Patent Description:
Crossflow filtration ("CFF" also referred to a "tangential flow filtration" (TFF)) systems are used in industry applications, such as, for example, manufacturing process separations, waste treatment plants and water purification systems where they can extend the lifetime of filtration membranes by removing and/or preventing the build-up of contaminants and promote consistency of the filtration process with time. Various filtration devices, e.g. using TFF, are known. See, for example, <CIT>, <CIT>, <CIT> and <CIT>.

The most commonly used CFF/TFF membrane processes are microfiltration and ultrafiltration. Such processes may be pressure driven and depend upon the "membrane flux", defined as the flow volume over time per unit area of membrane, across the microfiltration or ultrafiltration membrane. At low pressures, the transmembrane flux is proportional to pressure. As a result, by varying the transmembrane pressure difference driving force and average pore diameter, a membrane may serve as a selective barrier by permitting certain components of a mixture to pass through while retaining others. This results in two phases, the permeate and retentate phases, each of which is enriched in one or more of the components of the mixture. The retentate stream is recirculated in the flow circuitry and is pumped across the membrane again in a continuous fashion. Such CFF/TFF systems are used to significantly reduce the volume of the sample solution as a permeate stream is withdrawn from the system. So, the sample solution becomes concentrated when the system is driven in a concentration mode.

CFF/TFF systems have the advantage that due to the direction of the flow of the fluid sample, which is essentially parallel to the membrane surface, an automatic sweeping and cleansing takes place so that higher fluxes and higher throughputs can often be attained with such systems in relation to corresponding normal flow filtration systems. Further, a large fraction of sample flows continuously over the membrane surface so that a clogging and fouling is discouraged in such systems. With respect to these and other advantages, CFF/TFF systems are often used in industrial and/or biotechnological processes.

In an automated CFF/TFF system, buffer and other system treatment solutions need to circulate through the filter and other system components for equilibration prior or subsequent to the separation process. Ideally, such circulation and equilibration of buffer and other system treatment solutions is performed by an automated method without the need for manual intervention.

Filtration systems are a critical component of the pharmaceutical and biotechnology industries for purifying bioprocessing liquids. Due to the high value of the purified liquid extensive research has been focused on improving all aspects of the filtration systems. Such filtration systems also cover a broad spectrum of utility including micro-filtration, ultrafiltration, tangential or cross-flow filtration, as well as constant volume diafiltration. Generally, in these systems, the liquid to be filtered is forced through a flow path to a porous membrane sheet or a porous hollow fiber column. Such sheets or membranes are commercially available and utilizing these different pore sizes molecules or particulates smaller than the average membrane or column pore size will pass, together with solvent for example, through the membrane or hollow fiber walls and are collected as filtrate. A retentate flow is left behind. In many filtration approaches, such as those incorporating ultrafiltration or other tangential-flow filtration devices, the retentate is repeatedly re-circulated with the objective of improving filtration efficiency and enhancing the yield of the filtrate or permeate. Each of these flows contains valuable product up to <NUM>-<NUM>% of the total recovery potential. Examples of such systems can be found in <CIT>; <CIT>; <CIT> and International Patent Publication <CIT>.

Quantitative recovery of the valuable concentrated bioprocess liquid after purification and or concentration is one area of interest. Once maximal purification and/or concentration processing is complete a significant amount of residual bioprocess liquid remains in the flow path of the filtration system. Numerous strategies have been applied to facilitate recovery of this residual liquid. Unfortunately none of these methods has resulted in the efficient and quantitative recovery of all residual liquid.

Further, there is a need for removal of air from the flow path during startup of the process, which is not adequately addressed by the current art.

Accordingly there is a need for further developments to ensure complete recovery of valuable bioprocess liquids as well as complete air removal during startup. This need applies to filtration systems but also to other bioprocess systems, such as e.g. chromatography systems and bioreactors.

One aspect of the invention is to provide a unit for treatment of a bioprocess liquid which allows complete recovery of liquid and facilitates the removal of air from the system. This is achieved with a first unit as defined in claim <NUM>.

An advantage is that the unit improves the drainage of a disposable flow path mounted on the unit prior to disposal of the flow path. It is always advantageous to to drain while the flow path is in a controlled position, i.e. mounted on the unit, compared to draining a loose flow path after dismounting it from the unit and manually directing the tubing towards a draining point. The latter procedure is not compatible with GMP manufacturing and definition of standard operating procedures necessary in a biopharmaceutical production setting.

A second aspect of the invention is to provide an apparatus for treatment of a bioprocess liquid which allows complete recovery of liquid and facilitates the removal of air from the system. This is achieved with an apparatus as defined in the claims.

A third aspect of the invention is to provide a method of installing a disposable flow path on a unit for treatment of a bioprocess liquid. This is achieved with a method as defined in the claims.

A fourth aspect of the invention is to provide a method of tangential flow filtration of a bioprocess liquid. This is achieved with a method as defined in the claims.

Further suitable embodiments of the invention are described in the dependent claims.

To more clearly and concisely describe and point out the subject matter of the claimed invention, the following definitions are provided for specific terms that are used in the following description and the claims appended hereto.

The singular forms "a" "an" and "the" include plural referents unless the context clearly dictates otherwise. Accordingly, a value modified by a term such as "about" is not to be limited to the precise value specified. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the embodiments of the present invention. At the very least each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

Any directional terms such as "top", "bottom", "above", "below" "up", "down", "high", "low" and "height" herein refer to the devices as they appear in the drawings. Joinder references (e.g., joined, attached, coupled, connected, and the like) are to be construed broadly and may include intermediate members between a connection of elements and relative movement between elements. As such, joinder references do not necessarily imply that two elements are connected directly and in fixed relation to each other. Further, various elements discussed with reference to the various embodiments may be interchanged to create entirely new embodiments coming within the scope of the present invention.

In one aspect, illustrated by <FIG>, the present invention discloses a first unit <NUM> for treatment of a bioprocess liquid, which can e.g. be a filtration unit, such as a tangential flow filtration unit or a dead end filtration unit. Alternatively, the first unit can be a chromatography unit or a bioreactor unit. The first unit comprises a first lateral face <NUM>, a second lateral face <NUM> and a front face <NUM> which meets the two lateral faces. Suitably, the front face and optionally also the lateral faces can be vertically oriented. The first unit may comprise or be adapted to receive a filter element <NUM>, e.g. on one of the lateral faces. This filter element may be fluidically connected to a disposable flow path <NUM>. The first unit, in particular the front face <NUM>, comprises:.

The plurality of valves and optional pumps and sensors are vertically offset from each other to give one or more legs, such as all legs, of a disposable flow path received by the valves and optional pumps and sensors a slope of at least <NUM> degrees from the horizontal plane h. The slope can be defined as the angle α between a straight line from one end <NUM> of a leg <NUM> to an opposite end <NUM> of the leg and the horizontal plane h. Suitably, the slope may be <NUM>-<NUM> degrees from the horizontal plane. The slope allows efficient draining of the system, which is essential for the recovery of valuable material after completion of a treatment, e.g. a filtration run, a chromatography run or a cell culture. This also minimizes the amount of liquid discarded with the disposable flow path after use, facilitating incineration of the flow path and reducing the amount of potentially biohazardous material to be handled as waste. Further, removal of air from the system is also facilitated by the slope. The slope is particularly important when a flow path with lengths of tubing <NUM> connected by hose barb couplings <NUM> is used, as the lower inner diameter of the hose barb couplings causes stagnating pools and can trap air bubbles. Hose barb couplings are particularly desirable for braided tubing and other types of tubing which is not amenable to connection by welding or molding. We have found that a slope larger than <NUM> degrees drastically improves the draining, particularly when connectors are used, but also to counteract any slack in flexible flow path legs. The volume of the flow path should generally be kept as low as possible to minimize the hold-up volume, thus allowing high concentration factors and low volumes of processed fluid. Fort this reason, the slopes can suitably be up to <NUM> degrees or up to <NUM> or <NUM> degrees, as higher slopes lead to longer legs. Short branch legs connecting the longer legs may however need to have a higher slope, e.g. about <NUM> degrees. As illustrated in <FIG>, also one or both of the lateral faces <NUM> and <NUM> may comprise a plurality of valves <NUM> and optional pumps <NUM>/sensors <NUM> adapted to receive one or more flow path legs <NUM> in a sloped configuration.

In some embodiments, illustrated by <FIG>, <FIG> and <FIG>, the first unit further comprises guides <NUM> on the front face, and optionally one or both of the lateral faces, between the valves and any optional pumps and sensors for installation of the disposable flow path. The guides can be essentially linear with slopes of at least <NUM>, or <NUM>-<NUM> degrees from the horizontal plane. They may comprise visually and/or tactilely distinguishable lines, such as e.g. coloured lines <NUM> or relief lines <NUM> along which the legs of a disposable flow path can be arranged. The guides may also comprise means for restraining a disposable flow path with the desired slope, e.g. pegs <NUM>, ledges <NUM> and/or recesses <NUM> adapted to receive the disposable flow path. The legs of the disposable flow path can suitably be aligned with the guides, and in case the guides comprise restraining means this can minimize any slack in flexible flow path legs. During use, single use systems for treatment of bioprocess liquids require frequent installation and removal of the flow paths. This is greatly facilitated by the presence of guides.

In certain embodiments, illustrated by <FIG>, the first unit (or the apparatus <NUM> as discussed below) further comprises a processor <NUM> with an optical display <NUM>. A graphical user interface <NUM> on the optical display shows an outline of the front face <NUM> with valves <NUM>, optional pumps <NUM> and sensors <NUM> and the flow path <NUM>, with one or more legs <NUM> of the flow path having a slope of at least <NUM>, or <NUM>-<NUM> degrees from the horizontal plane h. The graphical user interface with the slopes visualized is helpful for the user to understand the orientation of the flow path legs. Further it facilitates the programming of methods for draining/recovery and/or air removal with appropriate flow directions. This is particularly important for draining/recovery methods, where the draining flow directions in the flow path may be the reverse of the pump flow directions during the main process operation.

In some embodiments, illustrated by <FIG>, the first unit is adapted to be juxtaposed by the first lateral face against a second unit <NUM>. The first unit can also be adapted to be juxtaposed by the second lateral face against a third unit <NUM>. At least one of the second and third units may be adapted to receive a tank, such as a flexible bag <NUM>,<NUM>, fluidically connected to the disposable flow path. One of the second and third units may e.g. be adapted to receive a feed/retentate tank or bag <NUM> and the other of the second and third units may e.g. be adapted to receive a permeate tank or bag <NUM>. Alternatively, one of the second and third units may be adapted to receive both a feed/retentate tank or bag and a permeate tank or bag. The other of the second and third units may e.g. be adapted to receive a filtration element, e.g. a cassette holder for flat sheet filtration cassettes.

In a second aspect, illustrated by <FIG>, the invention discloses an apparatus <NUM> for treatment of a bioprocess liquid. The apparatus can typically be a filtration apparatus, such as a tangential flow filtration apparatus, but it can also be e.g. a chromatography apparatus. This apparatus comprises the first unit <NUM> as discussed above and at least one of a second <NUM> and a third <NUM> unit juxtaposed by the first and/or second lateral faces. The apparatus may further comprise one or more of a filtration element <NUM>, a feed/retentate tank or bag <NUM> and a permeate tank or bag <NUM>, all of which may be fluidically connected by the disposable flow path <NUM> described above. The disposable flow path may comprise a retentate loop received by a retentate pump and fluidically connected with a retentate inlet and a retentate outlet on the filter element. The retentate loop can also suitably be fluidically connected with a feed/retentate tank or bag, such as with a feed/retentate tank or bag outlet and a feed/retentate tank or bag inlet. Further, the disposable flow path may comprise a permeate line or permeate loop fluidically connected to at least a permeate outlet on the filter element. The permeate line/loop may be received by a permeate pump and fluidically connected to a permeate tank or bag.

In a third aspect, the invention discloses a method of installing a disposable flow path on the first unit as discussed above, comprising receiving the disposable flow path in the valves and optional pumps and sensors, wherein all legs of said disposable flow path have a slope of at least <NUM>, degrees from the horizontal plane. Suitably, one or more legs have a slope of <NUM>-<NUM> degrees from the horizontal plane. The disposable flow path can be supplied presterilized, e.g. sterilized by gamma irradiation. It can be equipped with sanitary connectors for aseptic connection to a filtration element, a feed/retentate tank or bag and a permeate tank or bag. Alternatively, it can comprise lengths of tubing for sterile welding to tubing extending from the filtration element, feed/retentate tank/bag and or permeate tank/bag. In a fourth aspect, the invention discloses a method of tangential flow filtration of a bioprocess liquid, comprising the steps of:.

The method can also comprise, before or during step b), a step a') of letting out any residual air through an air outlet leg of the disposable flow path. The air outlet leg may be a branch of the flow path located in a high position and may comprise a sterilization grade filter to prevent contamination of the flow path.

In some embodiments, the method comprises, after step c), a step d) of draining the disposable flow path. The draining can e.g. be performed via a draining leg of the disposable flow path. This leg can e.g. be a branch of the flow path located in a low position and it may be connected to a drain vessel. After the draining step d), the method may further comprise a step e) of discarding the disposable flow path. This can e.g. be done by incineration.

Claim 1:
A first unit (<NUM>) for treatment of a bioprocess liquid comprising a first lateral face (<NUM>), a second lateral face (<NUM>) and a front face (<NUM>) which meets the two said lateral faces; said front face comprising:
- a plurality of valves (<NUM>) adapted to receive and act upon one or more legs (<NUM>) of a disposable flow path (<NUM>);
- optionally one or more pumps (<NUM>) adapted to receive and act upon one or more legs of said disposable flow path;
- optionally one or more sensors (<NUM>) adapted to receive and to measure one or more parameters in one or more legs of said disposable flow path; characterised in that:
- said plurality of valves and optional pumps and sensors are vertically offset from each other to give all legs of a disposable flow path received by said valves and optional pumps and sensors a slope of at least <NUM> degrees from the horizontal plane (h),
wherein the unit comprises a disposable flow path with legs connected by hose barb couplings (<NUM>), said first unit (<NUM>) further comprising guides (<NUM>) on said front face between said valves and optional pumps and sensors for installation of said disposable flow path, wherein said guides (<NUM>) are essentially linear with slopes of at least <NUM> degrees from the horizontal plane.