmospheric pressure. It is used to separate and purify components and/or substances with high boiling points and/or those that are thermally sensitive. By lowering the pressure, the boiling point of the components can be reduced, allowing for distillation at lower temperatures. This is beneficial for substances that may decompose and/or react at higher temperatures. Vacuum distillation is typically used in industries such as petroleum refining, chemical production, and pharmaceutical manufacturing. It enables the separation of different components based on their boiling points, resulting in the purification and isolation of desired substances.

Besides lyophilization and/or other drying techniques, also vacuum distillation in a tray and/or bag is also conceivable as a form of drying the substance, i.e. not only water removal from the aggregate state solid to gaseous (sublimation) but also from liquid to gaseous with e.g. reduced phase transition temperature by using vacuum.

In this entire disclosure, the term “fluidically connecting” and/or “fluidically connected/connectable” may correspond to a process of establishing a connection and/or pathway for the flow of fluids between different components, volumes and/or systems. It may comprise linking various fluidic channels, chambers, volumes, tubes, and/or conduits to enable the transfer of liquids, gases and/or solid state substances such as powders and/or granules from one point to another. Fluidic connections are commonly used in a wide range of applications, including laboratory equipment, medical devices, industrial processes, and fluid handling systems. These connections may ensure the efficient and controlled movement of fluids, allowing for accurate measurements, analysis, and/or delivery of substances. There are different methods and components used for establishing fluidic connections, specifically being based on fittings, connectors, valves, tubing and/or removal of blockages, barriers and/or closings. Establishing fluidic connections may specifically help creating a secure and leak-free connection, ensuring the fluid flows smoothly without any interruption and/or contamination. In other words, a fluidic connection may be considered a connection between two positions through which a fluid can be exchanged. For example, an open pipe, a tunnel, a channel, and a tube may be considered a fluidic connection, which allows to exchange a fluid, such as a liquid, a gas, a granule and/or other fluid substance to be exchanged between an entrance opening and an exit opening.

The tubular filling lance may be understood as having a tube-like shape that has a round cross section in a specific case. It may however also correspond to a quasi-tubular shape, having for example an oval cross section or even a polygonal cross section. In this entire disclosure, the term “tubular shape” may refer in some cases to a form and/or structure that resembles a tube and/or cylinder. It may be characterized by having a hollow, elongated structure along the filling lance axis with a consistent and/or slightly varying diameter throughout its length. Tubular shapes may be found in various objects including pipes, hoses, tunnels, straws and/or the like. These shapes are often chosen fortheir strength, efficiency in carrying fluids and/or gases, and versatility in various applications. Tubular shapes may be utilized as tubing and/or pipes for fluid transportation. In this entire disclosure, the term "tubular" simply describes the general shape of an object and/or structure, emphasizing its hollow nature, specifically (but not strictly necessary) being cylindrical.

In this entire disclosure, the term “housing” as used in “lance housing” may refer to a protective and/or enclosing structure that may contain, at least partially enclose and/or support components such as the tubular filling lance. It may provide a physical barrier and may serve as a framework and/or casing at least partially enclose and/or support and/or protect the inner components from external elements, damage, and/or interference . The housing may be designed to provide structural integrity, to ensure proper alignment and/or positioning of internal components such as the tubular filling lance.

In this entire disclosure, the term “single-use” may refer to a product, a component and/or an item that is designed to be used only once and/or for a certain limited number of uses and/or for one preparation of a batch and is then discarded. It is intended and/or configured for one single application and/or a limited number of applications, and once it has served its purpose, it is not meant to be reused for another application and/or another preparation of a substance batch. In general, the concept of single-use is often employed in industries such as healthcare, biotechnology, and pharmaceuticals, specifically where the risk of contamination and/or infection is high and/or must be avoided and/or where a clearing procedure is cumbersome, expensive, inefficient and/or less safe than the disposal. Therefore, single-use items may typically refer to sterile and/or disposable elements, which helps minimize the risk of contamination and cross-infection. They offer convenience, efficiency, and/or cost savings by eliminating the need for cleaning, sterilization, and maintenance associated with re-usable items. Such single-use items, as for example a filling lance may be used once to ensure safety and/or hygiene standards. Single-use may specifically refer to using a material/element(s) such as the filling lance, the container, a hose material and/or fittings for the preparation of one product/substance batch, i.e. any number of containers may for example be filled with the same single-use filling lance within the batch (the filling lance may therefore be used more than once, i.e. several times within the same production batch). The single-use material/element(s) may therefore only be disposed once the entire batch has been filled. In this case, the term single-use may refer to “product-only use” of the disposable material/element(s).

The tubular filling lance and the lance housing are movably arranged relative to each other between at least one filling configuration and at least one de -contamination configuration which may in some cases correspond to the tubular filling lance being configured to slide inside the lance housing between at least one filling configuration and at least one de -contamination configuration.

The at least one filling configuration may in some cases correspond to a configuration in which the lower end of the tubular filling lance (on the side of dispense of the substance) substantially exceeds the lance housing, i.e. the tubular filling lance sticks out and/or reaches out of lance housing on the lower side and, in a case when a container is coupled, the tubular filling lance reaches into the inner volume of the container. The at least one filling configuration may in some cases correspond to a configuration in which the upper end of the tubular filling lance (on the side of introduction of the substance) substantially exceeds the lance housing, i.e. the tubular filling lance sticks out and/or reaches out of lance housing on the top side.

In the at least one de-contamination configuration, the lower end of the tubular filling lance (on the side of dispense of the substance) may substantially be covered by the lance housing. Then, in some cases, at least one channel system opening of the lance housing may align with at least one opening of the tubular filling lance. The at least one de-contamination configuration may in some cases correspond to a configuration in which the upper end of the tubular filling lance (on the side of introduction of the substance) substantially exceeds the lance housing, i.e. the tubular filling lance sticks out and/or reaches out of lance housing on the top side.

A “channel system” may in some cases refer to an arrangement and/or design of a pathway or pathways through which fluids (liquids or gases) flow in a controlled manner within a mechanical system. Typically, a channel system comprises a channel that directs a fluid along a pathway with more than one direction, i.e. along a pathway with two or more path axes. In other words, a channel system may specifically comprise at least one bend and/or change in flow direction. A channel system may in some cases be considered an organized network designed to facilitate the controlled movement of materials, fluids, forces, or information from one point to another.

An opening by itself may generally not be considered a channel system. While an opening can be a part of a channel system, a channel system may often encompass more than just a single or simple aperture. An opening may typically be considered simply a hole or gap in a structure that allows passage of a fluid through in one single direction, i.e. along one single path axis. An opening does typically not guide a fluid along a path that includes more than one directions and/or axes. It does also typically not inherently describe the structured, organized flow or direction of materials, fluids, forces, or information. An opening can be part of a channel system, specifically may define an end of a channel system that fluidically connects the channel system with another entity towards the opening is directed to, but typically lacks the organization and interconnected components that may define a channel system. Therefore, an opening can be part of a channel system, but it alone does not constitute a channel system without the additional structured framework and components that direct and control the flow within the system. While the formation of an opening may simply require drilling a hole, the formation of a channel system requires a more sophisticated production technique. For example, a channel system may require to be formed by 3D printing and/or injection molding. The channel system may be formed by 3D printing of a material that at least partially surrounds and/or encloses the channel system. Alternatively, or in addition, injection molding using a (complex) cast that defines the negative of the channel system and the material that at least partially surrounds and/or encloses the channel system may be applied to realize the (complex) channel system.

The channel system may comprise at least two channel system openings directed towards an inner side of the lance housing. The channel system may comprise two, three, four, five six, seven, eight, nine, ten or more channel system openings, for example 100 or more. The channel system may comprise exactly two channel system openings. The channel system may be configured to establish the fluid connection between the external suction pump and at least an inner portion of the volume enclosed by the lance housing.

The filling lance device may vary in length depending on the configuration. The filling lance device may have a length measured along the filling lance axis of about 50-700mm, specifically of about 100-300 mm and more specifically of about 162 mm. The filling lance device, specifically the housing and/or the tubular filling lance may have an inner diameter in cross section measured perpendicular to the filling lance axis of about 2-50 mm, specifically of about 5-30 mm and more specifically of about 19 mm and/or an outer diameter in cross section measured perpendicular to the filling lance axis of about 2-50 mm, specifically of about 5-30 mm and more specifically of about 19 mm. The wall thickness of the housing and/or the tubular filling lance may range between about 0,5-5 mm, specifically between about 1-3 mm.

There are three (opposing) effects to consider when choosing the diameter of the filling lance:

1) It is desired to keep flow velocities during the filling as low as possible in order to fill the product/substance as gently as possible and/or with reduced and/or without the generation of shear forces. To this end, a large cross-section of the hose diameter and the filling lance is desirable for low enough flow speeds.

2) It is desired to fill the bags and/or containers in a short time in order to keep filling and/or commissioning times for a production batch as short as possible. However, also in this case, product stress (working at room temperature) should be reduced by fast processing. To this end, a large cross-section of the hose diameter and the fdling lance is desirable for high enough flow speeds. For example, one bag may be fdled in one minute.

3) If a membrane is provided for lyophilization, it is desired to provide a large membrane surface of the containers, as it represents a barrier (resistance) for the evaporated water during lyophilization, which then leads to an increase in pressure in the container and thus to an increase in the evaporation temperature. To this end, a small flange and a small lance diameter is desirable.

To account for all three effects, an opening diameter of the housing and/or the tubular fdling lance of about about 5-30 mm and more specifically of about 19 mm may be considered a good compromise.

The filling lance device, specifically the housing and/or the tubular filling lance may comprise at least one of the following materials depending on the desired properties such as durability, weight, and heat resistance: a polymer, a thermoplast, a duroplast, a metal, a composite material.

The tubular filling lance and the lance housing may be movably arranged relative to each other along a filling lance axis, specifically the filling lance device may comprise at least one of: a sliding bush positioned between the tubular filling lance and the lance housing and being configured to restrict and/or prevent relative movements between the tubular filling lance and the lance housing which are not directed along the filling lance axis; a stopper mechanism being configured to restrict a relative movement between the tubular filling lance and the lance housing along the filling lance axis; a rotation blocking mechanism configured to restrict and/or prevent a relative rotational movement between the tubular filling lance and the lance housing.

The sliding bush may be considered as a bushing and/or plain bearing, and may have the function of reducing friction between two moving parts, i.e. between the tubular filling lance and the lance housing. It may comprise a cylindrical sleeve with an inner diameter that fits over the tubular filling lance and an outer diameter that fits into the lance housing. The sliding bush allows for smooth and controlled movement of the tubular filling lance within the lance housing by providing constraint surface, specifically a low-friction surface. It is typically used in various mechanical systems and applications where guided linear movements with or without rotation is required. The sliding bush may be affixed, attached and/or coupled to at least a portion of the inner surface of the lance housing.

The tubular filling lance and the lance housing may, with or without sliding bush, be movably arranged relative to each other along the filling lance axis such that a sliding movement of the tubular filling lance with respect to the housing can be performed. The filling lance axis may correspond to the longitudinal axis, also known as the length axis and/or the roll axis of the tubular filling lance and/or the lance housing and/or the filling lance device. The filling lance axis may be considered an imaginary line that runs lengthwise through the tubular filling lance and/or the lance housing and/or the filling lance device, preferably through all three elements. It is a reference line used to describe the rotation or movement of the objects or the entire system. Restricting and/or preventing relative movements between the tubular filling lance and the lance housing which are not directed along the filling lance axis may correspond to movements between the tubular filling lance and the lance housing which are perpendicular to the filling lance axis and/or have perpendicular components.

The stopper mechanism being configured to restrict a relative movement between the tubular filling lance and the lance housing along the filling lance axis may for example correspond to a mechanical element on the inner side of the lance housing that restricts the relative movement between the tubular filling lance and the lance housing such that it stops the tubular filling lance from further translation along the filling lance axis. It may correspond to a nose, a protrusion and/or a ring-like structure or the like that is smaller in diameter than the tubular filling lance. Generally, a stopper mechanism may be considered a device and/or mechanism used to prevent an unintended movement and/or displacement of an object and/or component. It may be designed to securely hold and/or lock the object, specifically the tubular filling lance, in place, providing stability and preventing unwanted motion. A specific form of a stopper mechanism may be a rotation blocking mechanism, which is configured to restrict and/or prevent a relative rotational movement between the tubular filling lance and the lance housing. It may consist of and/or comprise an elongated recess and a nose that is guided along the elongated recess. The elongated recess may be provided on an inner surface of the lance housing and the nose may be provided on an outer surface of the tubular filling lance or vice versa. The stopper mechanism and/or the rotation blocking mechanism may be constituted of one element on the tubular filling lance and/or the lance housing and/or the stopper mechanism and/or the rotation blocking mechanism may be constituted by at least one component and/or element on the lance housing and at least one component and/or element on the tubular filling lance.

In general, the tubular filling lance comprises at least two openings, namely an introduction opening of the tubular filling lance for introducing the substance into the tubular filling lance and a dispense opening of the tubular filling lance for dispensing, guiding and/or releasing the substance specifically into the container when the container is coupled with the filling lance device. In some cases, the introduction opening and the dispense opening are substantially directed to and/or aligned with/along the filling lance axis. In other cases, at least one of the introduction opening and the dispense opening, specifically the dispense opening is facing away from the filling lance axis, i.e. facing to the side of the tubular filling lance.

In other words, the dispense opening (may be considered an exit opening) of the tubular filling lance may define a dispense axis that deviates from the filling lance axis.

In other words, the dispense axis and the filling lance axis encloses an angle that is smaller than 180°. In that case, the substance is not dispensed along the filling lance axis but substantially along the dispense axis, i.e. to at least one side of the tubular filling lance. This helps controlling the outflow of the substance and prevents splashing. This also allows to easily and/or effectively de -contaminate the inside of the tubular filling lance via the channel system in the lance housing. In some cases, the tubular filling lance may comprise multiple (i.e. at least two) dispense openings, specifically each defining its own dispense axis which may each enclose a non-zero angle with the filling lance axis, i.e. leading the substance away from the filling lance axis towards a side of the tubular filling lance when dispensing the substance. This may lead to an improved distribution of the substance when dispensing. In general, one or more dispense openings may in all cases line up with an opening of the channel system in the housing, such that a fluidic connection can be established with the external suction pump for de -contaminating the inside of the tubular filling lance. In some cases, there is one opening of the channel system in the housing provided for each dispense opening, i.e. one channel system opening for one dispense opening, two channel system openings for two dispense openings, three channel system openings for three dispense openings, or more.

In some cases, the introduction opening may also face away from the filling lance axis such that the substance is introduced from a side of the tubular filling lance. Further, tubular filling lance may comprise several, i.e. two or more introduction openings.

A angle enclosed by the dispense axis and the filling lance axis may be considered an angle that is smaller than 180°, specifically smaller than 175° and more specifically larger than 170°. In the respective case, the dispense axis deviates from the filling lance axis by more than 0°, specifically by more than 5° and more specifically by more than 10°.

The dispense opening (also denoted “exit opening”) or at least one of several dispense openings of the tubular filling lance may have a diameter in cross section measured perpendicular to the dispense axis of about 1-50 mm, specifically of about 5-30 mm and more specifically of about 16 mm and may vary in dependence of the number of dispense openings, the volume flow and the inner diameter of the port. The introduction opening or at least one introduction opening of the tubular filling lance may have an inner diameter in cross section measured perpendicular to the dispense axis of about 2-55 mm, specifically of about 10-30 mm and more specifically of about 19mm.

The at least one de-contamination configuration may comprise at least one of: a lance volume decontamination configuration in which the channel system is in fluidic connection with a tube volume that is at least partially enclosed by the tubular filling lance, specifically via the dispense opening; a direct outer surface de-contamination configuration, in which the channel system is in a direct fluidic connection with an outer surface of the tubular filling lance; an indirect outer surface de-contamination configuration, for which the tubular filling lance comprises a passage, specifically a (micro)fluidic passage system, that is configured to fluidically connect the outer surface of the tubular filling lance, specifically an outer surface of an end portion of the tubular filling lance, with the channel system in the indirect outer surface decontamination configuration.

The lance volume de-contamination configuration may specifically correspond to a configuration in which at least one channel system opening of the lance housing aligns with at least one opening, specifically at least one dispense opening of the tubular filling lance. In a specific case, exactly one channel system opening aligns with exactly one dispense opening.

The direct outer surface de -contamination configuration, in which the channel system is in a direct fluidic connection with an outer surface of the tubular filling lance may be considered a configuration in which a channel system opening is brought close to and/or in contact with an outer surface of the tubular filling lance such that the suction force can de -contaminate a specific area and/or portion of the outer surface of the tubular filling lance, such as a lower tip of the tubular filling lance. It is considered direct as typically there is no element such as a channel, a tube or the like between the channel system opening and the specific area and/or portion of the outer surface of the tubular filling lance that is to be de -contaminated.

On the contrary, an indirect outer surface de -contamination configuration may refer to a configuration in which a specific area and/or portion of the outer surface and/or a portion inside of the tubular filling lance is de -contaminated via a passage inside the tubular filling lance. Therefore, the tubular filling lance comprises a passage that fluidically connects an outer surface of the tubular filling lance with a passage opening of the passage that can align with the channel system opening. The tubular filling lance may comprise a passage system, specifically a microfluidic and/or capillary passage system that fluidically connects one or more positions on the outer surface of the tubular filling lance with one or more passage openings of the passage that can align with one or more channel system openings. The passage and/or passage system may therefore comprise a droplet collection opening, specifically a capillary droplet collection opening, that may be positioned on a lower end, i.e. an end near the dispense opening being substantially opposite the introduction opening, for collecting droplets of the substance which reside the lower portion of the outer surface. The droplets may be passively collected by capillary forces of the capillary passage system via the capillary droplet collection opening. When the at least one passage opening of the passage system aligns with at least one channel system opening, the suction force of the external pump may effectively de -contaminate the outer surface around the capillary droplet collection opening and the capillary passage system.

The fdling lance device may further comprise a lance coupling portion positioned on the lance housing and configured to couple the filling lance device to the container.

A coupling portion may refer to a section and/or a component of and/or on the lance housing designed to connect and/or join the lance housing with the container. It may serve to facilitate the transfer of substances via the filling lance device into the container. The lance coupling portion may comprise a ring-like section that fits in or over a filling flange on an opening of a container. The lance coupling portion may be one single piece with the lance housing or may be a separate piece being coupled, affixed and/or attached to the lance housing. The lance coupling portion may be specifically designed and/or dimensioned to match the dimensions and/or shape of a flange of the container. The lance coupling portion and the flange may be standardized such that a specific type of filling lance device matches a specific type of containers. In an embodiment, the overall filling system, i.e. the filling lance device may comprise two single-use parts, the product tube and the filling lance system comprising the tubular filling lance and the lance housing. Three positions of the tubular filling lance may in some embodiments be realized: filling, de-contamination and initial or transition state. Main parts are the lance housing with connection to the suction system/pump and the inner filling lance, i.e. the tubular filling lance. The inner moveable tubular filling lance may be guided vertically through a both-sided groove and may be featured with a single-use tri-clamp fitting towards a single-use product tube at the upper side and a filling opening on the side that reaches into the container. Its movement length in z-direction may be limited by an upper and lower stop and the groove may prevent rotation of the inner tubular filling lance and thus incorrect filling. The lance housing may face an inner web on top of the container integrated flange. Depending on the location of the filling port and regarding splashing through the effluent flow, the direction of the filling opening could be important. Additionally, for an improved capture of product/substance in the filling lance opening, it may face the side of the fitting towards the suction.

The filling flange may comprise closure flaps that are configured to break a fluidic connection between the container inside and another entity or the outside. In other words, the closure flaps of the filling flange are configured to close the container at the filling opening in a closed configuration and open the fill opening in an open configuration, preferably as a response to a pushing force. When reaching through the closure flaps for example with the tubular filling lance, the closure flaps open the filling opening in an opened configuration. The opened configuration may be achieved by reaching through the filling flange using a force to push an element through. The closed configuration may be achieved by retracting the element from the filling flange. The mechanism of transitioning from an opened configuration/state into a closed configuration/state may rely on a spring return force of a spring that is coupled to each one of the flaps. Such flaps have the effect that the inner volume of the container is only opened and/or exposed via the filling opening in the moment when the tubular filling lance and/or another element is pushed through the filling flange and the flaps open as a response. In all other cases, the flaps remain in the closed configuration and exposure of the inner volume of the container to the outside is avoided and/or stopped. Therefore, opening and/or exposure times and hence contamination from the outside to the inside of the container or vice versa can be reduced to a minimum.

To avoid and overcome cleaning steps and a quality control of the cleaning results, one or more elements/components which are potentially contaminated with the product/substance (i.e. tray, filling lance, tube material, filter, container) may therefore be realized as disposable equipment elements.

According to another aspect, a container system is configured for contamination-free filling of a container with a substance and comprises: the filling lance device as described herein according to any possible variant and/or embodiment; and the container with a container fill opening, the container being configured to be filled with the substance via the container fill opening, specifically wherein the container comprises a filling flange on and/or at the fill opening configured to be coupled with the filling lance device, specifically being configured to be coupled with and/or via the lance coupling portion of the filling lance device.

The term “coupling” may comprise a manual coupling, a coupling performed by a mechanical element that may be automatically controlled and/or controlled by a machine and/or a processor and/or a controller. Further, the term “coupling” may comprise at least one of a physical contacting of the filling lance device and the container specifically near the container fill opening, a fixing of the filling lance device to the container specifically near the container fill opening, a supporting of the filling lance device by the container specifically near the container fill opening comprising a lose (non-fixed) support, an attaching of the filling lance device to the container specifically near the container fill opening comprising a lose (non-fixed) attachment, a clamping of the filling lance device to the container specifically near the container fill opening, a screwing of the filling lance device onto the container specifically near the container fill opening.

The coupling may specifically have the nature of being easily and/or destruction-freely de-coupled by a user manually and/or by a machine automatically. The coupling and/or de-coupling may be established only by a user or only by a machine or by both, the user and the machine.

The container system may provide a simple and safe system for contamination-free handling and transferal of critical substances into a container to protect workers from contamination when handling such substances. The container system may be at least a part of a concept that helps replacing the known concepts, which are based on extensive de-contamination and cleaning procedures and/or expensive and complex isolating technologies.

The container may comprise a bag, a single-use bag, a polymer container, an at least partially flexible container, an at least partially non-flexible container. The container may be configured for storage and/or for lyophilization of a substance. A container for lyophilization may be considered a “lyophilization container”, specifically a “lyophilization bag” and/or “lyo-bag”.

It may be possible to provide standardized groups of containers, which have the same ports and/or structures and/or features but having different volumes. For example, in some cases only a small amount of the substance is required and therefore a container having a small volume may contain a small amount of substance compared to a larger container. Often, it is the case that when the substance is re-solubilized and taken out of the container, remaining portions of the substance inside the container are disposed since repeated lyophilization and storage would substantially impact the activity of the substance, for example an enzyme. Therefore, a small container has the advantage of a reduced amount of disposed substance in a case when only a small amount is required. The length and depth of a container may be chosen such that several containers of same or different size may cover a complete shelf area of a lyophilization device. For example: If the dimension of the shelf area of a lyophilization device is in length about 1,2 m and in depth about 2,0 m the related container dimension may be about 0,6 m in length and about 0,5 m in depth. The complete number of containers for a shelf is in this case 4. Also, smaller dimensions like about 0,3 m in length and about 0,25 m in depth can be chosen, so in sum 16 containers per shelf can be placed.

The height of the container can be derived from the vertical distance between two shelfs. If for example the distance between to shelfs in a lyophilization device is about 0,1m, so the height of the frame of the container may be less than about 0,07m. The remaining headspace in lyophilization device is then about 0,03 m and offers sufficient space for the filling port and sufficient headspace for steam while lyophilization.

The container material may be chosen, such that it can be welded with the membrane material, the flange material and/or the temperature grommet material. For example, if the membrane is a composite material, comprising a pp supporting layer and a PTFE surface, the material of the flange, grommet and container may preferably comprise pp.

It is generally preferable, due to regulatory specifications, to provide elements that are free of PTFE. Therefore, the filling lance, the container, the membrane, hoses, pipes, flanges and/or other elements and/or portions are PTFE-free to fulfill such regulatory specifications.

The container may comprise a membrane, specifically a membrane wall, the membrane and/or the membrane wall being permeable for gas and impermeable for liquids and small solid particles, specifically wherein the container comprises a frame for supporting the membrane and/or the membrane wall.

Providing a membrane as a wall and/or a portion of a wall of/on the container allows performing the lyophilization while the solubilized substance is inside the container, since the solvent that is subject to the sublimation can escape via the membrane.

The frame, which serves as a support for the membrane, may prevent the membrane from being damaged due to unwanted folding of the membrane. Further, the frame allows stapling the containers in an efficient manner and provides a support for a preferred shape of the container. Gases, such as air may pass through the membrane which makes it easy to maintain the pressure and the atmosphere inside the container on a level of the outside atmosphere and pressure, which may be important when the suction force of the external suction pump generates an underpressure (and/or suction force) in the system. In that case, the pressure may be equilibrated due to the permeability of the membrane to gases. Therefore, the underpressure may not deform the container, which can maintain its shape.

The membrane may comprise a material that exhibits gas permeability while being impermeable to liquids and small solid particles such as polytetrafluoroethylene (PTFE), acrylic copolymer (AC), polyethylene terephthalate (PET), high density polyethylen(HDPE). PTFE is known for its non-stick properties and is commonly used in applications where gas transfer is desired while preventing liquid penetration.

The container and/or the cap of the flange may comprise a septum configured for removal of at least a portion of the substance from the container and/or addition of an additional substance to the container.

A septum may comprise a piece of rubber and/or silicone used as a closure for a container. It is typically placed over an opening of the container and provides a self-sealing barrier that can be pierced by a needle and/or syringe for the purpose of adding and/or extracting substances from the container. The septum may for example be included in a closure such as a cap that is used to close the container fill opening. Therefore, the cap may comprise a hole over which the septum is spanned. The septum may act as a barrier, preventing contamination or loss of the contents of the container while allowing for easy access . A septum is commonly used in laboratories and pharmaceutical manufacturing to facilitate the addition and/or withdrawal of samples, reagents, or other substances without the need to fully open and/or expose the contents of a container and/or vial. This system not only allows filling the container in a contamination-free manner but having the septum, the system also allows for contamination-free withdrawal of substances from the container.

The septum may comprise at least one of the following materials: a polymer, a rubber, an elastomer.

Alternatively or in addition to a septum, a tube end, specifically a fixed, open tube end positioned at/on an opening of the container and being closed by a tube clip and/or a squeezing valve, may be used having the same and/or a similar function as a septum, namely providing an access for re-solubilisation and/or adding content and/or taking content out of the container and allowing to open and/or close the access when needed. The filling flange and the lance coupling portion may be dimensioned such that the filling flange encloses the lance coupling portion at least partially, and/or the filling flange and the lance coupling portion may be dimensioned such that the lance coupling portion encloses the filling flange at least partially, and/or the filling flange may comprise a protrusion configured for supporting the lance coupling portion when the filling flange is coupled with the lance coupling portion.

This system allows to reliably and/or safely establish a stable fluidic connection between the inside volume of the container and a substance reservoir, since the filling lance device is supported by the filling flange and/or a sealed fluidic connection may be established due to the fitted shapes and the structural support.

The container fill opening and/or the filling flange may be dimensioned to receive a portion of the filling lance device. For example, a portion of the tubular filling lance may be allowed to reach through the container fill opening, therefore the container fill opening and/or the fill flange may be slightly bigger (about 0,1-5 mm) in diameter than the tubular filling lance . The fill flange may for example have a diameter in cross section of about 24,1 mm to 50 mm, specifically of about 24 mm to 42,2 mm. For example, a commercially available screw closure from Thermo Fisher may be chosen as a cap for the fill flange defining its size. The container may comprise: a temperature probe guiding tube coupled (and/or fixedly attached in a sealed manner) to a probe opening of the container (also denoted container probe opening) and at least partially extending into the container and configured for receiving a temperature probe from outside of the container, the temperature probe guiding tube may comprise: a temperature probe introduction opening configured for introducing the temperature probe from outside of the container into the guiding tube and into a position inside the container; a non-thermally conducting guide tube portion for guiding the temperature probe in the temperature probe guiding tube and positioned at least partially inside the container; and a thermally conducting guide tube end portion positioned opposite the temperature probe introduction opening and configured to provide a thermal bridge between the substance inside the container and the temperature probe when the temperature probe is introduced into the temperature probe guiding tube and is in contact with the thermally conducting guide tube end portion and when the substance is inside the container.

This system not only allows filling the container in a contamination-free manner but, having the temperature probe guiding tube, the system also allows for contamination-free temperature surveillance and/or monitoring from outside of the container. Therefore, the container has a probe opening in addition to the filling opening to which the temperature probe guiding tube is coupled in a sealed manner. The coupling may correspond to a heat-sealed, welded and/or fused coupling between the area of the container around the probe opening and a portion of the probe guiding tube. Alternatively, or in addition, the coupling may comprise a coupling mechanism such as a screwing mechanism for example.

The guiding tube may serve as a pathway for the temperature probe to be inserted into the container to measure a temperature at a position inside the medium that is remote from the probe opening, for example in the center and/or in the bottom section of the container. It helps guide the temperature probe to the desired location within the container without opening the container.

Therefore, the guiding tube at least partially extends into the container, i.e. the tube may fully extend into the container such that the guiding tube does not stick out of the container on the upper end or in other cases, the guiding tube partially sticks out of the container. It may even be that the guiding tube is movably coupled to the container, such that the position of the end of the guiding tube can be varied to reach different depths specifically depths inside the container. In that case, the guiding tube is coupled but not fixedly attached to the container specifically via a coupling element such as a rubber element that allows for a sliding movement of the guiding tube with respect to the container and that specifically reduces contaminations, resembling the concept of a septum.

The temperature probe introduction opening may have a diameter in cross section of about 15-70 mm, specifically of about 30 - 60 mm. The guiding tube may have a length of about 1-10 cm, specifically of about 4-8 cm and more specifically of about 5-5,5 cm. The temperature probe may have a length of about 3-150 % of the length of the guiding tube, specifically of about 30-90% of the length of the guiding tube. The thermally conducting guide tube end portion may comprise at least one of the following materials: a metal with high thermal conductivity for example comprising silver and/or 316L steel types. A thermally conducting element between the guide tube end portion and the temperature probe may further improve the thermal conductivity. The thermally conducting element may comprise at least one of the following: a thermopad, a thermopaste.

The non-thermally conducting guide tube portion may comprise at least one of the following materials: a polymer, a plastic, specifically a polymer that is compatible with other portions and/or elements of the container, such as the membrane material.

The container system may further comprise the temperature probe or at least one temperature probe for determining a temperature of the substance inside the container, when the substance is inside the container and contacts the guide tube end portion.

The temperature probe may be dimensioned to be received by the temperature probe guiding tube and/or configured to sense a temperature in the range of about -250° C to +250° C, specifically of about -180° C to +180° C and more specifically of about -80° C to +80° C.

At least one component may be a disposable component, specifically the filling lance device may be a disposable component and/or the container with or without a guiding tube may be a disposable component and/or all product-contaminated surfaces like tubes and filter elements between the vacuum generator and the vacuum suction of the filling lance.

The substance and/or components that are in contact with the substance may be considered toxic and/or special waste after use. Since cleaning may be harmful, expensive and/or difficult, it may therefore be favorable to dispose at least some components, which directly contact the substance as the substance may be harmful, hazardous and/or toxic. In some cases, the system and/or parts, which are in contact with the substance, is/are not opened and not exposed to the environment but disposed as an entire entity in a safe and/or professional manner. The disposable components may comprise cheap materials, biodegradable and/or eco-friendly materials.

The container system may further comprise: a lance holding device for holding the filling lance device in a fill position with respect to the container, specifically the lance holding device may be configured for multiple use; and/or an actuator configured to automatically establish the at least one filling configuration and/or the at least one de-contamination configuration.

The actuator may be controlled by a controller that causes the actuator to establish the at least one filling configuration and/or the at least one de-contamination configuration by shifting and/or sliding the tubular filling lance along the lance axis against the lance housing while the lance housing is coupled to the container. Providing a controlled actuator may allow to fill one or more containers at least partially in an automated manner. Therefore, multiple containers may be safely and efficiently filled without the need of a worker to assist which reduces the risk of contamination and/or human errors even more. Providing a controlled actuator may further allow high precision and/or efficient work results.

According to yet another aspect, a method of use of the container system for contamination-free filling of a container with a substance comprises: providing the container system; coupling the filling lance device with the container via the lance coupling portion of the filling lance device and the filling flange of the container and thereby establishing a first fluidic connection between a substance reservoir containing the substance and the container; coupling and fluidically connecting the external suction pump with the channel system via the lance port; filling, in the filling configuration, the container via the filling lance device by transferring via the first fluidic connection at least a portion of the substance from the substance reservoir into the container; and de -contaminating at least a portion of the tubular filling lance by applying an underpressure to the channel system by the external suction pump, in the at least one de-contamination configuration. The first fluidic connection may specifically refer to a sealed fluidic connection.

The method may provide a simple and safe way for using the container system for contamination-free handling and transferal of critical substances into a container to protect workers from contamination when handling such substances. The method may be at least a part of a concept that helps replacing the known concepts, which are based on extensive de-contamination and cleaning procedures and/or expensive and complex isolating technologies.

The method may be configured for drying the substance by lyophilization, i.e. freeze-drying and may therefore comprise: filling the substance into the container; providing the container system as described herein according to any one variant and/or embodiment; removing the first sealed connection between the substance reservoir and the container and closing the container after filling the substance into the container and de -contaminating at least a portion of the tubular filling lance which is to be de -contaminated, specifically the lance volume; lyophilizing the substance inside the container for storage preservation wherein liquid components in the substance sublime and escape at least partially from the container, specifically via the membrane wall; storing the lyophilized substance inside the container.

In a case when the substance is needed, the method may additionally comprise establishing a second fluidic connection between a liquid reservoir containing a liquid and the container; transferring via the second fluidic connection at least a portion of the liquid from the liquid reservoir into the container to re-solubilize the substance; and taking at least a portion of the re -solubilized substance via the second fluidic connection and/or another fluidic connection from the container. The second fluidic connection may specifically refer to a sealed fluidic connection. The step of taking at least a portion of the re-solubilized substance via the second fluidic connection and/or another fluidic connection from the container may refer to taking the entire amount of re-solubilized substance via the second fluidic connection and/or via another fluidic connection from the container. Alternatively, the step of taking at least a portion of the re-solubilized substance via the second fluidic connection and/or another fluidic connection from the container may refer to taking only a portion of the re -solubilized substance via the second fluidic connection and/or another fluidic connection from the container and keeping or preferably disposing the remaining amount of re-solubilized substance together with the container and/or all components, which were in contact with the substance including the container and elements thereof.

To increase the degree in versatility, containers of different sizes and volumes may be provided and therefore the amount of remaining amounts of re-solubilized substance inside the container that might be needed to be disposed may be reduced if a small amount (smaller than the volume of a large container) is required. Therefore, the variety of containers and/or a bundle/package of containers may comprise a variety of volumes and therefore dimensions to increase the degree of versatility such that a wide variety of amounts of substance can be obtained and the wasted amounts of substance can be reduced as much as possible. For example, an area for lyophilization that can receive containers may have a size of 120 cm x 200 cm. The containers may all have the same height at different volumes but having different area sizes, such as 60 cm x 50 cm (Volume = 4L) and 30 cm x 25 cm (Volume = IL). Optimized dimensions of the containers such as the said dimensions allow to optimally cover the provided space, i.e. the area for lyophilization that can receive containers.

Alternatively, the method may be configured for drying the substance by lyophilization, i.e. freeze-drying and may therefore comprise: providing the container system as described herein according to any one variant and/or embodiment; maintaining the first sealed connection between the substance reservoir and the container; lyophilizing the substance inside the container for storage preservation wherein liquid components in the substance sublime and escape at least partially from the container via the pathway towards the suction pump; after lyphilization, optionally de-contaminating at least a portion of the tubular filling lance which is to be de-contaminated and/or removing the first sealed connection between the substance reservoir and the container and closing the container; storing the lyophilized substance inside the container.

In a case when the substance is needed, the method may additionally comprise establishing a second fluidic connection between a liquid reservoir containing a liquid and the container; transferring via the second fluidic connection at least a portion of the liquid from the liquid reservoir into the container to re-solubilize the substance; and taking at least a portion of the re -solubilized substance via the second fluidic connection and/or another fluidic connection from the container.

In general, the step of de-contaminating the at least a portion of the tubular filling lance which is to be decontaminated refers to a de -contamination according to any one of the de -contamination configurations described herein.

The step of lyophilizing may comprise a step of freezing the substance to a temperature of about -60°C to -40°C. The step of lyophilizing may comprise a step of generating a vacuum of about 1 Pa to 0,1 Pa (0,lmbar to 0,001mbar) specifically for a duration of about 0,5 h to 170 h. The step of re-solubilizing the substance may comprise the addition of a solvent comprising at least one of the following: water, aqueous buffer, alcohol, organic liquids.

The method may be configured for drying the substance and may therefore comprise: providing the container system in which the container comprises: a temperature probe guiding tube coupled to a probe opening of the container and at least partially extending into the container and configured for receiving a temperature probe from outside of the container, the temperature probe guiding tube may comprise: a temperature probe introduction opening configured for introducing the temperature probe from outside of the container into the guiding tube and into a position inside the container; a non-thermally conducting guide tube portion for guiding the temperature probe in the temperature probe guiding tube and positioned at least partially inside the container; and a thermally conducting guide tube end portion positioned opposite the temperature probe introduction opening and configured to provide a thermal bridge between the substance inside the container and the temperature probe when the temperature probe is introduced into the temperature probe guiding tube and is in contact with the thermally conducting guide tube end portion; and in which the container system further comprises the temperature probe for determining a temperature of the substance inside the container; and the method may further comprise: removing the first sealed connection between the substance reservoir and the container and closing the container after filling the substance into the container and after de-contaminating the at least one portion of the tubular filling lance which is to be de-contaminated; inserting the temperature probe into the temperature probe guiding tube; drying the substance inside the container for storage preservation; when a completion of the drying is indicated in the temperature, storing the dried substance inside the container; in a case when the substance is needed, establishing a second fluidic connection between a liquid reservoir containing a liquid and the container; transferring via the second fluidic connection at least a portion of the liquid from the liquid reservoir into the container to re-solubilize the substance; and taking at least a portion of the re-solubilized substance via the second fluidic connection and/or another fluidic connection from the container.

The method may specifically be configured for drying the substance by lyophilization, i.e. freeze-drying. In other words, the method may comprise at least one step that is suited for lyophilization of the substance. The method may therefore in some cases comprise: providing the container system in which the container comprises: a temperature probe guiding tube coupled to a probe opening of the container and at least partially extending into the container and configured for receiving a temperature probe from outside of the container, the temperature probe guiding tube may comprise: a temperature probe introduction opening configured for introducing the temperature probe from outside of the container into the guiding tube and into a position inside the container; a non-thermally conducting guide tube portion for guiding the temperature probe in the temperature probe guiding tube and positioned at least partially inside the container; and a thermally conducting guide tube end portion positioned opposite the temperature probe introduction opening and configured to provide a thermal bridge between the substance inside the container and the temperature probe when the temperature probe is introduced into the temperature probe guiding tube and is in contact with the thermally conducting guide tube end portion; and in which the container system further comprises the temperature probe for determining a temperature of the substance inside the container; and the method may further comprise: removing the first sealed connection between the substance reservoir and the container and closing the container after filling the substance into the container and de -contaminating the at least one portion of the tubular filling lance which is to be de-contaminated; inserting the temperature probe into the temperature probe guiding tube; lyophilizing the substance inside the container for storage preservation wherein liquid components in the substance sublime and escape at least partially from the container and monitoring the temperature of the substance, reflecting a status of the lyophilization, by means of the temperature probe; when a completion of the lyophilization is indicated by the temperature, storing the lyophilized substance inside the container; in a case when the substance is needed, establishing a second fluidic connection between a liquid reservoir containing a liquid and the container; transferring via the second fluidic connection at least a portion of the liquid from the liquid reservoir into the container to re-solubilize the substance; and taking at least a portion of the re-solubilized substance via the second fluidic connection and/or another fluidic connection from the container.

According to yet another aspect, a method of contamination-free handling and drying of a substance comprises: establishing a first fluidic connection between a substance reservoir containing the substance and a container that comprises a container membrane which is permeable for a gas and impermeable for a liquid; transferring via the first fluidic connection at least a portion of the substance from the substance reservoir into the container; de -contaminating elements, regions and/or portions that are involved in establishing the first sealed connection (e.g. elements, regions and/or portions of the container and/or a coupler and/or a filling lance and/or a flange and/or tube) using an underpressure generated by a suction pump; removing the first sealed connection between the substance reservoir and the container and closing the container; drying the substance inside the container for storage preservation; storing the dried substance inside the container; in a case when the substance is needed, establishing a second fluidic connection between a liquid reservoir containing a liquid and the container; transferring via the second fluidic connection at least a portion of the liquid from the liquid reservoir into the container to re-solubilize the substance; and taking at least a portion of the re-solubilized substance via the second fluidic connection and/or another fluidic connection from the container.

Specifically, the method may be configured for contamination-free handling and lyophilization of a substance and may therefore comprises: establishing a first fluidic connection between a substance reservoir containing the substance and a container that comprises a container membrane which is permeable for a gas and impermeable for a liquid; transferring via the first fluidic connection at least a portion of the substance from the substance reservoir into the container; de-contaminating elements that are involved in establishing the first sealed connection using an underpressure generated by a suction pump; removing the first sealed connection between the substance reservoir and the container and closing the container; lyophilizing the substance inside the container for storage preservation wherein liquid components in the substance sublime and escape as a gas at least partially from the container via the container membrane; storing the lyophilized substance inside the container; in a case when the substance is needed, establishing a second fluidic connection between a liquid reservoir containing a liquid and the container; transferring via the second fluidic connection at least a portion of the liquid from the liquid reservoir into the container to re-solubilize the substance; and taking/removing at least a portion of the re-solubilized substance via the second fluidic connection and/or another fluidic connection from the container.

This method may provide a more general simple and safe way for contamination-free handling and transferal of critical substances into a container to protect workers from contamination when handling such substances. The method may be at least a part of a concept that helps replacing the known concepts, which are based on extensive de-contamination and cleaning procedures and/or expensive and complex isolating technologies.

According to yet another aspect, a computer program product has instructions stored thereon, which cause at least one machine and/or controller to initiate and/or perform the steps of the methods described herein, such as the method of contamination-free handling and lyophilization of a substance and/or the method of use of the container system for contamination-free filling of a container with a substance.

According to a further aspect, a method of re-solubilization of a dried (e.g. lyophilized and/or dried in another way) substance enclosed in a container and harvesting of the re -solubilized substance from the container comprises the following steps: providing a container (not necessarily the previously described container described herein) that encloses the dried substance; in a case when the substance is needed, establishing a fluidic connection between a liquid reservoir containing a liquid for re-solubilization and the container; transferring via the fluidic connection at least a portion of the liquid (such as a buffer, a solvent, a solution or the like) from the liquid reservoir into the container to re-solubilize the dried substance; and taking at least a portion of the re-solubilized substance via the fluidic connection and/or another fluidic connection (to be established) from the container.

The container is not required to be a bag for lyophilization (lyo bag) that may comprise a membrane. It may comprise a storage bag, a bioreactor container/bag or the like. The substance is not required to be previously transferred into the container by the contamination-free and/or quasi-contamination-free method(s) described herein.

The fluidic connection may be established by: providing a needle that is in fludic connection with the liquid reservoir containing the liquid for re-solubilization; providing a septum on/at the container and punching the needle through the septum of the container into the ineterior/inside of the container; and/or providing a flange for re -solubilization on/at the container and pushing the needle through the flange, preferably wherein the flange comprises: a tube with an open tube end and the tube is in fluidic connection with the inside of the container and a tube clip and/or clamp for opening and/or closing the tube end such that the tube end represents a port and/or fluidic connection between the inside and the outside that can be reversibly opened and/or closed. Instead of a needle, another open and specifically pointed end of a tube and/or a connector may be used.

In other words, the fluidic connection may be provided by punching a needle through a septum of the container and/or by opening a tube clip and/or clamp that is positioned on a tube as a permanent access and/or port of the container.

The method of re -solubilization of the dried substance enclosed in a container and harvesting of the resolubilized substance from the container may comprise separating the liquid reservoir (containing at least a portion of the re -solubilized substance) from the container and sealing the liquid reservoir and the container. The liquid reservoir and the container may be fluidically connected via a tube. The fluidic connection may be blocked by heat-sealing and - if required - by cutting and/or by clamping (off) and/or crimping.

Therefore, the sealing according to one embodiment may be performed by heat sealing. The tube may comprise at least a portion of a thermoplastic at which it can be heat-sealed, i.e. clamped and/or squeezed and heated to the melting point of the thermoplastic material. This may mean that heat is applied while pressing the tube together such that the fluidic connection between the liquid reservoir and the container is blocked. The heat allows melting the material such that the blocking remains permanently after cooling down. The tube may afterwards be separated by the influence of the heat or the tube may be cut afterwards to separate the two systems: 1. the liquid reservoir containing at least a portion of the re-solubilized substance together with a portion of the tube and 2. The container together with the other portion of the tube, which may be disposed as a sealed system. This may be beneficial if the substance is hazardous and/or toxic and the elements, which were in contact therewith, may therefore be considered hazardous waste and require a special treatment after disposal.

Alternatively, or in addition to using a septum and/or to the concept of heat-sealing after harvesting of the substance, a tube end of the tube (as described above) for re -solubilization having an open tube may be closed and/or opened by a tube clip and/or clamp and/or squeezing valve (not shown). This may be used as an alternative (or in addition) to a closure with septum and/or as an alternative concept of sealing the container and/or a connected system such as a liquid reservoir and/or another connected container. The tube/flange for re-solubilisation can be coupled, fluidically connected and/or fixed onto the container, more specifically onto an opening of the container. The tube end may be fluidically connected with the suction pump and/or the liquid reservoir for re-solubilization. The tube/flange for re -solubilization may correspond to and/or may comprise a fixed, open tube end positioned, fixed and/or coupled at/on an opening of the container and being closed by the tube clip and/or a squeezing valve. The tube/flange for re-solubilization and the clamp/tube clip may have the same and/or a similar function as a septum, namely providing an access for re-solubilisation and/or adding content to the container and/or taking content out of the container and allowing to open and/or close the access when needed. Alternatively, or in addition, the clamp/tube clip may be used to isolate and/or seal the container and/or the reservoir being fluidically connected to the container via the tube/flange. This may represent an alternative to the heat-sealing concept.

In general, all devices, systems, methods and/or processes described herein may be performed halfautomated, partially automated and/or fully automated. The terminology “half-automated” and/or “partially automated” and “fully automated” systems and/or processes refer to the level of automation in the processes and/or systems described herein. In a half-automated and/or partially automated system and/or process, some tasks and/or steps are performed by humans, specifically manually, while others are automated by machines and/or software. On the other hand, a fully automated system and/or process is one where substantially all tasks and/or steps are performed by at least one machine and/or software without human intervention. The main difference between “half-automated” and/or “partially automated” and “fully automated” systems and/or processes lies in the extent of human involvement and the level of control over the process/system. In a half-automated and/or partially automated system and/or process, humans are responsible for certain tasks, such as inputting data, making decisions, and/or performing physical actions, which may range between approximately 45-99%, specifically between approximately 50-80%. The automation may be used to streamline and/or assist with certain aspects of the process, but humans may still be required to oversee and manage the overall operation. In a fully automated system and/or process, at least one machine and/or software performs at least approximately 80%, specifically at least approximately 90% of all process steps. Preferably, a fully automated system and/or process is designed and/or constructed to operate substantially without human intervention. Substantially all tasks, from data input to decision-making and physical actions, may be handled by at least one machine and/or software. A high level of automation may increase efficiency, reduce errors, and allow for continuous operation.

It is to be understood that the present invention is not limited to the particular embodiments and examples described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

According to an example or a further aspect, a container for monitoring a temperature of a substance therein comprises: a temperature probe guiding tube coupled to a probe opening of the container and at least partially extending into the container and configured for receiving a temperature probe determining a temperature of the substance from outside of the container, the temperature probe guiding tube comprising: a temperature probe introduction opening configured for introducing the temperature probe from outside of the container into the temperature probe guiding tube and into a position inside the container; a non- thermally conducting guide tube portion for guiding the temperature probe in the temperature probe guiding tube and positioned at least partially inside the container; and a thermally conducting guide tube end portion positioned opposite the temperature probe introduction opening and configured to provide a thermal bridge between the substance inside the container and the temperature probe when the temperature probe is introduced into the temperature probe guiding tube and is in contact with the thermally conducting guide tube end portion.

The temperature probe guiding tube does not allow a physical contact between the temperature probe (sensor) and the content of the bottle. When being closed, there is no opening between the inside of the bottle and the outside, specifically not via the temperature probe guiding tube. This has the effect that liquid cannot escape the inside of the bottle via the temperature probe guiding tube. A fluid communication may only be allowed for gases over a membrane if a membrane is provided in the container. The temperature probe is hence not contaminated by the content of the container.

The container may comprise at least one of: a bag, a single-use and/or disposable bag, a polymer container, an at least partially flexible container, an at least partially non-flexible container, a container configured for storage of the substance and/or for lyophilization of the substance, specifically a lyophilization bag.

The container may correspond to a container for lyophilization of the substance and comprising a membrane wall being permeable for gas and impermeable for liquids, specifically wherein the container comprises a frame for supporting the membrane wall.

The container may further comprise a temperature probe holding portion configured to hold, clamp, fix, align and/or couple the temperature probe in the temperature probe guiding tube.

The temperature probe guiding tube may be configured to prevent the temperature probe to be in direct contact with the substance inside the container and/or the volume inside the container.

According to an example or a further aspect, a container system comprises: the container of any one of the described aspects or embodiments described herein; and the temperature probe.

Detailed Description of the Invention

In the following, some embodiments will be described in detail, wherein the invention should not be understood to be limited to the embodiments described. The following embodiments and figures are provided to aid the understanding of the present invention, the true scope of which is set forth in the appended claims. Single features being described in a particular embodiment may be arbitrarily combined, given that they are not excluding each other. In addition, different features which are provided together in the example embodiments are not to be considered restrictive to the invention.

Skilled artisans appreciate that elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale. For example, the dimensions of some of the elements in the figures may be exaggerated relative to other elements whereas other elements may have been left out and/or represented in a reduced number in order to enhance clarity and improve understanding of the aspects of the present disclosure. The same reference numerals are used among different embodiments and examples for the same or similar elements or elements that have similar or the same effects.

Description of the Figures

Fig. la is a schematic perspective top view onto a portion of a container system according to an embodiment;

Fig. lb is a schematic side view of a detail of the container of Fig. 1 a, namely the closure element according to an embodiment;

Fig. 2 is a constructional drawing of a fdling lance device according to an embodiment;

Fig. 3a is a schematic drawing of a container system according to an embodiment;

Fig. 3b is a schematic drawing of a container according to an embodiment;

Fig. 4a is a schematic drawing of a portion of a tubular filling lance comprising a passage system according to an embodiment;

Fig. 4b is a schematic drawing of a portion of a tubular filling lance comprising a passage system according to another embodiment;

Fig. 4c is a schematic drawing of a portion of a tubular filling lance comprising a passage system according to another embodiment;

Fig. 4d is a schematic drawing of a portion of a tubular filling lance comprising a passage system according to another embodiment;

Fig. 5 is a constructional drawing of a probe head system on a container according to an embodiment;

Fig. 6 is a schematic drawing of a lyophilization system according to an embodiment;

Fig. 7 is a schematic drawing of a substance reservoir, which is also denoted product container and which is comprised by the lyophilization system of Fig. 6;

Fig. 8 is a schematic drawing of a mobile control unit, which is comprised by the lyophilization system of Fig. 6;

Fig. 9 is a schematic drawing of a container system, which is comprised by the lyophilization system of Fig. 6;

Fig. 10 is a constructional drawing of a filling lance device in a filling configuration according to an embodiment;

Fig. 11 is a constructional drawing of the filling lance device of Fig. 10 in a lance volume de-contamination configuration according to an embodiment showing a closed filling lance device (left) and a cut-open filling lance device (right); Fig. 12 is a constructional drawing of the filling lance device of Fig. 10 in a passage de -contamination configuration according to an embodiment showing a closed filling lance device (left) and a cut-open filling lance device (right);

Fig. 13 is a constructional drawing of the filling lance device of Fig. 10 in an outer surface de-contamination configuration according to an embodiment showing a closed filling lance device (left) and a cut-open filling lance device (right);

Fig. 14 is a schematic and partially transparent side view of a closure element according to an embodiment showing a closed filling lance device (left) and a cut-open filling lance device (right);

Fig. 15 is a schematic and partially transparent side view of a closure element according to another embodiment;

Fig. 16 is a flow diagram for a method of using a container system according to an embodiment;

Fig. 17a-17e is a schematic workflow for a method of using a container system according to an embodiment;

Fig. 18 is a flow diagram for a method of contamination-free handling and lyophilization of a substance according to an embodiment;

Fig. 19 is a schematic process diagram according to an embodiment;

Fig. 20 is a concept of unloading of the freeze-dryer in a production area with defined moisture conditions;

Fig. 21 is a scheme demonstrating the function of a filling flange (also denoted “container filling flange”) with closure flaps in an open configuration (left) and in a closed configuration (right);

Fig. 22 is a scheme of a flange for re-solubilization having a tube clip to open and/or close the flange;

Fig. 23 is a flow diagram for a method of re-solubilization and harvesting of a substance enclosed in a container; and

Fig. 24 refers to a flow diagram of a method of drying a substance.

Fig. la shows at least some elements of a container system 30 according to an embodiment. Specifically, Fig. la shows a container 20, which may be considered a tray in the present case and having a container fill opening 22 through which a substance can be added and/or transferred into the container 20. A filling flange 25 is provided at the container fill opening 22. Further, the container 20 comprises a container membrane 24 or membrane element, which corresponds to a membrane wall of the container 20 in the present case. The container membrane 24 is supported and/or stabilized by a container frame 23. The container further comprises a container probe opening 21 through which a probe head system 10, specifically a temperature control grommet, reaches into the inner volume of the container 20 to measure a temperature of a medium and/or substance inside the container 20 being remote from the container probe opening 21. An identification label 26 is positioned on an outer surface of the container 20. Specifically, an identification label 26 may be positioned on a frame for identification of the container 20 and/or the content. Fig. lb is a schematic side view of a detail of the container 20 of Fig. la, namely the container fdl opening 22 with the fdling flange 25 and a closure element 31 being coupled to the filling flange 25 according to an embodiment. In the present case, the closure element 31 corresponds to a cap that can be screwed onto the filling flange 25.

Fig. 2 is a constructional drawing of a filling lance device 40 according to an embodiment. The filling lance device 40 is coupled via a lance coupling portion 47 to the filling flange 25 of a container 20. The filling lance device 40 is shown in a filling configuration A in which a fluidic connection is established between the inside I of the container 20 and the outside O of the container 20.

The filling lance device 40 is configured for contamination-free filling of the container 20 with a substance from a substance reservoir / product container 80. Therefore, the filling lance device 40 comprises a tubular filling lance 41 and a lance housing 46 as two separate elements being movably coupled with and/or to each other. The tubular filling lance 41 comprises in the present embodiment an introduction opening 24 with a funnel 42a, as well as a dispense opening 43 and a lance tube portion 44 connecting the introduction opening 24 and the funnel 42a with the dispense opening 43.

The lance housing 46 encloses at least partially the tubular filling lance 41. It can be seen in the present filling configuration A that the lower portion of the tubular filling lance 41 which comprises a dispense opening 43, sticks out of the lance housing 46. Further, an upper portion of the tubular filling lance 41 that comprises the introduction opening 24 and the funnel 42a also sticks out of the lance housing 46.

The tubular filling lance 41 and the lance housing 46 are movably arranged relative to each other between the filling configuration A, as also shown in Fig. 10 and de -contamination configurations B, C, D (not shown in Fig. 2 but in Fig. 11-13). In Fig. 10, a closed filling lance device 40 (left, lance port hidden on the backside) and a cut along the line AA of the closed filling lance device 40 (right) are shown. The tubular filling lance 41 can be slid or shifted against the lance housing 46 along the filling lance axis LA.

Fig. 10-13: Moveable tubular filling lance 41 in different positions/configurations A-D, depending on the filling/de-contamination process state. Position A in Fig. 10: While the tray 20 is being filled, the tubular filling lance 41 is positioned downwards. Position B in Fig. 11: After filling, the tubular filling lance 41 may be retracted and the fed line may be sucked out by the vacuum. Position C in Fig. 12: The area of the filling lance tip is sucked out through the pipe-channel system by vacuum. Position D in Fig. 13: The edge area of the tip is sucked out by vacuum.

To extract arising aerosols and to de -contaminate the moveable tubular filling lance wall from remaining product/substance reliable, vacuum is present between the inner housing wall and the filling lance wall and at the tip during the overall filling process. The through vacuum generated suction is distributed evenly over the entire perimeter of the filling lance and tip. Depending on the design, this could be done by grooves and/or 3D-printed vacuum passages in the wall and tip. Hereby, a sliding bush may ensure even spacing of the gap and a movement with minimum friction. The lance housing 46 has a channel system 48 that can be fluidically connected to an external suction pump 7 that may be coupled to the lance housing 46 via the lance port 49. In at least one de -contamination configuration B, C, D, the channel system 48 is in fluidic connection with the tubular filling lance 41, specifically the tube volume V, an outer surface S of the tubular filling lance 41 and/or a passage 45, specifically a capillary passage system of the tubular filling lance 41. In these cases, the external suction pump 7 is in fluidic connection with the tubular filling lance 41 via the lance port 49, the channel system 48 and a channel (system) opening 48a which is positioned close to the element of the tubular filling lance 41 that should be de-contaminated, such as the tube volume V, for example. In that specific case, the dispense opening 43 is aligned with the channel (system) opening 48a for a fluidic connection between the external suction pump 7 and the tube volume V, i.e. the volume of the inner space of the tubular filling lance 41.

The tubular filling lance 41 and the lance housing 46 are movably arranged relative to each other along a filling lance axis LA, wherein the filling lance device 40 comprises a sliding bush 46a positioned between the tubular filling lance 41 and the lance housing 46 for restricting and/or preventing relative movements between the tubular filling lance 41 and the lance housing 46 which are not directed along the filling lance axis LA, specifically movements that have a component perpendicular to the filling lance axis LA. In other words, the tubular filling lance 41 is substantially prevented from shaking and/or wobbling inside the lance housing 46. The sliding bush 46a may be considered a bearing and/or a support that allows for gliding and/or sliding translation of the tubular filling lance 41 against the lance housing 46.

The filling lance device 40 comprises a stopper mechanism 44a for restricting and/or stopping a relative movement between the tubular filling lance 41 and the lance housing 46 along the filling lance axis LA. In this embodiment, the tubular filling lance 41 is prevented from sliding (downwards) through the lance housing 46 beyond a certain position and/or in an uncontrolled manner. The stopper mechanism 44a is realized in this embodiment as a protrusion 44b of the tubular filling lance 41 and a protrusion and/or base 44c of the lance housing 46 that stops the tubular filling lance 41 from further moving along the filling lance axis LA towards the inner side I of the container 20. The protrusion and/or base 44c of the lance housing 46 may be understood as a position where a tubular diameter of the lance housing 46 is becoming smaller towards a lance coupling portion 47 for coupling the filling lance device 40 to the filling flange 25 of a container 20. The protrusion 44b of the tubular filling lance 41 may be realized as a ring -like and/or nose-like protrusion, in that the tubular filling lance 41 has a ring that protrudes from the tubular filling lance 41 or one or more noses which protrude from the tubular filling lance 41. The protrusion and/or base 44c of the lance housing 46 stops and supports the tubular filling lance 41 when it slides downwards for example in an uncontrolled manner or when it is pushed downwards.

The configuration in which the protrusion 44b of the tubular filling lance 41 contacts the protrusion and/or base 44c of the lance housing 46 may define the filling configuration A, as shown in Fig. 2. A further stopper mechanism may be included to stop the tubular filling lance 41 from sliding (upwards) through the lance housing 46 beyond a certain position (not shown in this embodiment).

In the present embodiment of Fig. 2, the dispense opening 43 of the tubular fdling lance 41 defines a dispense axis DA that deviates from the filling lance axis LA. In an alternative embodiment, the dispense opening 43 can line up with the filling lance axis LA such that both, the dispense opening 43 and the introduction opening 42 of the tubular filling lance 41 define the filling lance axis LA which technically equals the dispense axis DA.

In the present embodiment of Fig. 2, the tubular filling lance 41 comprises capillary droplet collection openings 45b as openings of the passage 45, specifically the capillary passage system. The capillary droplet collection openings 45b are positioned on the lower side of the tubular filling lance 41 to passively collect and/or suck in remaining droplets of a liquid substance by means of capillary forces. Each capillary droplet collection opening 45b is connected with at least one passage opening 45c via at least one passage 45 or a capillary passage system 45.

The at least one de-contamination configuration (B, C, D) comprises in the present embodiment as shown in Fig. 11, Fig. 12 and Fig. 13, respectively, the following:

A lance volume de-contamination configuration B is shown in Fig. 11, in which the channel system 48 is in fluidic connection with the tube volume V that is at least partially enclosed by the tubular filling lance 41, specifically via the dispense opening 43. In the present de-contamination configuration B, the dispense opening 43 aligns with an opening 48a of the channel system 48. A closed filling lance device 40 (left, lance port hidden on the backside) and a cut along the line BB of the closed filling lance device 40 (right) are shown.

A passage de-contamination configuration C is shown in Fig. 12, for which the tubular filling lance 41 comprises the passage 45, specifically the microfluidic and/or capillary passage system 45, that is configured to fluidically connect the outer surface S of the tubular filling lance 41 (specifically an outer surface of an end portion (45) of the tubular filling lance (41) on a lower tip portion) with the channel system 48 in the passage de-contamination configuration C. In the present de-contamination configuration C two openings 48a of the channel system 48 align each with an opening 45c of the capillary passage system 45. A closed filling lance device 40 (left, lance port hidden on the backside) and a cut along the line DD of the closed filling lance device 40 (right) are shown.

An outer surface de-contamination configuration D is shown in Fig. 13, in which the channel system 48 is in a fluidic connection with an outer surface S of the tubular filling lance 41, specifically with an edge of the tubular filling lance 41 below the dispense opening 43. In the present de-contamination configuration D, a portion of the outer surface S aligns with an opening 48a of the channel system 48. The closed filling lance device 40 (left, lance port hidden on the backside) and a cut along the line DD of the closed filling lance device 40 (right) are shown. Fig. 3a shows a container system 50 that comprises a filling lance device 40 as described together with Fig. 2 being coupled to the container fill opening 22 of a container 20. The container system 50 of Fig. 3a is configured for contamination-free filling of a container 20 with the substance 1. The container system 50 comprising the filling lance device 40 and the container 20 with the container fill opening 22. The container 20 is configured to be filled with the substance 1 via the container fill opening 22. The container 20 comprises the filling flange 25 at/on the fill opening 22 to be coupled with the filling lance device 40. More specifically, the filling flange 25 can be coupled with the lance coupling portion 47 of the filling lance device 40.

A substance 1 is indicated inside the container 20. It can be seen in the present filling configuration A that the lower portion of the tubular filling lance 41 which comprises a dispense opening 43, sticks out of the lance housing 46 into the inside I/inner volume of the container 20. The container 20 is permeable for gases to escape from the inside I of the container 20 to the outside o via the membrane 24 (dashed line). In other words, the container 20 comprises a membrane wall 24 being permeable for gas and impermeable for liquids. The container 20 may comprise a frame 23 for supporting the membrane wall 24 as shown for example in Fig. la.

Fig. 3b shows the container 20 of Fig. 3a in a closed state, namely with the container fill opening 22 with the filling flange 25 being closed with the closure element 31. The closure element 31 being coupled to the filling flange 25 according to an embodiment. In the present case, the closure element 31 corresponds to a cap that can be screwed onto the filling flange 25.

The filling flange 25 may comprise closure flaps 27 as shown in Fig. 21. The closure flaps 27 are configured to break a fluidic connection between the inside/inner volume of the container 20 and another entity or the outside. In other words, the closure flaps 27 of the filling flange 25 are configured to close the container 20 at the filling opening in a closed configuration (Fig. 21, right scheme). When reaching through the closure flaps 27 for example with the tubular filling lance 41, the closure flaps 27 open the fill opening 22 in an opened configuration and a fluidic connection between the inside of the container 20 and the outside and/or another entity may be established (Fig. 21, left scheme - tubular filling lance 41 not shown). The open configuration may be achieved by reaching through the filling flange 25 using a force to push an element, such as the tubular filling lance through. The closed configuration may be achieved by retracting the element from the filling flange 25. The mechanism of transition from an opened configuration/state into a closed configuration/state may rely on a spring return force of a spring that is coupled to each one of the flaps 27. Such flaps 27 have the effect that the inner volume I of the container 20 is only opened and/or exposed via the fill opening 22 in the moment when the tubular filling lance 41 in configuration A and/or another element is pushed through the filling flange 25 and the flaps 27 open as a response. In all other cases, also the tubular filling lance 41 is in configuration B, C, or D, the flaps 27 remain in the closed configuration and exposure of the inner volume I of the container 20 to the outside O is avoided and/or stopped. Therefore, contamination from the outside O to the inside I of the container 20 or vice versa is reduced to a minimum. Summarized, it can be said, that there is no contact (fluidic connection) between the inside of the container I and the outside O for the process steps before, during and after filling of the container 20. Thereby, the complete process can be described as a closed filling process.

The container system 50 of Fig. 3a may comprise a septum 32 configured for removal of at least a portion of the substance 1 from the container 20 and/or addition of an additional substance 1 to the container 20 (not shown in Fig. 3a). Therefore, the septum 32 may be provided in a container wall and/or in a closure element 31 for closing the container fill opening 22 as shown for example in Fig. 14 and Fig. 15.

In Fig. 14, a filling flange 25 at/on a fill opening 22 is shown together with a closure element 31, i.e. a cap in the present case with a septum 32, which is coupled to the filling flange 25. In more detail, the closure element 31 with the septum 32 is screwed onto the filling flange 25 via threaded compatible portions on the closure element 31 and the filling flange 25. In other words, a filling port and/or filling flange 25 is equipped with an external thread so that it can be closed with a cap after the filling process. In the interior of the filling port there is a mechanical stop on which the outer tube of the filling lance is placed.

In Fig. 15, a further filling flange 25 at/on a fill opening 22 is shown together with a closure element 31, i.e. a cap in the present case with a septum 32, which is coupled to the filling flange 25 according to another embodiment. Instead of the cap 31 being coupled directly to the filling flange 25 as in Fig. 14, an adapter piece/fitting 33 is coupled to the filling flange 25 and the cap 31 is coupled to the fitting 33. The fitting 33 may elongate the filling flange 25 and fixes a second septum 32 as a second protection port and/or provide a thread that differs from the thread provided on the filling flange 25 but fits the thread of the cap 31.

The filling flange 25 (and/or the fitting 33 that fits the filling flange 25) and the lance coupling portion 47 are dimensioned such that the filling flange 25 encloses and/or surrounds the lance coupling portion 47 at least partially as shown for example in Fig. 2 or Fig. 3. Further, the filling flange 25 comprises in these embodiments, as already indicated before, a supporting protrusion and/or base 25a configured for supporting the lance coupling portion 47 when the filling flange 25 is coupled with the lance coupling portion 47.

Alternatively, or in addition to a septum and/or to the concept of heat-sealing after harvesting of the substance - as shown in Fig. 22 - a tube end of a flange for re-solubilization 29 having an open tube may be closed by a tube clip 28 or a squeezing valve (not shown). This may be used as an alternative (or in addition) to a closure 31 with septum 32 as shown in Fig. 15. The flange for re-solubilisation 29 can be coupled, fluidically connected and/or fixed onto the container 20, more specifically onto an opening of the container 20. The tube end may be fluidically connected with the suction pump 3 and/or the liquid reservoir for re -solubilization. The flange for re-solubilization 29 may correspond to and/or may comprise a fixed, open tube end positioned, fixed and/or coupled at/on an opening of the container 20 and being closed by the tube clip 28 and/or a squeezing valve. The flange for re-solubilization 29 and the tube clip 28 may have the same or a similar function as a septum, namely providing an access for re-solubilisation and/or adding content to the container 20 and/or taking content out of the container 20 and allowing to open and/or close the access when needed.

The container 20 may comprise as indicated in Fig. la but not shown in Fig. 3a or Fig. 3b, a probe head system 10. The probe head system 10 is shown in greater detail in Fig. 5 which shows the design of the probe head system 10, specifically a temperature probe guiding tube 12 also being considered a temperature control grommet.

The probe head system 10 comprises a temperature probe guiding tube 12 which may be an injection molded part comprising PP and which is coupled and/or fixedly attached to a probe opening 21 of the container 20, for example via a plate to enable welding to the membrane or the frame structure of a tray. The temperature probe guiding tube 12 at least partially extends into the inside I/inner volume of the container 20 and is configured for receiving a temperature probe 11 from outside O of the container. The temperature probe guiding tube 12 comprises a temperature probe introduction opening 13 configured for introducing the temperature probe 11 from outside O of the container 20 into the temperature probe guiding tube 12 and into a position inside the container 20.

In general, the inside I/inner volume of the container 20 may be considered the inner volume that would be enclosed by the container walls if the holes were closed by a plane that spans over the holes and aligns with the container walls. Therefore, the portion of the chamber inside the probe guiding tube 12 which may receive the temperature probe 11 may be considered a portion of the inside I/inner volume of the container 20 even though it is not a portion of the actual container volume that can receive the substance 1. In other words, the “inner volume” of the container 20 includes the volume that is replaced by the volume of the elements that stick into the container 20, such as the temperature probe guiding tube 12 and the “actual container volume” refers to the inner volume of the container 20 excludes the volume that is replaced by the volume of the elements that stick into the container 20 and refers to the volume that may receive the substance 1.

The temperature probe guiding tube 12 comprises a non-thermally conducting guide tube portion 14 for guiding the temperature probe 11 in the temperature probe guiding tube 12 and positioned at least partially inside the container 20, i.e. in the inner volume of the container. The temperature probe guiding tube 12 further comprises a thermally conducting guide tube end portion 15 positioned opposite the temperature probe introduction opening 13 and configured to provide a thermal bridge between the substance 1 in the inside I of the container 20 and the temperature probe 11 when the temperature probe 11 is introduced into the temperature probe guiding tube 12 and is in contact with the thermally conducting guide tube end portion 15. Specifically, to improve temperature absorption, the tip of the nozzle/ temperature probe guiding tube 12 may be equipped with a metal cap 15. In order to improve the conductivity between the temperature probe 11, which may be a T-sensor and the metal cap 15, there may be athermal conductivity pad 17 inside the temperature probe guiding tube 12. After positioning of the T-sensor 11 in the grommet, the T-sensor 11 may be fixed using a cable lock 16.

The container system 50 may comprise the temperature probe 11 for determining a temperature of the substance 1 inside the container 20.

The temperature probe 11 may be coupled and/or fixed and/or fixedly attached to the temperature probe guiding tube 12 by a probe head lock system 16 which may comprise means such as a thread (shown in Fig. 5) and/or a clamp and/or the like being compatible with a counterpart on the temperature probe guiding tube 12. The temperature probe guiding tube 12 has a temperature probe introduction opening 13 through which the temperature probe 11 can be introduced into the temperature probe guiding tube 12. The guide tube end portion 15 of the temperature probe guiding tube 12 can be in thermal contact with a substance 1 inside I the container 20 on the side of the guide tube end portion 15 that faces away from the temperature probe 11. When the tip of the temperature probe 11 is contacted with the other side of the guide tube end portion 15, a thermal connection between the substance 1 and the temperature probe 11 is established. The temperature probe 11 may, on the opposite side, be electrically contacted with/to a power source and/or a display to monitor and/or display the temperature, which is measured and/or detected.

At least one component of the container system 50 may be a disposable component, specifically the filling lance device 40 may be a disposable component and/or the container 20 and/or the closure element/cap 31 may be a disposable component.

As previously described, the tubular filling lance 41 may comprise a capillary passage system 45. In Fig. 4a-4d, several embodiments are described.

Different designs of the tip itself may therefore be also considered. Depending on the implemented suction passages, the tip may have different conical designs pointing outwards and inwards or a porous surface to generate suction and support the de -contamination of product-wetted surfaces.

All capillary passage systems 45 comprise multiple passage openings 45c through which the capillary passage system 45 can be fluidically contacted via the channel system 48 of the lance housing 46 with an external suction pump 7 and therefore, a passage opening 45c is aligned with an opening 48a of the channel system 48. In Fig. 4a and 4b, the tip of the corresponding tubular filling lance 41 is concave substantially in the shape of a cone being cut-out. In Fig. 4c and 4d, the tip of the corresponding tubular filling lance 41 is convex substantially in the shape of a cone being added. Both shape types, concave or convex cones, define an outer surface S on which a liquid, specifically a droplet of liquid of the substance can remain after and/or during filling the substance into the container 20. Therefore, the capillary passage systems 45 comprise at least one capillary droplet collection opening 45b each being an opening of the passage 45 on the opposite side of the passage opening 45c for lining up with the channel system opening 48a. The capillary droplet collection openings 45b are positioned on the lower side, i.e. the surface S of the tip of the tubular filling lance 41 to passively collect and/or suck in remaining droplets of a liquid substance by means of capillary forces. Each capillary droplet collection opening 45b is connected with at least one passage opening 45c via at least one passage 45 or a capillary passage system 45.

In Fig. 4a one centered capillary droplet collection opening 45b is positioned on the surface S of the concave cone of the tubular fdling lance 41. Two passage openings 45c are indicated, one to the left side and one to the right side positioned in a region of the dispense opening 43 of the filling lance 41 and having a fluidic connection with the dispense opening 43.

In Fig. 4b a multitude of capillary droplet collection openings 45b with min 3 or more capillary droplet collection openings 45b with one in the middle and a multitude in a concentric arrangement (only three shown in the cut drawing). The capillary droplet collection openings 45b are positioned on the surface S of the concave cone of the tubular filling lance 41.

In Fig. 4c one centered capillary droplet collection opening 45b are positioned on the surface S of the convex cone of the tubular filling lance 41. Two passage openings 45c are indicated, one to the left side and one to the right side positioned in a region of the dispense opening 43 of the filling lance 41 but not having a fluidic connection with the dispense opening 43.

In Fig. 4d a multitude of capillary droplet collection openings 45b with min 3 or more capillary droplet collection openings 45b with one in the middle and a multitude in a concentric arrangement). The capillary droplet collection openings 45b are positioned on the surface S of the concave cone of the tubular filling lance 41.

In Fig. 6 a filling system 90 is schematically shown, which may be considered a dripless filling system and which comprises the container system 50 according to an embodiment. The container system 50 is configured for substantially contamination-free filling of the container 20 with the substance 1. The filling system 90 comprises four elements: a pallet jack with weighing capabilities on which a substance reservoir 80 containing the substance 1 is positioned, a mobile control 70 which comprises elements for realizing a desired degree of automation, pumping and suction generation, a functional carrier system comprising a lance holding device 60 and the tubular filling lance 40 coupled to a container 20. The lance holding device 60 which may be considered or which may comprise a filling lance frame and the tubular filling lance 40 may be moved between containers, exchanged, replaced, disposed and/or operated by a human operator and/or by a machine. Therefore, the lance holding device 60 and/or the tubular filling lance 40 may be realized in a robust and lightweight design having a weight of less than 0,5 kg.

The container 20 is configured to be filled with the substance 1 via the container fill opening 22. The container system 50 comprises the filling lance device 40 and the container 20. The filling lance device 40 is in the shown configuration inserted in the container fill opening 22 and the first fluidic connection 9a between the container and the substance reservoir 80 is established for filling the container using a tube 81 specifically used for the first fluidic connection 9a. The substance 1 may be provided as a solubilized substance 1 inside the substance reservoir 80 which makes it easy to fill and/or transfer the substance 1. The container system 50 further comprises a lance holding device 60 for holding the fdling lance device 40 in a fdl position with respect to the container 20. The lance holding device 60 may be configured for multiple use. The container system 50 may further comprise an actuator 63 configured to automatically establish the at least one filling configuration A and/or the at least one de -contamination configuration B, C, D. A mobile control unit 70 comprising a controller may be connected to the actuator 63 for controlling the configuration of the filling lance device 40.

In Fig. 7, the substance reservoir 80 of Fig. 6 is shown in more detail. The substance reservoir 80 is at least partially filled with the substance 1, which may be an enzymatic bulk suspension, for example. The substance reservoir 80 can be fluidically connected with the container 20 via the product filling line 81, which may be or may comprise a tube. Further, the substance reservoir 80 is positioned on a pallet jack with included weighing system/balance for monitoring the weight of the substance reservoir 80 and/or the content.

The pallet jack with included weighing system may comprise four main functions. Its main function is to transport and weigh the product container 80, for example in a clean room environment. An interface with the mobile control 70 in Fig. 8 may comprise a tri-clamp and/or product filling line 81 to transfer product/substance 1 and an opportunity, such as a data cable 82 to transfer data of measured weight.

Based on the weight, the transfer of substance 1 from the substance reservoir 80 to the container 20 may be controlled. Therefore, a data connection between balance and controller can be provided using a data cable 82. The data connection 82 is configured for data transfer related to the product mass/substance 1 from the palette to the control unit 82. In other words, data related to the substance mass that is transferred can be provided to the controller to control the substance transfer.

In Fig. 8, the mobile control unit 70 of Fig. 6 is shown in more detail. The control unit 70 comprises a process control unit 72, which may be configured to control the configuration of the tubular filling lance 40 via the lance holding device 60 and/or processes such as the filling of the container 20 with the substance 1, the lyopilization and/or the re-hydration of the substance 1. In other words, the mobile control and device unit 70 comprises four main parts positioned for example on one mobile equipment carriage. The main parts are : a product pumping system, comprising a product pump 71 , a suction system 75 , such as a vacuum generator and a filtration system 74, such as a HEPA gas filter with water trap 73, such as a liquid separator and the overall automation of the system 72, such as a process control unit 72. Depending on the used actuator technology, inputs in the mobile control unit 70 are a power connection, compressed air 84 and a data port 83 to connect the system to the intranet.

The suction and filtration system comprises a pressured air system 84, a suction-generating pump 75, a single-use liquid separator 73 and a single-use HEPA filtration system 73. The pressured air system has connection to a supply line/ pressured air system 84 and can be used to move and/or control air pistons connected to the pressured air system 84 or to generate suction power 75, 76 flexibly controlled via the process control system 72. For a sufficient de-contamination of product drops at the tip of the tubular filling lance, the vacuum generation may be in a range of about min. 800 mbar abs. An ejector module, specifically the suction system 75 or similar technologies with high volumetric flow and low vacuum generation may provide the suction capacity. Such technologies are for example electrical powered laboratory suction systems, vacuum blower pumps or turbo-molecular vacuum pumps. This technique includes that a low volume of liquid product and aerosols are transported with the airflow through the suction tubing system 85 and has to be separated until it can be released into the environment 86. Therefore, a single-use a liquid separator 73 and a HEP A filtration system 74 may be used in the category of > H14.

The mobile control unit 70 comprises a product pump 71, which may correspond to a peristaltic pump for example. The product pump 71 is typically not the same as and/or does not correspond to the pump 3 for liquid transport shown in Fig. 17a-e, without limitation. The product pump 71 is configured to transport the substance 1 from the substance reservoir 80 to the container 20 and/or create a force that transfers the substance 1 from the substance reservoir 80 to the container 20 via the product filling line 81 that fluidically connects the substance reservoir 80 with the container 20. The process control unit 72 may control the performance of the product pump 71. Without limitation, the filling system with the pump 71 is typically a different system than the system for re-solubilization, since the filling lance 40 is only used for filling the container 20 and the re-solubilization process is carried out with a technical needle. Without limitation, the control logic behind both processes is typically also different.

For an automated, semi-automated and manual operation mode, the mobile control and device unit 72 may also include a display and control panel. This may involve a recipe manager, which controls process steps and consequential signals. The control panel on the mobile control and device unit 72 may be used for manual control and/or for communication with other devices of the mobile control and device unit 72 including the connection/data port 83 to the carrier system of the filling lance. It may monitor the overall product mass/substance 1 in the product container 80 and may control the product pump 71, specifically the direction of rotation, the rotational speed and/or the resulting filling quantity depending on the used technology. This technology may be controlled by mass based on the weighing capability of the pallet jack or by volume through a product/substance 1 unaffected and/or single-use flow meter. Additionally, it may be in control of direction and speed of relevant pistons and actuators. The movements may be driven pneumatically and/or electrically and may move the tubular filling lance 40 in z-direction and the secure lock at the filling flange. To generate a vacuum suction in time, it may also operate the suction generation system 75. Data generation and product-tracking monitors as an overarching unit may be important for tracking operations and may be in communication with data networks. The control panel on the mobile control and device unit 72 may comprise an input field for receiving commands and/or a button to stop the process in a controlled and/or immediate manner. Most important inputs of the user may be filling quantity and filling velocity. In Fig. 9, the container system 50 is shown in greater detail. The functional lance carrier system 60 may comprise two main parts, the filling lance lifting and safety lock system and the carrier system with visualization and data tracking 64.

To dose the substance 1 into the container 20 and to achieve a de -contamination-free transfer/exchange between containers 20, 80, it is necessary to move the tubular filling lance

41 in the z-direction and provide the system with a safety mechanism during the single filling operations. Such elements may help to establish a clean and safe filling operation and/or to reduce the possibility of misuse and/or erroneous operation.

A single-use product tube 81 may be connected to the filling lance via a tri -clamp connection and/or similar fast coupling single-use technology, which may also serve as a point for the fixing system for moving the tubular filling lance 41.

In dosing position, i.e. the filling configuration A, the tubular filling lance 41 shows a downwards curved position and in rest position, the guidance element may lead to an upwards flexed tube position to avoid further overrun of product. To improve the de -contamination via suction, the fluidic connection towards the inner volume of the tubular filling lance may face a horizontal or downwards leading course . The suction coupling may be based on a single-use element, such as a tri-clamp or other established fast coupling techniques like Festo 6 ports.

The Actuator / Positioning system 63 for configuration A-D comprises two pistons: one is moving the tubular filling lance through the fixing system in z-direction and the second piston underneath the first piston drives the clamping mechanism 62 for the safety lock system. Both actuators 63 may be driven pneumatically and/or electrically and/or may be integrated elements of the filling lance frame. Profiles at the piston housing of the actuators 63 may serve together with the lance housing 46 as click-and-play mechanism. Additionally, the actuators 63 may be operated by the process control system 72 and may be adjustable in speed and length of movement. Depending on the design of the driving mechanism, it is also possible to reduce the number of actuators. As described before, the tubular filling lance 41 of the filling lance device 40 may only be driven into the container 20 in an active modus. To avoid product contamination on the membrane while product filling, it may be achieved that the upper edge of the dispense opening 43 has a distance of more than 5 mm from the membrane.

Main parts of the carrier system may be the filling lance frame and centralized connections of all hoses and cables associated with the system in one user-friendly docking area towards the mobile control and device unit 72. This docking station may include a single-use product tube 81, compressed air or power lines for pistons and actuators 84, tubing for the suction system 85 and communication lines 83 for control, visualization and data generation. In the filling lance frame, the drive assemblies comprising the actuators 63 and mechanisms, the visual traffic light display and/or a start and stop button may integrated. Additionally, it may support the single-use product tube 81 by a guide frame. To improve the product tracking and data acquisition of the overall product handling the carrier frame may also provide a reading unit, such as a scanner 61 for in the container integrated tracking system 26 like RFID-tags, QR-code or Bar-code.

Fig. 16 refers to a method 200 of use of the container system 50 according to any one embodiment or example described herein, for example as described for the container system 50 or elements thereof shown in Fig. 1 to 15. The method 200 achieves contamination-free filling of a container 20 with a substance 1 and comprises in this embodiment the steps: providing 201 a multitude of container systems 50; coupling 202 the filling lance device 40 with the container 20 via the lance coupling portion 47 of the filling lance device 40 and the filling flange 25 of the container 20 and thereby establishing a first fluidic connection 9a (see Fig. 9) between a substance reservoir 80 (see Fig. 6 and 7) containing the substance 1 and the container 20; coupling 203 and fluidically connecting the external suction pump 7 with the channel system 48 via the lance port 49 (indicated in Fig. 2, for example); filling 204, in the filling configuration A (see Fig. 10 showing a filling configuration), the container 20 via the filling lance device 40 by transferring via the first fluidic connection 9a at least a portion of the substance 1 from the substance reservoir 80 into the container 20; and de-contaminating 205 at least a portion of the tubular filling lance 41 by applying an underpressure to the channel system 48 by the external suction pump 7, in the at least one de -contamination configuration B, C, D (see Fig. 11-13 showing each different de -contamination configurations) and at least decoupling 206 the filling lance device 40 from the container 20 and capping of the container flange with of closure. The filling process 202 - 206 of one container 20 is finished now and the process 202 starts again with coupling to the next container system until all containers 20 of a product batch are filled. These steps or at least some of these steps may be repeated until all desired containers 20 are filled.

The method 200 may optionally comprise providing 201 the container system 50 in which the container 20 comprises: a temperature probe guiding tube 12 coupled to a probe opening 21 of the container 20 and at least partially extending into the container 20 and configured for receiving a temperature probe 11 from outside O of the container 20 (see Fig. 5), the temperature probe guiding tube may comprise: a temperature probe introduction opening 13 configured for introducing the temperature probe 11 from outside O of the container 20 into the guiding tube 12 and into a position inside the container 20 which is remote from the probe opening 21; a non-thermally conducting guide tube portion 14 for guiding the temperature probe 11 in the temperature probe guiding tube 12 and positioned at least partially inside I the container 20; and a thermally conducting guide tube end portion 15 positioned opposite the temperature probe introduction opening 13 and configured to provide a thermal bridge between the substance 1 inside the container 20 and the temperature probe 11 when the temperature probe 11 is introduced 207 into the temperature probe guiding tube 12 and is in contact with the thermally conducting guide tube end portion 15; and in which the container system 50 further comprises the temperature probe 11 for determining a temperature of the substance 1 inside I the container 20. The method 200 may further comprise lyophilizing 208 the substance 1 inside the container 20 for storage preservation wherein liquid components in the substance sublime 1 and escape as a gas at least partially from the container 20. Therefore, the method 200 may in specific cases comprise inserting 207 the temperature probe 11 into the temperature probe guiding tube 12; lyophilizing 208 the substance 1 inside the container 20 for storage preservation wherein liquid components in the substance sublime 1 and escape as a gas at least partially from the container 20 and monitoring 209 the temperature of the substance 1, reflecting a status of the lyophilization, by means of the temperature probe 11 ; when a completion of the lyophilization is indicated in the temperature, storing 210 the lyophilized substance 1 inside the container 20; in a case when the substance 1 is needed, establishing 211 a second fluidic connection 9b, specifically a sealed one (see Fig. 17a-17d between a liquid reservoir 8 containing a liquid and the container 20; transferring 212 via the second fluidic connection 9b at least a portion of the liquid from the liquid reservoir 8 into the container 20 to re-solubilize the substance 1 ; and taking 213 at least a portion of the re -solubilized substance 1 via the second fluidic connection 9b or another fluidic connection from the container 20.

A filling process may be realized as follows:

Depending on its size (IL to 1300 L), a production batch (comprising the substance) is divided/filled into a large number of containers. The process workflow may therefore comprise the following steps:

I Preparation and Drip-free filling

201: SET-UP: 1) Providing the right number of containers 20 for the product batch; 2) Preparing components specifically single use components, e.g. the components having the reference numerals 40, 73, 74, 85, 81;

202: Coupling filling lance 40 with container flange 22

203: Start suction via vacuum generator 75

204: Product transfer from product container 80 to container 20 in Configuration A

205: Decontamination with (Filling lance) Configuration B,C,D

206: Decoupling, Capping

Steps 202 -206 are repeated for filling the desired amount of batch volume into the desired number of containers.

II Freeze drying/Lyophilization

207: Optional placement of temperature probe 11 in temperature probe guiding tube 12

208: Lyophilization, i.e. Freezing, 1st product drying, 2nd product drying

III Unloading of freeze dryer and storage

209: Unloading container 20 from freeze dryer and packaging of container 20 in a moisture barrier bag;

210: Commissioning and storage IV Re -solubilization

211 establish second connection

212 Liquid dosing

213 Re-solubilization

214 Remove suspension

215 Thermal seal & cut of the hose through which content is added to the container or removed from the container

In terms of methods, this is conceivable:

Process steps I-III, the end customer then takes the container and e.g. for Custom Biotech (sale of the feedstock on the world market) and fills this into end customer-specific containers in the isolator

And/or:

Process steps I-IV, the end customer re-solibilizes in the container, adds the suspension to its preparation, e.g. for the production of a COBAS TestKit

In Fig. 17a-17e, the concept of re -solubilization of the dried (e.g. lyophilized) substance la and removal of the re-solubilized substance lb is shown according to an embodiment. In Fig. 17a a situation is shown in which a liquid reservoir 8 containing a liquid for re-solubilization 2 of the dried (e.g. lyophilized) substance la inside the container 20 is fluidically connected to the container 20 by establishing 211 a second fluidic connection 9b (the first fluidic connection 9a was established for filling the container 20, see Fig. 9 for example). The second fluidic connection 9b may comprise a pipe and/or a tube 5. The second fluidic connection 9b may be established by pushing a needle or another pipe-like element through a septum that is provided in the container 20 and/or a cap of the container 20. The use of a septum may allow to reduce and/or avoid contaminations with a gas and/or other substances from outside O of the container 20 and the liquid reservoir 8. In other words, the container 20 and the liquid reservoir 8 together with connecting elements may correspond to a closed system or a substantially closed system for at least some substances. A septum may help to achieve such a closed system. In the case in which the container comprises a membrane, the system may however be open for the exchange of gases between the outside of the container 20 and the inside of the container 20. In that case, the pressure inside the container 20 may remain the same, i.e. being passively equilibrated when a liquid is added or removed. A pump for liquid transport 3, e.g. peristaltic pump is arranged between the liquid reservoir 8 and the container 20. The container 20, which may correspond to a tray a shown in Fig. la, is positioned on a rocker 4.

The liquid reservoir 8 may correspond to a sterilized container that contains a sterilized liquid which may have a high purity. The liquid may comprise at least one of: an aqueous solution, a buffer solution, a solvent, an organic solvent, a stabilizer, a detergent, a suspension, a salt. In Fig. 17b, the step of transferring 212 at least a portion of the liquid 2 from the liquid reservoir 8 to the container 20, i.e. the liquid dosing, via the second fluidic connection 9b is shown. In Fig. 17c, the resolubilization 212a of the substance la inside the container 20 with the liquid 2 is indicated. The rocker 4 is therefore activated to contribute a rocking movement for enhancing the process. The rocker 4 may in addition comprise a thermo-element for heating or cooling the substance la, lb. The dried (e.g. lyophilized) substance la becomes a re -solubilized substance lb and the content of the container 20 may therefore be considered a suspension.

In Fig. 17d, the step of removing 213 at least a portion of the suspension comprising the re-solubilized substance lb is indicated. The rocker 4 may be stopped in this situation and the pump for liquid transport 3 is reversed to transfer the suspension with the re-solubilized substance lb into the liquid reservoir 8. Therefore, the second fluidic connection 9b is used to avoid contaminations through an additional connection, which is established.

In Fig. 17e, the step of separating the liquid reservoir 8 (containing at least a portion of the re-solubilized substance lb) from the container 20 and sealing 214 them is indicated. The sealing 214 may be performed by heat sealing. The tube 5 may comprise at least a portion of a thermoplastic at which it can be heat-sealed. This means that heat is applied while pressing the tube together such that the fluidic connection between the liquid reservoir 8 and the container 20 is blocked. The heat allows melting the material such that the blocking remains permanently after cooling down. Either the tube 5 is also separated by the influence of the heat or the tube 5 is cut afterwards to separate the two systems: 1. the liquid reservoir 8 containing at least a portion of the re-solubilized substance lb together with a portion of the tube 5 and 2. The container 20 together with the other portion of the tube 5, which may be disposed as a sealed system. This may be important if the substance is hazardous and/or toxic and the elements, which were in contact therewith, are therefore hazardous waste and require a special treatment after disposal.

Fig. 18 refers to a method 100 of contamination-free handling and lyophilization of a substance 1. The method comprises in this embodiment establishing 102 a first fluidic connection 9a between a substance reservoir 80 containing the substance 1 and a container 20 that comprises a container membrane 24 which is permeable for a gas and impermeable for a liquid; transferring 103 via the first fluidic connection 9a at least a portion of the substance 1 from the substance reservoir 80 into the container 20; de-contaminating 104 elements that are involved in establishing the first sealed connection using an underpressure generated by a suction pump; removing 105 the first sealed connection between the substance reservoir 80 and the container 20 and closing the container 20; lyophilizing 106 the substance 1 inside the container 20 for storage preservation wherein liquid components in the substance 1 sublime and escape as a gas at least partially from the container 20 via the container membrane 24; storing 107 the dried (e.g. lyophilized) substance inside the container 20; in a case when the substance is needed, establishing 108 a second fluidic connection 9b between a liquid reservoir 8 containing a liquid and the container 20; transferring 109 via the second fluidic connection 9b at least a portion of the liquid from the liquid reservoir 8 into the container 20 to re-solubilize the substance 1; and taking 110 at least a portion of the re-solubilized substance 1 via the second fluidic connection 9b or another fluidic connection from the container 20.

Fig. 24 refers to a method 500 of drying a substance 1, the method comprising: providing 501 a container 20 for lyophilization of the substance 1 , the container 20 comprising a membrane wall 24 being permeable for gas and impermeable for liquids and a temperature probe guiding tube 12 coupled to a probe opening 21 of the container 20 and at least partially extending into the container 20 and for receiving a temperature probe 11 determining a temperature of the substance 1 from outside of the container, wherein the temperature probe guiding tube 12 comprises: a non-thermally conducting guide tube portion 14 for guiding the temperature probe 11 in the temperature probe guiding tube 12 and positioned at least partially inside the container 20; and a thermally conducting guide tube end portion 15 positioned opposite the temperature probe introduction opening 13 and for providing a thermal bridge between the substance 1 inside the container 20 and the temperature probe 11 when the temperature probe 11 is introduced into the temperature probe guiding tube 12 and is in contact with the thermally conducting guide tube end portion 15; inserting 502 the temperature probe 11 via an introduction opening 13 of the temperature probe guiding tube 12 from outside of the container 20 into the temperature probe guiding tube 12 and into a position inside the container 20; drying 503, specifically lyophilizing the substance 1; monitoring 504 the temperature of the substance 1 with the temperature probe 11 and stopping the step of drying the substance 1 when a threshold temperature value is reached; removing 505 the temperature probe 11; and storing 506a and/or shipping 506b the container 20 with the lyophilized substance 1 inside.

The method 500 may further comprise prior to the step of lyophilizing the substance 1: providing 507 a filling lance device 40 for contamination-free filling of the container 20 with the substance 1, the filling lance device 40 comprising: a tubular filling lance 41 and a lance housing 46 enclosing at least partially the tubular filling lance 41, wherein the tubular filling lance 41 and the lance housing 46 are movably arranged relative to each other between at least one filling configuration A and at least one decontamination configuration B, C, D, wherein the lance housing 46 comprises a channel system 48 being fluidically connectable to an external suction pump 7 and wherein the at least one de -contamination configuration B, C, D corresponds to a configuration in which the channel system 48 is in fluidic connection with the tubular filling lance 41 ; coupling 508 the filling lance device 40 with a substance reservoir 80; coupling 509 the filling lance device 40 with the container 20 via a lance coupling portion 47 of the filling lance device 40 and the filling flange 25 of the container 20 and thereby establishing a first fluidic connection 9a between the substance reservoir 80 containing the substance 1 and the container 20; coupling 510 and fluidically connecting the external suction pump 7 with the channel system 48 via a lance port 49; filling 511, in the filling configuration A, the container 20 via the filling lance device 40 by transferring via the first fluidic connection 9a at least a portion of the substance 1 from the substance reservoir 80 into the container 20; and de-contaminating 512 at least a portion of the tubular filling lance 41 by applying an underpressure to the channel system 48 by the external suction pump 7, in the at least one de-contamination configuration B, C, D.

The method 500 may comprise in a case when the substance 1 is needed, establishing 513 a second fluidic connection 9b between a liquid reservoir 8 containing a liquid 2 and the container 20; transferring 514 via the second fluidic connection 9b at least a portion of the liquid 2 from the liquid reservoir 8 into the container 20 to re-solubilize the substance 1; and taking 515 at least a portion of the re-solubilized substance 1 via the second fluidic connection 9b or another fluidic connection from the container 20.

In the following an embodiment of the invention was tested for its performance regarding the dust retention capacity. The dust retention capacity of the tray solution was checked with a validated measurement method:

1. Filling and freeze-drying of trays with an appropriate, detectable product/substance (e.g. an enzyme like glucose oxidase, detection limit of 3.6 ng/m³)

2. Connecting lOM-head to the pump inlet using a hose

3. Attach lOM-head at employee’s breathing height or at the location where the measurements are to be taken

4. Attach sampling pump to test person or to an appropriate location

5. Switch on pump (suction capacity of 2 1/min)

6. Unload trays

7. Switch off pump after the end of the process

8. At the end of sampling, remove and seal the filter of each pump and send/deliver clearly labelled samples to external or internal laboratories for analysis

Even values below 10 ng/m³ could be achieved. In the following, a process according to an embodiment is described:

The complete dust-free (< 60 ng/m³) freeze-drying process may be divided into 4 main steps:

I) Preparation & Drip-Free Filling with process steps 201 - 206 (opt. 207)

1) II) Freeze-Drying with process steps 208 -209

III) Unloading of the freeze dryer and storage with process step 210

IV Re-solubilization/Harvesting with process steps 211-214

I. Preparation & Drip-Free Filling

The trays are fdled with suspension directly on the shelves of the freeze dryer in order to avoid the membrane being wetted with suspension during transport. In a first step, the trays are distributed on the freeze dryer floor space. Whereby the filling port should be accessible. In a second step, the filling process can start by placing the filling lance device on the filling port/opening of the container. The filling process may be controlled by the filling device (described in embodiments) and may runs in a semi-automatic mode according to the process described in the process diagram of Fig. 19. At the end of the filling process the filling port is manually capped by the employee and the filled tray may be positioned on the shelf.

II. Freeze-Drying

The temperature sensor should be placed and fixed in the grommet after finishing of the filling process, capping and positioning of the trays. Now, the freeze drying process may be ready to start. Typically, the freeze-drying process is characterized by the two main process steps: Freezing and sublimation. It is not considered necessary to describe the details of the freeze drying process, because the dust retention capacity (< 60 ng/m³) is independent from the process mode while freeze drying. At the end of the freeze-drying process the product/substance may have the morphology of a dried cake, housed by the tray. Both single product freeze-drying but also multiproduct freeze-drying are possible.

III. Unloading of the freeze dryer and storage

The dried (substance) cake may be removed from the freeze-dryer at the end of the (freeze-) drying process. In a first step the temperature control sensors are removed from the grommets. Then, the trays can be unloaded from the shelves of the freeze dryer. In a last commission step, the closed trays are packed in water-impermeable containers for long-term storage. In Fig. 20, the circumstances for the unloading area of the freeze-dryer are indicated. A moisture control may be used to prevent increased moisture in the dried product cake.

IV Re -solubilization and Harvesting

The process of resolubilization is decribed in Fig. 17a-17e. The liquid 2 for re solubilization is added from the reservoir 80 to the container 20 either by connecting with a needle through the septum 32 of the closure 31 and/or via a corresponding port at the end of the tube 28. To improve resolubility of the solids (dried substance), the container 20 may be placed on a rocker 4 (not necessary in all embodiments) that ensures continuous movement of the container 20. After re -solubilization, the re -solubilized substance corresponding to a suspension, solution and/or liquid may be finally pumped out of the container 20 for being used.

The steps of Re -solubilization and Harvesting of a substance may be independent from the herein described concept of contamination-free filling and/or drying of the substance - however some of the features and/or steps may be combined therewith. For example, the container described herein may be provided for this method without necessarily realizing the method described herein. Such steps may correspond to the steps 211-214 described in Fig. 16 but not necessarily being preceded by the steps 201-210. The concept described together with Fig. 17a-17e may apply to this case.

These independent steps of the method 400 are described in Fig. 23 and for better understanding Fig. 17a- e:

In step 401, any kind of container 20 (not necessarily the container described herein) is provided that encloses a dried substance. In a case when the substance 1 is needed, establishing 411 a fluidic connection 9b between a liquid reservoir 8 containing a liquid 2 and the container 20; transferring 412 via the fluidic connection 9b at least a portion of a liquid 2 (such as a buffer, a solvent, a solution or the like) from a liquid reservoir 8 into the container 20 to re-solubilize the dried substance 1; and taking 413 at least a portion of the re-solubilized substance 1 via the fluidic connection 9b or another fluidic connection from the container 20. The container 20 is not required to be a bag for lyophilization (lyo bag) that may comprise a membrane. It may comprise a storage bag, a bioreactor container/bag or the like.

When applying the steps according to an embodiment of Fig. 17a-e to method 400, a situation is shown in Fig. 17a in which a liquid reservoir 8 containing a liquid for re-solubilization 2 of the dried substance la inside the container 20 is fluidically connected to the container 20 by establishing 211 a fluidic connection 9b. The fluidic connection 9b may comprise a pipe and/or a tube 5. The fluidic connection 9b may be established by pushing a needle or another pipe-like element through a septum that is provided in the container 20 and/or a cap of the container 20. The use of a septum may allow to reduce and/or avoid contaminations with a gas and/or other substances from outside O of the container 20 and the liquid reservoir 8. In other words, the container 20 and the liquid reservoir 8 together with connecting elements may correspond to a closed system or a substantially closed system for at least some substances. A septum may help to achieve such a closed system. In the case in which the container comprises a membrane (not necessary, specifically in the present case of method 400), the system may however be open for the exchange of gases between the outside O of the container 20 and the inside I of the container 20. In that case, the pressure inside the container 20 may remain the same, i.e. being passively equilibrated when a liquid is added or removed. Otherwise, a valve for releasing a gas from the inside I to the outside O may be provided but may not be necessary in all cases. A pump for liquid transport 3 (e.g. peristaltic pump) is arranged between the liquid reservoir 8 and the container 20. The container 20, which may correspond to a tray a shown in Fig. la, is positioned on a rocker 4 - Alternatively, the container 20 may be any kind of container not being described herein (e.g. a bioreactor bag, a storage container/bag, a transportation container/bag or the like).

The liquid reservoir 8 may correspond to a sterilized container that contains a sterilized liquid, which may have a high purity. The liquid may comprise at least one of: an aqueous solution, a buffer solution, a solvent, an organic solvent, a stabilizer, a detergent, a suspension, a salt.

In Fig. 17b, the step of transferring 412 at least a portion of the liquid 2 from the liquid reservoir 8 to the container 20, i.e. the liquid dosing, via the second fluidic connection 9b is shown. In Fig. 17c, the resolubilization 412a of the substance la inside the container 20 with the liquid 2 is indicated. The rocker 4 is therefore activated to contribute a rocking movement for enhancing the process. The rocker 4 may in addition comprise a thermo-element for heating or cooling the substance la, lb. The dried (e.g. lyophilized) substance la becomes a re -solubilized substance lb and the content of the container 20 may therefore be considered a suspension.

In Fig. 17d, the step of removing 413 at least a portion of the suspension comprising the re-solubilized substance lb is indicated. The rocker 4 may be stopped in this situation and the pump for liquid transport 3 is reversed to transfer the suspension with the re-solubilized substance lb into the liquid reservoir 8. Therefore, the second fluidic connection 9b is used to avoid contaminations through an additional connection, which is established.

In Fig. 17e, the step of separating the liquid reservoir 8 (containing at least a portion of the re-solubilized substance lb) from the container 20 and sealing 414 them is indicated. The sealing 414 may be performed by heat sealing. The tube 5 may comprise at least a portion of a thermoplastic at which it can be heat-sealed. This means that heat is applied while pressing the tube together such that the fluidic connection between the liquid reservoir 8 and the container 20 is blocked. The heat allows melting the material such that the blocking remains permanently after cooling down. Either the tube 5 is also separated by the influence of the heat or the tube 5 is cut afterwards to separate the two systems: 1. the liquid reservoir 8 containing at least a portion of the re-solubilized substance lb together with a portion of the tube 5 and 2. The container 20 together with the other portion of the tube 5, which may be disposed as a sealed system. This may be important if the substance is hazardous and/or toxic and the elements, which were in contact therewith, are therefore hazardous waste and require a special treatment after disposal.

The following list of items correspond to an aspect of the present disclosure (previously described for example together with Fig. 17a-e and Fig. 23) which are not covered by the claims but which may be explicitly combined with all aspects and/or features of all embodiments, claims and examples:

Item 1. A method (400) of re-solubilization of a dried substance enclosed in a container and harvesting of the re-solubilized substance from the container comprises the following steps: providing a container (401) that encloses the dried substance; in a case when the substance is needed, establishing (411) a fluidic connection (9b) between a liquid reservoir (8) containing a liquid (2) for re-solubilization and the container (20); transferring (412) via the fluidic connection (9b) at least a portion of the liquid (2) from the liquid reservoir into the container (20) to re-solubilize (412a) the dried substance (la); and taking and/or removing (413) at least a portion of the re-solubilized substance (lb) via the fluidic connection (9b) or another fluidic connection (to be established) from the container (20).

Item 2. The method of item 1, wherein the fluidic connection (9b) is established by: providing a needle that is in fludic connection with the liquid reservoir (8) containing the liquid (2) for resolubilization; providing a septum on/at the container (20) and punching the needle through the septum of the container (20) into the ineterior/inside of the container (20); and/or providing a flange for re-solubilization on/at the container (20) and pushing the needle through the flange, preferably wherein the flange (29) comprises a tube with an open tube end and the tube is in fluidic connection with the inside of the container (20) and a tube clip (28) and/or clamp for opening and/or closing the tube end such that the tube end represents a port and/or fluidic connection between the inside (I) and the outside (O) that can be reversibly opened and/or closed.

Item 3. The method of item 2 may comprise closing and/or blocking the fluidic connection (9b) and thereby separating (414) the liquid reservoir (8) from the container (20) and sealing the liquid reservoir and the container, specifically by heat-sealing the tube; or clamping (off) and/or crimping the tube using the tube clip (28) and/or the clamp.

Item 4. The method of any one of the items, wherein the container (20) is disposed after taking and/or removing (413) at least a portion of the re -solubilized substance (lb) via the fluidic connection (9b) or another fluidic connection from the container (20).

Item 5. A container (20) for monitoring a temperature of a substance therein, wherein the container (20) comprises: a temperature probe guiding tube (12) coupled to a probe opening (21) of the container (20) and at least partially extending into the container (20) and configured for receiving a temperature probe (11) determining a temperature of the substance (1) from outside of the container, the temperature probe guiding tube (12) comprising: a temperature probe introduction opening (13) configured for introducing the temperature probe (11) from outside of the container (20) into the temperature probe guiding tube (12) and into a position inside the container (20); a non-thermally conducting guide tube portion (14) for guiding the temperature probe ( 11 ) in the temperature probe guiding tube (12) and positioned at least partially inside the container (20); and a thermally conducting guide tube end portion (15) positioned opposite the temperature probe introduction opening (13) and configured to provide a thermal bridge between the substance (1) inside the container (20) and the temperature probe (11) when the temperature probe (11) is introduced into the temperature probe guiding tube (12) and is in contact with the thermally conducting guide tube end portion (15).

Item 6. The container (20) of item 5 comprising at least one of: a bag, a single-use and/or disposable bag, a polymer container, an at least partially flexible container, an at least partially non-flexible container, a container configured for storage of the substance and/or for lyophilization of the substance, specifically a lyophilization bag.

Item 7. The container (20) of items 5 or 6 corresponding to a container (20) for lyophilization of the substance and comprising a membrane wall (24) being permeable for gas and impermeable for liquids, specifically wherein the container (20) comprises a frame (23) for supporting the membrane wall (24).

Item 8. The container (20) of any one of items 5 to 7, further comprising a temperature probe holding portion configured to hold, clamp, fix, align and/or couple the temperature probe (11) in the temperature probe guiding tube (12).

Item 9. The container (20) of any one of items 5 to 8, wherein the temperature probe guiding tube (12) is configured to prevent the temperature probe (11) to be in direct contact with the substance (1) inside the container (20) and/or the volume inside the container.

Item 10. A container system (50) comprising: the container of any one of the preceding items 5 to 9; and the temperature probe (11).

Item 11. A method (100) of contamination-free handling and drying of a substance (1), the method comprising: establishing ( 102) a first fluidic connection (9a) between a substance reservoir (80) containing the substance (1) and a container (20) that comprises a container membrane (24) which is permeable for a gas and impermeable for a liquid; transferring (103) via the first fluidic connection (9a) at least a portion of the substance (1) from the substance reservoir (80) into the container (20); de -contaminating (104) elements that are involved in establishing the first sealed connection using an underpressure generated by a suction pump; removing (105) the first sealed connection between the substance reservoir (80) and the container (20) and closing the container (20); drying (106) the substance (1) inside the container (20) for storage preservation; storing (107) the dried substance inside the container (20); in a case when the substance is needed, establishing ( 108) a second fluidic connection (9b) between a liquid reservoir (8) containing a liquid and the container (20); transferring (109) via the second fluidic connection (9b) at least a portion of the liquid from the liquid reservoir (8) into the container (20) to re-solubilize the substance (1); and taking (110) at least a portion of the re -solubilized substance (1) via the second fluidic connection (9b) or another fluidic connection from the container (20).

Reference list

1 substance la dried (e.g. lyophilized) substance lb re-solubilized substance

2 liquid for re-solubilization

3 pump for liquid transport, e.g. peristaltic pump

4 rocker

5 tube used for second fluidic connection

7 external suction pump

8 liquid reservoir

9a first fluidic connection

9b second fluidic connection

10 probe head system

11 temperature probe

12 temperature probe guiding tube

13 temperature probe introduction opening

14 guide tube portion

15 guide tube end portion

16 probe head lock system

17 thermally conducting element

20 container

21 container probe opening

22 container fill opening

23 container frame

24 container membrane filling flange a supporting protrusion and/or base identification label closure flaps tube clip flange for re -solubilization container system or portion of container system closure element septum fitting filling lance device tubular filling lance introduction opening of the filling lance a funnel dispense opening of the filling lance lance tube portion a stopper and/or rotation blocking mechanism b protrusion of tubular filling lance c protrusion of lance housing passage, specifically capillary passage system b capillary droplet collection opening c passage opening lance housing a sliding bush lance coupling portion channel system a channel (system) opening lance port container system lance holding device/ lance carrier system scanner fixing and connecting system between lance carrier system and filling port 63 actuator / Positioning system for configuration A-D

64 status display and operating button

70 mobile control unit

71 product pump

72 process control unit

73 liquid separator

74 HEPA gas filter

75 vacuum generator

76 valve for compressed air supply

80 substance reservoir / product container

81 product filling line/ e.g. tube used for first fluidic connection

82 data cable

83 data and signal exchange between carrier system and control unit

84 compressed air for piston movement and vacuum generation

85 product contaminated air from lance system to control unit

86 air after de -contamination for vacuum generation with compressed air

90 filling system

100 method of contamination-free handling and lyophilization of a substance

101-110 method steps of the method of contamination-free handling and lyophilization of a substance

200 method of use of the container system

201-216 method steps of the method of use of the container system

A filling configuration

B lance volume de-contamination configuration

C passage de-contamination configuration

D outer surface de-contamination configuration

DA (main) dispense axis

I inside of the container

LA filling lance axis, specifically length axis of filling lance device

O outside of the container

S outer surface of tubular filling lance

V tube volume I preparation & Drip-Free Filling with process steps 201 - 206

II freeze-Drying with process steps 208 -209

III unloading of the freeze dryer and storage with process step 210

IV re-solubilization/Harvesting with process steps 211-214

Claims

Patent claims

1. A container system (50) configured for contamination-free filling of a container (20) with a substance (1), the container system (50) comprising: a filling lance device (40) configured for contamination-free filling of the container (20) with a substance (1), the filling lance device (40) comprising: a tubular filling lance (41) and a lance housing (46) enclosing at least partially the tubular filling lance (41), wherein the tubular filling lance (41) and the lance housing (46) are movably arranged relative to each other between at least one filling configuration (A) and at least one de -contamination configuration (B, C, D), wherein the lance housing (46) comprises a channel system (48) being fluidically connectable to an external suction pump (7) and wherein the at least one de -contamination configuration (B, C, D) corresponds to a configuration in which the channel system (48) is in fluidic connection with the tubular filling lance (41); and the container system (50) further comprising: the container (20) with a container fill opening (22), the container (20) being configured to be filled with the substance (1) via the container fill opening (22), specifically wherein the container (20) comprises a filling flange (25) on the fill opening (22) configured to be coupled with the filling lance device (40), specifically being configured to be coupled with the lance coupling portion (47) of the filling lance device (40).

2. The container system (50) of claim 1, wherein the channel system (48) comprises at least two channel system openings (48a) directed towards an inner side of the lance housing (46).

3. The container system (50) of claim 1 or 2, wherein the container (20) comprises a membrane wall (24) being permeable for gas and impermeable for liquids, specifically wherein the container (20) comprises a frame (23) for supporting the membrane wall (24).

4. The container system (50) of any one of the preceding claims, wherein the container system (50) comprises a septum (32) configured for removal of at least a portion of the substance (1) from the container (20) and/or addition of an additional substance (1) to the container (20), specifically wherein the septum (32) is provided in a closure element (31) for closing the container fill opening (22).

5. The container system (50) of any one of the preceding claims, wherein the filling flange (25) and the lance coupling portion (47) are dimensioned such that the filling flange (25) encloses the lance coupling portion (47) at least partially, and/or wherein the filling flange (25) and the lance coupling portion (47) are dimensioned such that the lance coupling portion (47) encloses the filling flange (25) at least partially, and/or wherein the filling flange (25) comprises a protrusion (25a) configured for supporting the lance coupling portion (47) when the filling flange (25) is coupled with the lance coupling portion (47).

6. The container system (50) of any one of the preceding claims, wherein the container (20) comprises: a temperature probe guiding tube (12) coupled to a probe opening (21) of the container (20) and at least partially extending into the container (20) and configured for receiving a temperature probe (11) from outside of the container, the temperature probe guiding tube (12) comprising: a temperature probe introduction opening (13) configured for introducing the temperature probe (11) from outside of the container (20) into the temperature probe guiding tube (12) and into a position inside the container (20); a non-thermally conducting guide tube portion (14) for guiding the temperature probe ( 11 ) in the temperature probe guiding tube (12) and positioned at least partially inside the container (20); and a thermally conducting guide tube end portion (15) positioned opposite the temperature probe introduction opening (13) and configured to provide a thermal bridge between the substance (1) inside the container (20) and the temperature probe (11) when the temperature probe (11) is introduced into the temperature probe guiding tube (12) and is in contact with the thermally conducting guide tube end portion (15), specifically wherein the container system (50) further comprises the temperature probe (11) for determining a temperature of the substance (1) inside the container (20).

7. The container system (50) of any one of the preceding claims, wherein at least one component of the container system (50) is a disposable component, specifically wherein the filling lance device (40) is a disposable component and/or the container (20) is a disposable component.

8. The container system (50) of any one of the preceding claims, further comprising a lance holding device (60) for holding the filling lance device (40) in a fill position with respect to the container (20), specifically wherein the lance holding device (60) is configured for multiple use; and/or an actuator (63) configured to automatically establish the at least one filling configuration (A) and/or the at least one de-contamination configuration (B, C, D).

9. A filling lance device (40) configured for contamination-free filling of a container (20) with a substance (1), the filling lance device (40) comprising: a tubular filling lance (41) and a lance housing (46) enclosing at least partially the tubular filling lance (41), wherein the tubular filling lance (41) and the lance housing (46) are movably arranged relative to each other between at least one filling configuration (A) and at least one de-contamination configuration (B, C, D), wherein the lance housing (46) comprises a channel system (48) being fluidically connectable to an external suction pump (7) and wherein the at least one de -contamination configuration (B, C, D) corresponds to a configuration in which the channel system (48) is in fluidic connection with the tubular filling lance (41).

10. The filling lance device (40) of claim 9, wherein the channel system (48) comprises at least two channel system openings (48a) directed towards an inner side of the lance housing (46); and/or wherein the tubular filling lance (41) and the lance housing (46) are movably arranged relative to each other along a filling lance axis (LA), specifically wherein the filling lance device (40) comprises at least one of: a sliding bush (46a) positioned between the tubular filling lance (41) and the lance housing (46) and being configured to restrict and/or prevent relative movements between the tubular filling lance (41) and the lance housing (46) which are not directed along the filling lance axis (LA); a stopper mechanism (44a) being configured to restrict a relative movement between the tubular filling lance (41) and the lance housing (46) along the filling lance axis (LA); a rotation blocking mechanism configured to restrict and/or prevent a relative rotational movement between the tubular filling lance (41) and the lance housing (46).

11. The filling lance device (40) of claim 10, wherein a dispense opening (43) of the tubular filling lance (41) defines a dispense axis (DA) that deviates from the filling lance axis (LA).

12. The filling lance device (40) of any one of the claims 9-11, wherein the at least one de -contamination configuration (B, C, D) comprises at least one of: a lance volume de-contamination configuration (B) in which the channel system (48) is in fluidic connection with a tube volume (V) that is at least partially enclosed by the tubular filling lance (41), specifically via the dispense opening (43); an outer surface de-contamination configuration (D), in which the channel system (48) is in a fluidic connection with an outer surface (S) of the tubular filling lance (41), specifically with an edge of the tubular filling lance (41); a passage de-contamination configuration (C), for which the tubular filling lance (41) comprises a passage (45), specifically a microfluidic and/or capillary passage system, that is configured to fluidically connect the outer surface (S) of the tubular filling lance (41) with the channel system (48) in the passage decontamination configuration (C).

13. The filling lance device (40) of any one of the claims 9-12, further comprising a lance coupling portion (47) positioned on the lance housing (46) and configured to couple the filling lance device (40) to the container (20).

14. A method (200) of use of the container system (50) according to any one of claims 1 to 8 for contamination-free filling of a container (20) with a substance (1), the method (200) comprising: providing (201) the container system (50) according to any one of claims 1 to 8; coupling (202) the filling lance device (40) with the container (20) via the lance coupling portion (47) of the filling lance device (40) and the filling flange (25) of the container (20) and thereby establishing a first fluidic connection (9a) between a substance reservoir (80) containing the substance (1) and the container (20); coupling (203) and fluidically connecting the external suction pump (7) with the channel system (48) via the lance port (49); filling (204), in the filling configuration (A), the container (20) via the filling lance device (40) by transferring via the first fluidic connection (9a) at least a portion of the substance (1) from the substance reservoir (80) into the container (20); and de -contaminating (205) at least a portion of the tubular filling lance (41) by applying an underpressure to the channel system (48) by the external suction pump (7), in the at least one de-contamination configuration (B, C, D).

15. The method of claim 14 for the contamination-free filling of the container with the substance (1) and for drying the substance (1), the method comprising: providing (201) the container system (50) according to claim 6; removing (206) the first sealed connection (9a) between the substance reservoir (80) and the container (20) and closing the container (20) after filling (204) the substance (1) into the container (20) and after de -contaminating (205) the at least one portion of the tubular filling lance (41) which is to be decontaminated; inserting (207) the temperature probe (11) into the temperature probe guiding tube (12); drying (208) the substance (1) inside the container (20) for storage preservation; when a completion of the drying is indicated in the temperature, storing (210) the dried substance (1) inside the container (20); in a case when the substance (1) is needed, establishing (211) a second fluidic connection (9b) between a liquid reservoir (8) containing a liquid (2) and the container (20); transferring (212) via the second fluidic connection (9b) at least a portion of the liquid (2) from the liquid reservoir (8) into the container (20) to re-solubilize the substance (1); and taking (213) at least a portion of the re -solubilized substance (1) via the second fluidic connection (9b) or another fluidic connection from the container (20).