Storage/containment unit for flexible pouch filled with biopharmaceutical fluid, and method of assembling a freeze/thaw containment system, using a protecting body

A protecting device is provided, having two plates forming a rectangular protecting body for sandwiching, constraining and protecting a flexible pouch. The two plates are attached together at a peripheral margin. Each plate has an outer surface with ribs provided in a peripheral annular region of a covering part receiving the pouch, along the peripheral margin. The peripheral margin is mounted in supporting parts of a frame and sliding positioning members may be secured to the peripheral margin, so that the peripheral margin is guided and allowed to be displaced inwardly during filling of the pouch, while the protecting body extends generally planar, at least at panel parts surrounded by the ribs. This allows for progressive conformational change of the protecting body when filling the pouch with biopharmaceutical product, while facilitating reverse displacement of the peripheral margin during draining operations.

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention generally relates to the protection of a flexible pouch specially designed to contain a biopharmaceutical fluid and more broadly to a system for containing a biopharmaceutical fluid. The invention also relates to methods for manufacturing/assembling such a system that is adapted for freezing and thawing the biopharmaceutical fluid within the system. A biopharmaceutical fluid means a biotechnological derived fluid, for example a fluid derived from a culture medium, a cell culture, a buffer solution, an artificial nutrition liquid, a blood fraction, a blood derived component or a pharmaceutical fluid or, more broadly, a fluid specifically designed to be used in the medical field. Of course, the fluid may become solid or partly solid after freezing (typically at a temperature much lower than 0° C.).

DESCRIPTION OF RELATED ART

It is known to use a flexible pouch to contain biopharmaceutical fluid. The flexible pouch is able to withstand low mechanical stress without damage. Hence, the leakage risk is reduced. Moreover, the flexible pouch is advantageous since it can be folded or stored flat when there is no biopharmaceutical fluid inside. Hence, the flexible pouch occupies a small volume.

The flexible pouch is generally designed for a single use and to contain a biopharmaceutical fluid volume which is between 1 liter and 500 liters.

However, specifically for shipping of the flexible pouch filled with fluid, for example, between several plant areas or from the provider of the fluid to its client which will use it, but also for storage, the flexible pouch must be protected, although the leakage risk is small.

The document EP-2 322 442 discloses a container for a flexible pouch. The container comprises a lower part and an upper part which are rigid and joined along a common edge and which form a single piece container. The container has a volume which is much more important than the volume of the flexible pouch. Consequently, the container has a useless volume. Moreover, if the flexible pouch is not retained by suitable positioning means provided in the container, it could be moved within the container, especially during shipping. Thus, the leakage risk increases.

Single-use polymeric containers, hereafter called bags or pouches, are successfully used for the storage of biopharmaceuticals in liquid state. Today, bags made of ethylene vinyl acetate (EVA) or low-density polyethylene (LDPE) have been found suitable for the storage and shipping of biological bulks at ambient or cold temperature (2 to 8° C.). However, problems exist in freezing applications with bags as currently configured. At low temperatures, the physical properties of plastic materials may change sufficiently to introduce brittleness that can reduce the capacity of the bag to absorb external forces, i.e., shocks without fracturing. In addition, ice volumetric expansion can cause significant mechanical stress leading to bag, port, tubing, or connector breakage. It is well known that current commercially available unprotected bags do not adequately protect frozen products.

To eliminate problems related to bag breakage, Sartorius Stedim Biotech has developed the Celsius™ FFT concept (FFT for “Flexible Freeze and Thaw”), which combines a flexible pouch with a semi-rigid protective shell. The contribution of the protective shell is predominant in the absorption of stresses resulting from processing or handling conditions.

Document US 2018/125757 provides a protecting body, so that the flexible pouch is sandwiched by the two plates of the protecting body, with a constraining effect. A freeze/thaw protection system may be obtained, by combining a single-use flexible container wrapped by such a protecting body and a protective shell. However, uniform fluid distribution may be difficult because, in a filled state of the flexible container, a significant bulge (big belly) in the middle is formed. In frozen state, ice expansion is thus relatively significant, and more time will be needed to freeze this big mass in the middle of the interior volume of the pouch.

Besides, some radial/transverse folds or waves may be formed at the pouch outer surfaces during filling, which may interfere with appropriate fluid distribution, especially in the four corner regions.

Document WO 2015/200218 discloses a single-use flexible freezer bag, in which a tufting coupling is provided, in order to divide the cavity of the container into a plurality of regions. This is of interest to limit risk of having a significant bulge, so that liquid mass concentration is prevented in a middle part of the flexible container. Such design cannot be widely used, especially because the bag design is more complex, which increases the cost of the single-use container. Besides, this kind of container cannot extend planar in empty state and may be more difficult to be drained, especially if the container is filled with a large volume of fluid.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a protecting device for obtaining a robust freeze/thaw containment and protection system efficient for limiting liquid mass concentration in middle area of a flexible pouch (typically a 2D-pouch than inflates in a filled state), while keeping flexibility of design for the flexible pouch.

To this end, embodiments of the present invention provide a protecting device for use in freezing, storing and thawing biopharmaceutical materials contained in a flexible pouch, the protecting device comprising:

a protecting body comprising two plates for protecting the flexible pouch, the protecting body comprising a longitudinal axis and having four sides, the four sides comprising two longitudinal sides extending parallel to the longitudinal axis and two other sides that include a first end side and a second end side each perpendicular to the longitudinal axis,

an attachment system for fastening the two plates so that in an assembled state of the two plates, the protecting body comprises a peripheral margin that extends annularly in a protecting body reference plane, the peripheral margin being provided with at least one opening able to receive at least one port of the flexible pouch;

wherein the two plates define two mutually unfixed facing parts forming a covering part for covering the flexible pouch, the covering part being surrounded by the peripheral margin;

wherein in the assembled state:

the protecting body extends planar in an empty state of the flexible pouch, along the protecting body reference plane;

the two plates are configured to sandwich the flexible pouch for constraining the flexible pouch in a filled state of the flexible pouch, the protecting body being deformable due to shrinking of the two plates in at least one direction belonging to the protecting body reference plane; and

the two plates respectively form a first outer surface and a second outer surface of the protecting body, facing in opposite directions, at least one amongst the first outer surface and the second outer surface being a surface having a plurality of ribs, which extend at least on a peripheral annular region of the covering part, along the peripheral margin.

With such ribbing, geometry of the protecting device in filled state of the pouch constrained by the plates can be impacted favorably. For large volumes (about 50 liters, 75 liters or more for instance), a full surround rib or similar pattern of ribs parallel to the peripheral margin can prevent undesirable formation of waves that create dead volumes and impair efficient drainage operation.

More generally, the ribs can locally structure a plate, preferably the two plates, near the peripheral margin to prevent undesirable folding/bending of a plate while still allowing the protecting body to expand with filling of the pouch contained therein. The ribs thus may be ribs arranged to locally structure the covering part of the protecting body, for instance around a panel part which may be substantially rectangular or provided with a square shape.

A good compromise may be obtained between ease of the covering part at expanding transversally (vertically when the protecting body reference plane is horizontal), with suitable flexibility of the plates using, while also preventing fold formation neat the peripheral margin. The plates may be accordion-like, using several ribs arranged parallel to the respective four margin portions of the peripheral margin.

Accordion effect in a plate may be obtained by having parallel ribs, each of the parallel ribs locally having a thickness lower than in other portions of the plate. When a pouch filled with fluid constrains the interior faces of the plates (where the ribs define an elongated hollow or groove), the ribs may help for having a greater expansion in direction transverse (perpendicular) to the protecting body reference plane, despite low flexibility of the plate material as compared to plastic material of the pouch.

Each rib of the plate may be obtained by locally drawing the plastic material, thus causing a reduction in thickness at the ribs. This may be sufficiently deep drawing, in order to have the hollow or groove of each rib deeper than average thickness of the plate. Each of the ribs may have a flaring shape, typically forming a U-shape profile in a section view (section transverse to length direction of the rib).

Depth or height of the ribs may be at least twice or at least three times the thickness of the plate (plate material thickness), preferably at least four or height times. With such height and with slight decrease in thickness, the ribs located close to the peripheral margin efficiently improve expansion (with a higher shift relative to the protecting body reference plane) near the margin portions, as if the plate was locally more expandable. Even if the margin portions cannot expand, due to the attachment system, all or part of the peripheral annular region may expand/deviate from the protecting body reference plane quicker than if the plate was deprived from such ribs.

The grooves formed by the ribs are elongated, such grooves having a groove length corresponding either to length extension, or to width extension of the plate, which is a generally rectangular plate. The groove interior width may be superior to 10 mm, preferably superior or equal to 15 mm. In some embodiments, such width is between 20 and 40 mm. As apparent inFIGS.5A,5B, a wavy profile may be obtained due to the grooves (between panel part(s) and peripheral margin), before any filing operation.

The region provided with the ribs may be an annular region formed as a transition region between a panel part without ribs and the peripheral margin that is typically not allowed to move transverse to the protecting body reference plane. Such transition region may form a homogenous sloped region in expanded/filled state of the system, as formation of undesirable waves/folds is prevented.

The peripheral margin is configured to remain flat along the protecting body reference plane in the assembled state, independently of a filling state of the flexible pouch covered by the covering part. Optionally, the attachment system may be a fastening assembly, two opposite sides (opposite margin portions) of the peripheral margin being part of the fastening assembly to prevent any shifting in position between the two plates once they are mutually fastened at least in the two margin portions, in a predetermined superimposed configuration for forming the protecting body.

The plates typically are separate pieces, preferably two pieces. The constraining effect is of interest for a step of emptying the flexible pouch, and is advantageous to limit vertical expansion of the fluid, especially during freezing, when the protecting body reference plane extends substantially horizontal.

The vertical expansion may be also limited by having a belt effect exerted in a middle region of the covering part, possibly by retaining the shrink stroke of the peripheral margin, selectively in margin middle portions located on both sides of this middle region.

In some embodiments, ribs of the plurality of ribs are distributed at least in two opposite parts of the surface which are longitudinally opposite parts.

Besides, the ribs of the plurality of ribs include one or more first transverse rib portions proximal or adjacent to the first end side and one or more second transverse rib portions proximal or adjacent to the second end side.

In various embodiments of the device, recourse may optionally also be had to one or more of the following dispositions:

the one or more first transverse rib portions include two first transverse ribs portions, while the one or more second transverse rib portions include two second transverse ribs portions.

the attachment between the plates is a removable attachment, allowing the plates to be fully separated.

the plates are removably fixed to each other by the attachment system distributed (selectively distributed) in the peripheral margin.

two opposite margin portions, provided longitudinally in the peripheral margin, are part of a fastening assembly to prevent any shifting in position between the two plates once they are mutually fastened at least in the two margin portions, in a predetermined superimposed configuration for forming the protecting body.

each of the two plates comprises embossments or boss portions, which define, in assembled state of the plates (to form the protecting body), several protecting body embossments protruding in a first direction perpendicular to the protection body reference plane, forming corresponding cavities opening in a second direction opposite to the first direction.

the embossments may be longitudinally distributed in the peripheral margin.

a number of the embossments provided in one of the two plates are engaged in a same number of the corresponding cavities provided in the other one of the two plates.

the two plates are two pieces.

the two plates may have a same thickness that is lower than 2 mm, each of the two plates having a density superior to 1.10 g/cm3and being made of plastic material.

the two plates are made of same plastic material, preferably transparent or translucent.

the protecting body is made of a freeze resistant polyester or copolyester material that is not brittle at about 25° F. or −4° C.

the material of the protecting body is PET.

the material of the protecting body is TRITAN (i.e. a copolyester compound called TRITAN™, which is a transparent amorphous thermoplastic material, typically made by combining three monomers; some formulations of this material do not contain additives, while others contain about or less than 10% additives).

the material of the protecting body is an amorphous copolyester made by combining the following monomers: dimethyl terephthalate, 2.2,4,4-tetramethyl-1,3-cyclobutanediol, and 1.4-cyclohexanedimethanol.

the protecting body is directly engaged by positioning members that belong to the attachment device, in order to have a profile of shrink at the protecting body circumference, optionally with almost no reduction or less shrink due to direct engagements of the positioning members engaged in a middle region of the protecting body, at the margin portions.

the positioning members may be sliders or similar members housed in a guiding or covering part of a holding and retaining assembly, which may forms a stationary frame around a hollow space/location for the pouch.

each of the positioning members may have inserting pin or inserting member that is inserted either in a protecting body through-slot or in a hollow part delimited by a pair of respective embossments of the two plates (the slot or hollow part being provided in the peripheral margin, in order to not interfere with expansion of the covering part that covers the pouch).

the ribs of the plurality of ribs further include a group of elongated rib portions, extending in the peripheral annular region of the covering part.

the elongated ribs may be parallel to the longitudinal axis, thus extending perpendicular to any one of the first transverse rib portions and the second transverse rib portions.

the group of elongated rib portions may consist in longitudinal ribs and/or comprise two opposite elongated rib portions/ribs, which are longer than any one of the first transverse rib portions and the second transverse rib portions.

each plate is provided with a clearance area (which is an area without any relief/rib) provided between and/or separating longitudinal rib portions that are distributed in respective halves of the plate.

each plate has one or two pairs of elongated continuous rib portions, parallel to the longitudinal axis, which extend cross a middle section or middle transverse band of the plate.

the elongated continuous rib portions extend longitudinal to remain close, typically only at a distance of less than about 30 or 50 mm from a respective one of the two opposite margin portions of the rectangular peripheral margin, while the transverse distance between the two opposite margin portions is at least equal to 500 or 600 mm, preferably superior or equal to 700 mm, when the plate extends planar (when the plates are assembled to sandwich the pouch, this planar state is obtained for non-filled state of the pouch).

amongst each pair of elongated continuous rib portions, parallel to the longitudinal axis, which extend cross a middle section or middle transverse band of the plate, each elongated continuous ribs extends straight to remain close from a margin portion, at a distance less than 10% of the total plate width from this margin portion.

the plate has longitudinal rib portions of relatively shorter length, as compared to the elongated continuous rib portions, also called side rib portions, which are crossing over the middle section/middle transverse band, the longitudinal rib portions of relatively shorter length not interfering with the clearance area or not interfering with a plate middle area only provided with transverse rib portions.

the corner ribs comprise first corner ribs interconnecting one of elongated rib portions with one of the first transverse rib portions.

the corner ribs further comprise second corner ribs interconnecting one of elongated rib portions with one of the second transverse rib portions.

in the surface provided with the plurality of ribs, a continuous rectangular region without any ribs is surrounded by (and possibly delimited between) a first group of ribs extending annularly in the peripheral annular region of the covering part, and a second group of ribs extending parallel to the first group of ribs and arranged closer to the peripheral margin as compared to the first group.

the first group of ribs may extend annularly at a maximal distance from the peripheral margin, which is a first distance, while the second group of ribs may extend at a minimal distance from the peripheral margin, which is a second distance, the second distance being typically superior to the first distance.

In some embodiments, the protecting body may extend substantially horizontally and/or the first outer surface, which is delimited by the peripheral margin, is a lower surface of the protecting body, while the second outer surface, delimited by the peripheral margin, is an upper surface of the protecting body.

In particular embodiments, each of the lower surface and the upper surface comprises a pattern of ribs distributed in two halves, the first transverse rib portions being provided in a first half of the two halves, while the second transverse rib portions are provided in a second half of the two halves.

Optionally, the pattern of ribs in the lower surface and the pattern of ribs in the upper surface are symmetric relative to the protecting body reference plane, the two halves being preferably two symmetrical halves relative to a median plane that is perpendicular to the protecting body reference plane.

In some embodiments, the pattern of ribs is surrounding at least one smooth panel region extending away from the peripheral margin.

Around the panel, one or two continuous or discontinuous ribs of the pattern of ribs are configured to allow fluid (liquid) to be spread to the edges and corners. In embodiments, the ribbing pattern provides more flexibility to the protecting body edge regions to be deformed (regions adjacent to the four respective side edges) by forming sloped portions, parallel to the peripheral margin. Such rib delimiting the panel may be a continuous or discontinuous annular rib.

The longitudinal ribs, elongated, may propagate the hinge effect at junction (which may be a rectilinear junction) between the peripheral margin where the plates remain fixed in a plane and one long side amongst the four sides of the rectangular covering part.

The transverse ribs, typically also elongated, may propagate the deployment with hinge effect at junction (which may be a rectilinear junction) between the peripheral margin where the plates remain fixed in a plane and one short side amongst the four sides of the rectangular covering part.

In various embodiments of the device, recourse may optionally also be had to one or more of the following dispositions:

the protecting body is provided with ribs in the first outer surface and in the second outer surface, so that a first plurality of ribs is formed on the first outer surface and a second plurality of ribs is formed on the second outer surface.

the protecting body is configured to expand along a direction perpendicular to the body reference plane due to filling of the flexible pouch sandwiched between the two plates, so that the two mutually unfixed facing parts form respective panels, which are each: extending parallel to the protecting body reference plane, and surrounded by reliefs elongated to extend parallel to the peripheral margin.

the reliefs may be protruding outwardly and formed by a part of the ribs included in

each of the two plates comprises at least one plate panel part extending between the first transverse rib portions and the second transverse rib portions.

a single panel may be formed by each plate outer surface provided with ribs.

two panel portions, longitudinally distributed, may be formed by each plate outer surface provided with ribs.

each the two plates has at least one central portion arranged away from the two end sides.

one or two ribs may extend transversally to separate two panel parts in a same plate, such ribs typically extending transverse in such central portion.

each panel part is formed without any ribs or hinge lines.

in non-filled state of the pouch or in any flat state of the of the protecting device, each surface amongst the first and second outer surfaces is provided with height differences of 0.8 to 20 mm (and not protruding more),

the maximum height reliefs are provided on areas surrounding the one or two panel parts, while no height difference is found in the panel part(s).

In some embodiments, the protecting device may be provided with a holding and retaining assembly, separate from the attachment system, for supporting the protecting body at the peripheral margin, away from any one of the ribs of the protecting body. Typically, the holding and retaining assembly may comprise a frame with abutment surfaces arranged between the covering part and the peripheral margin, in order to allow the two plates moving, extending, and shrinking in a transverse direction belonging to the protecting body reference plane, without having the peripheral margin displaced inwardly beyond the abutment surfaces.

In various embodiments of the protecting device, recourse may optionally also be had to one or more of the following dispositions:

the peripheral margin is provided with positioning members spaced from any one of the ribs of the protecting body.

the positioning members are configured to limit movement in the transverse direction of at least one part of the peripheral margin, in order to limit expansion of the flexible pouch in at least one region that is intermediate between the first transverse rib portions and the second transverse rib portions.

the first transverse rib portions are typically proximal to the first end side and distal from the second end side, while the second transverse rib portions are proximal to the second end side and proximal form the second end side (preferably, the first transverse rib portions are not spaced from the corresponding first end side by a distance more than 15 or 25% of the total length of the plate, as measured along the longitudinal axis in the planar empty state; similarly, the second transverse rib portions may be not spaced from the corresponding second end side by a distance of more than 15 or 25% of the total length of the plate, as measured along the longitudinal axis in the planar empty state).

each of the first transverse rib portions and the second transverse rib portions extends perpendicular to the longitudinal axis and belong to an intermediate region between two corner regions respectively adjacent to an intersection of two of the four sides.

the two corner regions are formed to be elastically more deformable than the intermediate region provided with the first transverse rib portions and the intermediate region provided with the second transverse rib portions.

each intermediate region is adjacent to one amongst the first end side and the second end side.

each amongst the first outer surface and the second outer surface comprises longitudinal rib portions that extend parallel to the longitudinal axis in two opposite side regions, in order to be each proximal to the peripheral margin and distal to the longitudinal axis.

each of the corner regions are formed to be elastically more deformable than any one of the side regions provided with the longitudinal rib portions.

In some embodiments, each plate may be provided with several ribs protruding outwardly (i.e. protruding upwardly for the top plate, downwardly for the lower plate). The ribs which are closer to the peripheral margin (so-called side ribs) may be protruding more than any other rib present in the plate.

The maximum in height (protruding height) is obtained at the side ribs, while a minimum in rib height may optionally be obtained in the corner regions.

Each of the lower surface and the upper surface has a planar surface, while height of the rib portions or similar protruding portions protruding from the planar surface is large (for instance greater than 6 or 10 mm) only in regions away from two virtual diagonal lines provided in each plate that is rectangular in shape.

In some embodiments, the protecting body may be have:

the two plates made as two separate pieces, having same circumferential size and same outer shape, each of the first outer surface and the second outer surface comprising first transverse rib portions proximal to the first end side and second transverse rib portions proximal to the second end side.

the two plates may be two separate identical pieces.

the plurality of ribs and the protecting body are made of same freeze resistant polyester or copolyester material, the two plates being two separate pieces.

the plate material is not brittle at about 25° F. or −4° C., the material being preferably PET or TRITAN.

the two plates a made of deformable plastic more rigid than the flexible pouch and configured so that an interspace between the two plates, as measured perpendicularly to the protecting body reference plane in a filled state of the flexible pouch, increases with increasing distance from the peripheral margin.

the protecting body is expansible with corner regions less strengthened by the ribs.

each rib of the plurality of ribs delimits an interior hollow opening inwardly, in order to open toward the flexible pouch.

each rib of the plurality of ribs delimits an interior hollow separate from the peripheral margin so that the interior hollow provides additional volume in an interspace between the two plates.

each of two plates is a plate having a rectangular shape with four corners and two virtual diagonal lines each intersecting a pair of corner vertices of the four corners, and wherein each of the two virtual diagonal lines intersects: a first series of corner ribs proximal to the first end side and protruding outwardly along a direction perpendicular to the protecting body reference plane, and a second series of corner ribs proximal to the second end side and protruding outwardly along a direction perpendicular to the protecting body reference plane.

each of the corner ribs are curved and are connecting two rib portions that are perpendicular one to each other.

the first transverse rib portions may be directly connected to the corner ribs of the first series, while the second transverse rib portions may be directly connected to the corner ribs of the second series.

Embodiments of the invention also provide a freeze/thaw containment system for containing a biopharmaceutical composition, comprising:

the protecting device according to the invention,

a flexible pouch sandwiched between the two plates, the flexible pouch being fillable with a biopharmaceutical composition via at least one port of the flexible pouch which protrudes outwardly through the least one opening, the flexible pouch being more flexible than material of the protecting body.

In some embodiments, the two plates constrain the flexible pouch by a covering part that extends between two margin portions of the peripheral margin.

The system may be provided with a frame for attachment of the protecting device selectively at the peripheral margin. Accordingly, the frame allows having the covering part of the protecting body suspended, as only the peripheral margin is fixed to and retained by the frame. In some options, the frame is rectangular and does not cover the covering part. In other portions, all or part of the frame may be included in a protective shell provided with shell parts forming a housing for accommodating the covering part. Such protective shell preferably includes all or part of the attachment system, thus allowing the peripheral margin to be maintained in the protecting body reference plane that typically coincides with an interspace provided by the frame.

The frame may be provided with upper parts and lower parts in some embodiments, such parts being assembled to form the frame with the retaining feature relative to the peripheral margin. Positioning members may be either provided on the peripheral margin, or be included in the parts of the frame.

The freeze/thaw containment system (which is a protection system for storing and withstanding freezing and thawing of the biopharmaceutical composition contained in the flexible pouch) may be assembled using a method that comprises:

sandwiching a flexible pouch between two plates of a protecting body, selectively by a covering part distributed in the two plates for covering the flexible pouch, the protecting body being configured for protecting the flexible pouch and comprising the two plates, the protecting body further having a longitudinal axis and comprising four sides, the four sides comprising two longitudinal sides extending parallel to the longitudinal axis and two other sides that include a first end side and a second end side each perpendicular to the longitudinal axis,

fastening the two plates by an attachment device at a peripheral margin so that in an assembled state of the two plates, the protecting body has the peripheral margin which extends annularly in a protecting body reference plane, around the covering part,

inserting through the peripheral margin, in at least one opening, thereof, at least one port of the flexible pouch (which is thus received in such at least one opening);

maintaining the peripheral margin parallel to the protecting body reference plane, by a holding and retaining assembly accommodating the peripheral margin in an annular housing, so that the peripheral margin remains flat along the protecting body reference plane in the assembled state, independently of a filling state of the flexible pouch covered by the covering part;

wherein in the assembled state:

the two plates are configured to sandwich the flexible pouch for constraining the flexible pouch in a filled state of the flexible pouch; and

the two plates respectively form a first outer surface and an upper surface of the protecting body, at least one amongst these surfaces being a surface having a plurality of ribs which extend at least on a peripheral annular region of the covering part, along the peripheral margin, in order to locally structure the covering part of the protecting body.

The assembling may be easy and the ribs are provided to protrude outside, with these ribs distributed in two opposite parts of the surface which are longitudinally opposite parts.

The protecting body may be less ribbed or provided with low height reliefs in four corner regions of the protecting body, each corner region being respectively adjacent to an intersection of two of the four sides.

The flexible pouch is inflated when filling the flexible pouch with the biopharmaceutical composition in a fluid state, and the covering part is constraining the flexible pouch, while guided when expanded due to side ribs that prevent undesirable centripetal folds near the peripheral margin.

Other features and advantages of the invention will become apparent to those skilled in the art during the description which will follow, given by way of a non-limiting example, with reference to the appended drawings.

DETAILED DESCRIPTION OF EMBODIMENTS

In the various figures, the same references are used to designate identical or similar elements.

In the different Figures, a vertical direction, a longitudinal direction and a lateral direction are based on the freeze/thaw containment system horizontally stored in a shelf. A direction perpendicular to the longitudinal direction is the lateral direction. One direction according to the height of the freeze/thaw containment system1is the vertical direction, reflected by direction Z in theFIGS.4and6-8in particular.

In embodiments, the freeze/thaw containment system1may be such as illustrated inFIGS.3,4or inFIG.6,7or8, in order to include a protecting body (12,112,212) that covers both faces of a flexible pouch2for biopharmaceutical materials, hereafter called biopharmaceutical composition Q.

Thus, when the biopharmaceutical composition Q is frozen, the containing region or useful part of the flexible pouch2, i.e. inner region relative to the peripheral seal J, may be slightly curved. Hence, a dimension on the longitudinal direction (along longitudinal axis X1) of the protecting body12slightly decreases. In this case, the biopharmaceutical composition is slightly constrained by the two plates12A,12B.

In accordance with embodiments, the plate dimension reduction (as considered in XY plane) is obtained with a profile of shrink strokes, such reduction being adjusted to be different, depending on longitudinal positions of some positioning members PM integral with margin portions of the protecting body that locally prevent or limit such dimension decrease, for a control of the shrink stroke, as it will be described below. Additionally or in variants, a ribbing is provided for controlling that the shrinkage is obtained without decreasing height on pouch sides or altering an optimal shape of the pouch2.

Referring toFIGS.1,3and4, the protecting body12or112comprises two plates12A,12B for protecting the flexible pouch2. The two plates12A and12B may be made separate. The protecting body12,112here comprises ribs R1, R2, R2′, R3, R4typically on each plate12A,12B. The two plates12A,12B may be two pieces, which define the protecting body12,112, preferably without any additional piece. More generally, only two pieces may form the covering part8receiving the pouch2.

The protecting body12,112,212is obtained by fastening the two plates12A,12B in a circumferential part that surrounds a covering part8of the protecting body12. For instance, the protecting body12,112,212is assembled when sandwiching the empty pouch2by the covering part8, by securing the circumferential parts of the plates12A and12B together. For this, an attachment device or attachment system18is provided, in order to fasten the two plates12A,12B. In an assembled state of the two plates12A,12B, the protecting body12,112,212comprises a peripheral margin80. The peripheral margin80is obtained by securing respective margin portions8a,8bof the plates. Each margin portion8a,8bmay be composed of four outer band regions of the plates12A and12B.

The protecting body12,112,212extends planar, along a protecting body reference plane P, and cannot inflate like a thin rubber balloon, as the plates12A,12B are relatively rigid to constrain the pouch2. The protecting body12,112,212may be typically as rigid as or more rigid than a PET bottle for containing sparkling water, thus allowing very limited deformation as compared to the material of the flexible pouch2. In the plates12A,12B, ribs R1, R2, R2′,800also structure the covering part8in a peripheral annular region8pthereof, typically along the peripheral margin80to have a guiding effect when the protecting body12expands. The structuring is not impairing the expansion as only linear regions for local/linear strengthening are provided, so that plate deviation angle α as illustrated inFIG.10Bmay be sufficiently high. For instance, such angle α is greater than 25 or 30° relative to the reference plane P, in full filled state of the pouch2sandwiched by the plates12A,12B.

In the illustrated embodiment ofFIGS.1,2A-2B, the ribs R1and the ribs R2, R2′ may be spaced and arranged parallel in the ribbing pattern of the plate12A or12B, in order to delimit a continuous rectangular region between them, without any ribs. The ribs R1, which are closer to the peripheral margin80as compared to the ribs R2, R2′, may form a continuously rectangular ribbing, possibly with rounded corner ribs (curved ribs portions). The ribs R1thus may be included in a continuous rectangular rib, which is decomposed in two opposite transverse rib portions4,6and two elongated longitudinal rib portions110, possibly with four corner ribs interconnecting each transverse rib portion to the two longitudinal rib portions110.

Ribs R3and/or R4may optionally be added, with a shift toward a middle region, as compared to the side ribs R1or the ribs R, R2′. Accordingly, at least three transverse rib portions extending perpendicular to the longitudinal axis X1of the protecting body12may be provided, at each opposite ends of the plate12A and/or12B.

Here inFIGS.1,2A-2B,4and7, it can be seen that transverse ribs portions4,6are included in U-shaped ribs R2, R2′, R3, R4, with the “U” open toward a central region for the corresponding outer surface S or S′. The shape and location of these ribs R2, R2′, R3, R4is suitable to obtain a guiding or “pushing” effect for having more liquid composition Q near the peripheral margin80.

When a belt effect is obtained as described below (referring toFIG.13A-13B), a locally lower height may optionally be provided in the middle110aof each longitudinal rib portion110, as illustrated for instance inFIGS.3and5C.

The system1is suitable for containing, freezing/thawing a biopharmaceutical composition Q (seeFIG.10B). Referring toFIGS.4,6and10A-10B, such system1is here horizontal, using a horizontal frame. However, this system may also be vertical in variants, so that the pouch2can be stored vertically in a cavity of a vertical frame-like holder (see for instance pouches described in WO 03037082, received vertically by use of rigid slotted frames). Use of a rectangular frame15, provided with slots or cavities CP opening inwardly, may be of interest, in order to form a compact holder, able to accommodate respective margin portions of the protecting device10. A storage unit, forming a whole system1, is obtained when having the pouch2and the protecting device10together, allowing efficient protection of the biopharmaceutical composition Q.

The flexible pouch2is typically a 2D-type pouch, delimited by two longitudinal sides LS1, LS2and having a substantially rectangular shape without predefined folds on its two main outer faces, as illustrated inFIG.1or4(empty pouch). Accordingly, the pouch2extends substantially planar in non-filled state. The pouch2may have two main walls W1, W2. These walls W1, W2may be directly welded one to each other at a weld or peripheral seal J to delimit an interior volume for containing the biopharmaceutical fluid Q. More generally, the flexible pouch2may be of any suitable material for containing a biopharmaceutical composition Q and forms a freezer bag, which may be of large capacity, typically superior or equal to 5 L. More generally, the flexible pouch2is of a first capacity and the pouch2can expand to have an increase in thickness at least in a middle region away from the four pouch corners, such thickness increasing with the level of filling the pouch2.

Referring toFIG.1, the flexible pouch2extends in a main plane XY which is, here, the horizontal plane. The pouch2has a longitudinal axis A parallel to its long sides, which are here the two longitudinal sides LS1, LS2in the non-limiting illustrated embodiment. The flexible pouch2is sandwiched by the plates12A,12B and cannot be removed without detaching at least one of the two plates12A,12B, here by disconnecting the plate margin portion8afrom the plate margin portion8b(the plates are secured between them, without specific fixation between the pouch2and any one of the plates). A holding and retaining assembly HR may be provided, additionally to the attachment system18, for holding the unit composed of the protecting body12and the attachment system18. The assembly HR is here provided with the frame15that includes slides SL or similar slotted structures for holding the protecting device10at its peripheral margin80.

Typically, the receiving part2rof the containing pouch2for receiving the biopharmaceutical composition Q cannot be in contact with the rigid structures of the holding and retaining assembly HR, thanks to the protecting body12,112or212. In the assembled state, the protecting body12,112,212may entirely cover the receiving part2rof the pouch2, while the peripheral margin80remains planar (here always coinciding with the reference plane P, due to the attachment system18).

The protecting device10provides efficient protection in freezing, storing and thawing operations, while the biopharmaceutical composition Q is contained in the receiving part2rof the flexible pouch2. The covering portion8of the protecting body12is not as flexible as the receiving part2rof the flexible pouch2, due to a difference in material (more rigid for the two pieces forming the plates12A,12B).

When placed horizontally and maintained by the holding and retaining assembly HR, the two plates12A,12B respectively form a lower surface and an upper surface of the protecting body12,112,212.

Each pouch2may be filled with a solution, fluid composition, to be frozen and held with slight compression between the two plates12A,12B that serve as heat-exchange surfaces. For this purpose, the plates completely cover the pouch2, at least in the fluid receiving part, i.e. region defining the interior volume of the pouch2(i.e. typically all the walls W1, W2with possible exception of the annular seal J and optional outer extension(s)). In the illustrated embodiments, the pouch2is entirely covered by a protecting body12,112which is formed by the two plates12A,12B. During freeze/thaw operations, the plates12A,12B are cooled/heated by circulating heat transfer fluid, for instance from an external, programmable refrigeration unit. The slight compression (containment effect) provides improved contact and heat transfer, resulting in a frozen pouch having the general shape of a pillow (seeFIG.6,7or8).

Arrangement for Maintaining and Guiding the Protecting Body

The pouch2, sandwiched between the plates12A,12B may be supported by a structure surrounding the pouch. Such structure may include a frame15or similar holding and retaining device HR, arranged peripherally around the covering part8, so as not to damage the material inside during handling and transport. Referring toFIGS.6-8, the frame15may be a rigid part of a supporting structure. Here, the frame15may be a modular part of a device or shelf that may be located in a freezing apparatus. Rollers (not shown) may be provided for facilitating transportation. The frame15is typically a rectangular protective frame, leaving the outer surfaces S, S′ of the protecting body12exposed but forming four protecting sides of the protecting device10.

The frame15may be included in a holding and retaining assembly HR, which also includes positioning members PM engaged in the peripheral margin80of the protecting body12, as illustrated inFIGS.9and10A-10Bin particular. The assembly may comprise a plurality of feet115, possibly of tubular shape and suitable for stacking.FIG.11Cillustrates a non-limiting example of integration of feet115, suitable for obtaining a shelf structure.

More generally, the protecting body12and the holding and retaining assembly HR may be assembled in such a way that outer surfaces S, S′ (here corresponding to the lower surface S′ of the lower plate12A and the upper surface S of the upper plate12B) remain exposed (uncovered), while the flexible pouch2is placed inside the storage assembly, the pouch2being covered by the two plates12A,12B. A shown in particular inFIG.3, the protecting body12has a peripheral portion80which is engaged in interspaces of the holding and retaining assembly HR. The protecting device10is suitable for use in freezing, storing and thawing biopharmaceutical fluid contained in a flexible pouch2, the fluid being typically introduced after obtaining the whole system1for constraining and holding the flexible pouch2, which is typically a disposable pouch.

The freeze/thaw containment system1is provided with several positioning members PM that are secured to or formed on this peripheral margin80. This peripheral margin80may be seen as the part of the protecting body which is complementary to a covering part8where the pouch conformation changes, depending on the level of filling of the pouch2. The system1also comprises a frame15that is constructed to surround a hollow space where the pouch2extends. The frame15may be provided with two longitudinal supporting parts that are separate from the positioning members PM.

It is understood that interface Frame—Protecting body is shifted relative to the covering part8, thus not interfering with the expansion along Z-direction. Besides, ribs of plates12A,12B can be formed away from the arrangement provided for maintaining the protecting body12,112, since only the peripheral margin80is include or in contact with the positioning members PM.

Referring toFIGS.9to12, the positioning members PM may be parts of the attachment system18and/or may participate to sandwich the two plates12A,12B of the protecting body, at the peripheral margin80. The positioning members PM may be composed of at least two pieces, which are distinct and separate from the pouch2and from the plates12A,12B. Here, they comprise a pair of flat bars, possibly pinching the plates12A,12B when using an insert piece IP such as a screwing element for assembling the flat bars and form the positioning member PM. More generally, the positioning members PM may be rigid parts, typically made of plastic material (for instance HDPE), provided with fastening pieces or integrated fastening means.

The positioning members PM are configured to protrude each from at least one amongst a lower surface S′ and an upper surface S of the protecting body12,112,212, in the peripheral margin80. Typically, the positioning members PM comprise each a lower part LP and an upper part UP that are two separate flat bars or any suitable pair of pieces configured to sandwich the protecting body, in a region of the peripheral margin80, outside the hollow space of the frame15where the pouch2extends.

Referring toFIG.10A, each front protruding portion of these parts UP, LP has a slanted surface reaching the pressing face in contact with the protecting body2, in order to form a V-like section groove GS (distributed on both sides of the body peripheral margin80) that opens inwardly. This groove GS may guide the expansion of the protecting body near the peripheral margin80, in order to prevent direct contact of the surfaces S, S′ against the frame15(thus preventing any contact against any profile edge/surface). This of interest for protecting the protecting body material, as the profiles91,92,93,94are typically in more rigid material, for instance steel, metal, aluminum or rigid plastic.

In the system shown inFIGS.9and10A-10B, it is understood that a protecting device10can be obtained with the protecting body12,112,212unable to be detached from the frame15, once this frame is assembled, here with a U-shape or rectangular shape surrounding the pouch2contained in the protecting body. Indeed, the positioning members PM that have been provided in or already fixed to the peripheral margin80, may be housed/retained in the respective parts or profiles91,92,93,94of the frame15. Here, the fastening is adapted to allow the protecting body to move, extend, and shrink along the protecting body reference plane P, i.e. providing a degree of freedom along at least one amongst the directions of axes X and Y shown inFIGS.1,4and6-8.

Use of four rigid profiles is here illustrated inFIGS.11A-11Cfor forming the frame15, which is of interest for forming a rectangular frame15, efficient for protection purpose. Optionally, the pouch2may be of the Flexboy® type, and thus is a sterile, single-use, disposable container, adapted to be sandwiched by the protecting body and surrounded by the frame15obtained after assembling the profiles91,92,93,94or similar holding elements.

In some options the holding and retaining assembly HR may have less than four members, so as not to form a rectangular frame. For instance, only three members may be sufficient, with a transverse member interconnecting two longitudinal covering parts31,32parallel to the longitudinal axis A of the pouch2.FIG.3only shows two covering parts31,32that may be integral with feet or which may be associated to a transverse structure member. In some options, the covering parts31,32may extend vertically. In the illustrated embodiments, the covering parts31,32extend horizontally, which may be preferred when the pouch contains more than 50 L, for instance about 75 L or at least 100 L.

When the positioning members PM are part of the attachment system18, the attachment system18can be considered as an assembly of several displaceable parts that can move inwardly relative to the frame15. Here, the frame15comprise two elongated longitudinal supporting parts formed by two pieces or profiles93,94, that define each a housing for accommodating respective positioning members PM. At least one of the positioning members PM constitutes a slider movable inwardly inside the corresponding housing. Referring toFIGS.10A-10B, it can be seen each lower part LP and an upper part UP are two separate pieces configured to sandwich the protecting body, in a sandwiching region of the peripheral margin80. Each sandwiching region may be elongated, parallel to a protecting body edge, by extending longitudinally to be at least four times longer (with a length L8) than a maximal width W8of the positioning members PM, as illustrated in non-limiting embodiment ofFIG.11Ain particular.

Referring toFIGS.10A-10B, all or part of the frame15forms a holding and retaining assembly HR. This assembly HR has surfaces BS1, BS2for abutment of the positioning members PM, here provided in the two profiles93,94that are exemplary pieces forming longitudinal supporting parts for supporting the protecting body provided with the fastening system18.

More generally, it is understood that the frame15typically comprises abutment surfaces included and distributed in the two longitudinal supporting parts, all or part of the positioning members PM connecting the peripheral margin80to the frame15so that the frame15retains and supports:

the protecting body12,112,212; and

the pouch2that is sandwiched between the two plates12A,12B.

Some or all of the positioning members PM may constitute sliders, which are slidably mounted on or in the two longitudinal supporting parts, in order to be movable along a direction transverse to the longitudinal axis X1(seeFIG.3showing the axis of the protecting body, which may be merged with longitudinal axis A of the pouch2), between:

a first position, in a non-filled-state of the pouch2, in which the sliders are pushed outwardly or maintained away from the surfaces BS1, BS2for abutment, by the protecting body12,112,212(when having its flat rectangular shape with a maximal perimeter), so that the sliders are able to be further displaced inwardly,

and a second position, in a filled-state of the pouch2, in which the sliders are each engaged against one of the surfaces BS1, BS2for abutment.

In some options, positioning members PM may form guiding parts for receiving one or more body crossing members, screws or the like. Referring toFIG.10A, an insertion piece IP may be provided in the positioning members PM, this piece IP being for instance a rod-like crossing members cooperating with a locking part, a nut or bolt. Of course, slots may be provided in the protecting body12,112or212, for allowing the body crossing members or any insertion piece IP to cross the peripheral margin80at a plurality of locations, thus stabilizing the positioning members PM (which remain integral with the peripheral margin80, once assembled in this kind of embodiment). However, in preferred options, the positioning members PM may simply sandwich, with discontinuous distribution, the margin portions8a,8, while being unable to being disassembled once they are introduced in the frame15, typically inside profiles91,92,93,94. Thus, there is no need for insertion piece IP and the margin portions8a,8bmay be provided with boss portions B12, B12′ or similar embossments for engaging with corresponding cavities of the positioning members PM.

Pouch Properties and Access for Filling or Emptying the Pouch

Referring toFIGS.3-4and10A-10B, the pouch2may have a form or shape that is initially planar in empty state. The pouch2is flexible, in order to be inflatable, and may be made from a pair of flexible sheets (which form the respective walls W1, W2), having a rectangular or other plan form, and joined together at the four peripheral edges, to provide a containment volume (interior volume Q) between the sheets21,22, which are spaced by a spacing in a filled state. One or more openings or ports24may be provided, for example formed as closable tubes between facing parts of said peripheral edges of the sheet, to allow the pouch2to be filled or emptied.

In the illustrated embodiments, the protecting body12,112preferably has an attachment system18for fastening the two plates12A,12B so that in an assembled state of the two plates, the protecting body12,112,212comprises a peripheral margin80that extends annularly in a protecting body reference plane P.

As shown inFIGS.3and4in particular, the peripheral margin80may be provided with at least one opening80aable to receive at least one port24of the flexible pouch2, for instance two ports24. The protecting body12,112may be provided with:

a first end side120a, which is composed of the ends E1of the two plates in the assembled state of the protecting body12,112, and

a second end side120b, which is composed of the ends E2of the two plates in the assembled state of the protecting body12,112.

The one or more ports24may protrude axially outward from the second end side120b. This arrangement with an opening80amay be provided in any other version of the protecting body, in order to accommodate a flexible pouch2having one or more ports24(with flexible hose(s)).

Tubes T may be associated to the ports24. Here, each of the tubes T is connected to the flexible pouch2by a port24. Two front ports24may be provided. For example, one port24forms an inlet for the flexible pouch2and the other port24forms an outlet of the flexible pouch2.

The pouch2is also designed to provide a high surface area/volume ratio at a thin thickness or spacing. By way of non-limiting example, a pouch2may have rectangular dimensions of about 600 mm by about 1300 or 1400 mm, and/or a holding volume of between about 10 liters and about 120 or 200 liters (preferably between 50 and 120 liters), and/or a spacing or pouch thickness (height along Z direction) of between about 8 or 10 mm to about 25 or 30 mm.

Each pouch2may be made from any suitable biologically compatible material, and which preferably facilitates heat transfer between the inside and the outside of the pouch2. To reduce or avoid damage to the pouch2during cryopreservation due to the expansion of the biopharmaceutical material, it is preferred that the material would have a glass transition temperature that is below that of the biopharmaceutical material. By way of non-limiting example, each pouch2may be made from a multilayer composite material only made of thermoplastic material, for instance including polyethylene.

Tubing Holder

Referring toFIG.4, the plates12A,12B of the protecting body optionally comprise an assembly22for holding the two tubes T associated to the two ports24. The two plates12A,12B comprise, on their peripheral sides, complementary parts (complementary shape along Z direction, for instance) which form the assembly22for holding the tubes T.

The assembly22for holding the two tubes16is symmetrically arranged with respect to the longitudinal direction X (i.e. pouch longitudinal axis A which typically coincides with axis X1). Each symmetrical part is able to hold one tube T or hose.

In other options, especially suitable for accommodating pouches of high capacity (for example between 30 or 50 liters and 200 liters), the frame15may directly support at least one bracket or similar holding member, as illustrated inFIGS.7-8, for holding the tubes T.

Referring toFIGS.6-8, one or two hoses or tubes T are typically connected to a front edge of the flexible pouch2. A rear edge of the flexible pouch2, at a longitudinal end opposite to the front longitudinal edge, may extend substantially parallel to the front edge. While each tube T may be bent and have a length superior to length of the longitudinal sides LS1, LS2of the pouch2, any size of hose/tube may be used. Each tube T may be maintained substantially parallel to the protecting body reference plane P, by attachment to a tubing holder provided in or attached to the frame15of the assembly HR.

Each hose/tube T is provided with a connector17for fluid connection, typically a connection to another biopharmaceutical device. The connector17thus makes it possible to fluidly connect the flexible pouch2to another element, for example a tank. In storage position of the tube (s) by use of the fixation means MF1, MF2, each connector17may be located between the longitudinal rear side120bof the protecting body12and the middle region MR.

Referring toFIGS.6-8, one or more of the elongated profiles, here the profile94, may be provided with one or more fixation means MF1, MF2for supporting at least one tube T that is connected to the port24or included in the pouch2as an extension defining the port24. The tubing holder, formed by the fixation means MF1, MF2, may be distributed at at least two spaced locations along a side of the frame15, in a peripheral area of the system1.

Referring toFIGS.6A and10, the fixation means MF1, MF2may comprise at least one fixing element that can be snapped on the frame15, here by engaging on the outer part of the rail-like profile of the frame15. For instance, the fixing element is a bracket that partly surrounds a receiving profile, which may be one of the longitudinal profiles93,94or another profile91,92. Some holes in the profiles may receive a pin or similar retaining inner protruding part of the bracket, for instance for an anti-sliding effect.

The bracket may be resiliently deformable, allowing removal of the fixing element relative to the frame15, for instance by spacing the arms of the bracket further away. Accordingly, the tubing holder formed by the fixation means MF1, MF2may be removed once line is no more used (inlet line not useful anymore after filling line disconnected).

Referring toFIG.7or8, the tube T may be a filling line connected in removable manner to the pouch2, for the purpose of the filling operation. For instance the tube T received and held/positioned by the fixation means MF1, MF2, is attached to the pouch2via a connector forming a quick seal connector.

The more the flexible tube T is away from the periphery of the system1, the lower is risk for accidentally handling and disconnecting this hose or tube T, during transportation steps for instance. But, this tube T remains here easily available for operators.

The tubing holder may be an assembly for holding two tubes T, in order to be symmetrically arranged with respect to the longitudinal direction X (i.e. pouch longitudinal axis A). Each symmetrical part is able to hold one hose/tube T.

WhileFIGS.6-8show each a solution for horizontal storage, it is understood that the pouch2can also be stored vertically or along any suitable direction, thanks to a protecting device10. A sliding structure may be used for having the protected pouch (in frozen state) carried by an annular frame or similar holding means that can extend vertically for storage purposes.

Protecting Body

Referring toFIGS.1and3-4, the protecting body12or112comprises or consists in two plates12A,12B for protecting the flexible pouch2. The plates12A,12B are entirely separate, here without hinging or connecting part. Typically, the plates12A,12B are two separable pieces. These pieces are relatively rigid, for instance sufficiently rigid so that they cannot form folding lines with bending angle of more than 45°. The plates12A,12B are thus configured to remain relatively flat. The protecting body12,112,212comprises a longitudinal axis X1and has four sides120a,120b,120c,120d, the four sides comprising two longitudinal sides120c,120dextending parallel to the longitudinal axis X1and two other sides that include a first end side120a, and a second end side120beach perpendicular to the longitudinal axis X1.

The protecting body12comprises two substantially planar plates12A,12B that are each made of a single thermoformed plastic piece. The planar plates12A,12B extend also in a plane parallel to the main plane XY (here parallel to the protecting body reference plane P). The plate12A forms a lower surface S′ and the plate12B forms an upper surface S, with respect to the vertical axis Z. In preferred embodiments, the two plates12A,12B are identical and symmetrically face each other, with respect to the main plane XY.

The protecting body is a thin body, as the plates12A,12B may be compared to sheets of relatively low flexibility, the plates being made of same material. The thickness e of each plates12A,12B is lower than a minimal thickness of the positioning members PM. The plates12A,12B can have a general curvature but cannot easily folding (flexibility being substantially as low as PET).

While the illustrated embodiments show a protecting body12,112,212covering entirely the two main walls W1, W2by the covering part8, other size may be used for the covering part8. For instance, the protecting body12could only cover a transverse band portion of each wall W1, W2, at a distance from the pouch edges2A,2B. Besides, one or more complementary protecting bodies could be used to cover at least one of the end parts of the walls W1, W2.

Referring toFIGS.1and4, the protecting body12is also provided with an attachment system18for fixing the two plates12A,12B to each other. InFIG.1, boss portions B12, B12′ are provided for having the plates12A,12B fixed one to each other in removable manner, the boss portions forming interlocking forms with the outer projections of the first boss portions B12delimiting hollows, in which the second boss portions B12′ are received with plastic retaining contact. Here, the second boss portions B12′ are projections (preferably hollow projections) protruding inwardly from the corresponding plate12A or12B. More generally, the plates12A,12B may be removably fixed to each other by an attachment system18. Such system18may also be of the type that can be specifically seen (schematically illustrated) inFIGS.2A-2B and3.

Optionally, the attachment system18may comprise a plurality of snap buttons20A,20B. One of the two plates12A,12B comprises a first element20A of one snap button and the other plate comprises a second complementary element20B of one snap button. The second element20B (possibly a male element) engages the first element20A (possibly a female element) in a direction parallel to the vertical axis Z. Insertion pieces IP, for instance with screws or bolts may also be used, by crossing the peripheral margin at specific holes or slots S80(seeFIG.2B).

Alternatively, the attachment system18is a non-removable system, which means that, once the two plates12A,12B are fixed to each other, it is not possible anymore to detach the two plates12A,12B one from each other. Clips may be used for such non-removable fixation.

In the non-limiting embodiment ofFIGS.2A-2B and4, the protecting body12comprises snap buttons on transversal sides120a,120band on the two margin portions8a,8b(typically between the covering part8and the longitudinal sides121,122). More generally, each of the two plates12A,12B is provided with complementary members. Typically, the two opposite margin portions8a,8bmay be considered as part of a fastening assembly provided to prevent any shifting in position between the two plates12A,12B once they are mutually fastened at least in the two margin portions8a,8bof the peripheral margin80.

As can be seen inFIGS.5and8, when the two plates12A,12B are fixed to each other, they sandwich the flexible pouch2. The planar plate12A, which forms the lower surface of the protecting body12, presses the lower surface of the flexible pouch2, with respect to the vertical axis Z. Similarly, the planar plate12B, which forms the upper surface of the protecting body12, presses the upper surface of the flexible pouch2, with respect to the vertical axis Z. The two plates12A,12B have planar dimensions which are substantially identical to the ones of the flexible pouch2, with typical difference that ribs may be provided on the outer surfaces of the plates12A,12B.

Exemplary Ribbing Patterns

In each plate12A,12B, a group of ribs is provided with ribs R1, R2, R2′,800arranged close to the peripheral margin80. An optional other group of ribs may be provided with ribs R3, R4,83,84,85,86arranged at a greater distance from the peripheral margin80. Such ribs R3, R4,83,84,85,86, which can be considered as ribs of a first group, may surround one or two panel portions PP, PP1, PP2, which are typically forming rectangular panels, in each outer surface S, S′ of the protecting body12,112.

Referring toFIG.1, the plates12A,12B may have each a panel portion PP. For instance, the panel portion PP extends between:

ribs (front ribs) close to a front side provided with the opening for the one or more ports24,

and ribs (rear ribs) arranged at the opposite from the front side.

Each panel portion may be strictly planar before assembling, possibly except at few local projections, here except at two projections12p, which can be protruding (outwardly) in same direction as the ribs. The projections12pcan be used to support a temperature sensor. These projections12pmay be median projections, intersected by a median plane of the protecting body12which extends along Z direction, parallel to a width of the protecting body12. The projections12pmay be disposed at the rear of any one of the front ribs and at the front of any one of the rear ribs.

More generally, the ribs may be distributed in groups, a first group of which having ribs R3, R4,83,84,85,86extending annularly (possibly with square or rectangle shape with curved corners), typically in the peripheral annular region8pof the covering part8as they are outside any panel part PP or PP1, PP2, while a second group of ribs has ribs R1, R2, R2′,800extending parallel to the first group of ribs and arranged closer to the peripheral margin80as compared to the first group.

Here, it is seen that several transverse ribs portions may be provided, separating the short margin portion of the peripheral margin80from one of the panel part (panel PP1or PP2). At least six or eight transverse ribs thus may be provided and distributed at two opposite ends of each plate12A or12B. Referring toFIG.5B, it can be seen that grooves G′ (and transverse groove portion thereof as well) surrounding a panel PP1or PP2may be narrower than grooves G delimited by side ribs R1and/or82. They may typically be narrower and less deep than grooves G or transverse portions thereof delimited by the transverse rib portions RP1, RP2.

In the illustrated embodiments, the protecting body12,112,212preferably has an attachment device/system18for fastening the two plates12A,12B so that in an assembled state of the two plates, the protecting body12,112comprises a peripheral margin80that extends annularly in a protecting body reference plane P as illustrated inFIGS.3and4. In some options, the peripheral margin80that extends in an interior interspace delimited by the frame15is typically a margin without ribs. In variants, one or more ribs R1adjacent to the margin part for mutual attachment of the plates12A,12B may extend in such interspace.

The protecting body may be provided with:

a first end side120a, which is composed of the ends E1of the two plates12A,12B in the assembled state of the protecting body12,112,212, and

a second end side120b, which is composed of the ends E2of the two plates in the assembled state of the protecting body12,112.

The one or more ports24may protrude axially outward from the second end side120b. Here a part of the pouch front edge is thus accessible.

In empty state of the pouch2, the two plates12A,12B respectively form a first surface S′ and a second surface S of the protecting body12,112covering the pouch2. When having a substantially horizontal configuration, the first surface is a lower surface and the second surface is an upper surface. The fastening members146,147,148can be provided on one of these surfaces S, S′ near an end side chosen amongst the first end side120aand the second end side120b.

At least one amongst the lower surface S′ and the upper surface S may be a surface having a plurality of ribs distributed in two opposite parts of the surface, which are longitudinally opposite parts. Preferably, the ribs of this plurality include first transverse rib portions4proximal to the first end side120aand second transverse rib portions6proximal to the second end side120b.

More generally, such transverse rib portions4,6or RP1, RP2provide an accordion effect due to width of the corresponding grooves G1, G2formed by the ribs and/or height of the ribs (depth of the grooves G1, G2). This facilitates local expansion of the plates12A,12B despite the planar structure of the peripheral margin80forming the protecting body reference plane P. Typically, in corner regions CR, the first and second transverse rib portions4,6have a height decreasing with decreasing space from the corner vertices of the plate having such rib portions4,6. Accordingly, too great expansion that could create undesirable folds (along diagonal lines) may be limited or prevented when having height reduction for the corner rib portions, extending in the corner regions CR. In other words, accordion effect may be practically reduced in the four corner regions CR in each plate12A,12B. More generally, structuring of the plates12A,12B, using first and second transverse rib portions4,6, is helpful, in order to facilitate spreading of fluid toward the margin80and toward the corners of the protecting body12,112when filling the flexible pouch2sandwiched between the plates12A and12B.

This is of interest, in order to have or improve a belly retention effect. Indeed, the more the fluid can be distributed toward the four corners, the less bulged is the pouch2in a middle region. The protecting body12,112is typically able to move in interspaces of the holding and retaining assembly HR, as described in more detail below. Besides, the structuring effect of the ribs may prevent folding lines to form substantially along the diagonals DL1, DL2, when difference in thickness/expansion between the middle region including the center C of the protecting body and the covering portion edges is too pronounced.

Some detailed embodiments of a protecting body12or112provided with a ribbing pattern will be described hereinafter.

The plates12A,12B as illustrated inFIGS.1,2,4and7correspond to a first embodiment of the protecting body12, in which several ribs are provided. In each outer surface of the plate, the ribs are provided so that the inner face is provided with grooves. Some grooves G1, G2, such as shown inFIG.1, are including transverse groove portions extending perpendicular to the longitudinal axis X1and close to the opposite end sides120a,120bof the protecting body. An annular rib R1, protruding upwardly in the outer surface S or S′, may be provided to define the groove G1which is of annular shape on the plate interior surface. Two separate ribs R2, R2′ protruding upwardly in the outer surface S or S′, may be provided to define the two grooves G2which are each of annular shape on the plate interior surface.

Thanks to the ribs R1and R2, R2′, a pair of transverse rib portions4,6, here parallel to Y-axis direction (perpendicular to the longitudinal axis X1) may be arranged close to the respective end sides120a,120b. In other words, these ribs form the first transverse rib portions4proximal to the first end side120aand the second transverse rib portions6proximal to the second end side120b.

Referring toFIGS.1-2, it can be seen that each plate12A,12B may be rectangular with four corner regions CR, two virtual diagonal lines DL1, DL2(diagonal lines of the plate) intersecting each a pair of corner vertices of the four plate corners. More precisely, each of the two virtual diagonal lines DL1, DL2intersects:

a first series of corner ribs C1, C2proximal to the first end side120aand protruding outwardly along a direction perpendicular to the protecting body reference plane P, and

a second series of corner ribs C1, C2′ proximal to the second end side120band protruding outwardly along a direction perpendicular to the protecting body reference plane P.

Each of the corner ribs C1, C2, C1′, C2′ is curved and connects two rib portions that are perpendicular one to each other. Here the annular rib R1thus may include two pair of corner ribs C1, respectively C1′.

It can also be seen that the ribs may be provided with differences in height so that they protrude more or less outside. For instance, the transverse rib portions4,6included in the ribs of annular shape or U-shape R1, R2, R2′,800may be of increasing height (maximal height) with the decreasing distance to the peripheral margin80. Typically, the ribs very close to the peripheral margin80may have a progressive rounding (with greater radius of curvature) in their profile as viewed in cross section of the rib. Such ribs close to the peripheral margin80may also prevent waves or radial folds along angled/diagonal directions to be created in the plates12A,12B.

As such rib height may relatively great near the junction with the peripheral margin (thus locally allowing a greater slope effect), other ribs of lower height (possibly more rigid) may be provided around the panel PP, PP1or PP2, to have expansion of the plates12A,12B that remain substantially parallel to the protecting body reference plane P.

Besides, as the pair of U-shaped ribs R2, R2′ are separated, the same applying for the optional ribs800, also U-shaped, there is no additional rib in the middle region MR at equal distance from the front and rear ends E1, E2. Avoiding multiple longitudinal ribs in the middle/edges of the protecting body12is here preferred as having too many or too significant/pronounced ribs could cancel benefits of a belt effect made by stoppers41such as illustrated inFIG.12(the belt effect is explained in more detail below). If present, such longitudinal ribs would then allow the expansion of the protecting body12in its center (bulge effect as inFIG.6).

Referring toFIG.8, at an ending stage of the filling with more than 60 or 70% of full capacity reached, expansion of each plate12A,12B may be obtained with slope as reduced as possible at each panel, here at the panels PP1and PP2, if a belt effect is produced. As pushing force of the liquid becomes relatively high, there is side expansion due to accordion-effect at the longitudinal rib portions110and at the transverse rib portions4,6, RP1, RP2. Such accordion-effect facilitates circulation of liquid toward the edges rather than accumulating in the middle region M. The transverse rib portions114along the middle section MS also participate in preventing the liquid from accumulating only in a middle region.

In corner regions CR, the height may be significantly lower than in the transverse rib portions4,6formed by the ribs R1, R2, R2′,800, which may be of interests for not impairing integrity of the plates. Besides, having here lower height in the ribs may allow having a transition as smooth as possible between elongated sloped portions SP formed along the long sides of the peripheral margin80and the elongated transverse sloped portions SP′ formed along the short sides of the peripheral margin80.

It can also be seen that the ribs are provided in the thin regions of the protecting body once the pouch2has been filed, so that these ribs R1, R2, R2′,800extend perpendicular to the slope considered along Z direction. With such orientation, the parallel ribs can expand in accordion manner, with provision that the pouch2is filled at a sufficient level (for example filled more than 60% or 70% of the full capacity) as the content should provide sufficient internal pressure to push the ribs from inside.

Referring toFIG.14A, it can be seen that a ribbing is of interest for guiding the liquid (biopharmaceutical composition Q) toward the corners at least when the internal pressure is sufficient to slightly deform the grooves G1, G2delimited by the ribs R1, R2, R2′. In this exemplary embodiment, the wavy profile formed by the (accordion-like) ribs R1, R2, R2′, R3, R4is present near/on the edges of the covering part8so that the plates12A,12B can be stretched in these areas under the pressure of the pouch filling:a) When the pouch2(here of about 100 liters capacity) is filled to 60 L nothing significant happens in the peripheral annular region8pof the cover part8(see top ofFIG.14A), as the pressure is still insufficient to have the ribs deformed;b) When the pouch is filled to 75 L, the accordion-like arrangement of the ribs R1, R2, R2′, R3, R4will stretch under the pressure of the pouch filling and the plate12A will stretch even more in its center, if no belt effect is provided.

It thus shows that the arrangement of the ribs is of interest to delay/relatively reduce the increase in stretching, which causes higher filling at the panel part PP and lower filing outside the panel part PP.

Referring toFIG.14B, it is also shown a profile (which may be similar, along XZ or YZ plane) of the ribs for a high level of filing, here with the pouch2filled with at least 75 L. If the edges of the middle of the margin portions8a,8bare narrowed or provided with early stoppers41to limit shrinkage (belt effect), the accordion arrangement of the ribs R1, R2, R2′, R3, R4of the protecting body12(and same applies with similar ribbing patterns, such as in the embodiment ofFIG.3) will stretch under the filling pressure of the pouch2and the panel part(s) of the protecting body12will be kept more flat, as each panel part lengthens (along Y direction toward the margin portions8a,8band along X direction toward the ends E1, E2), thus minimizing size along Z-direction in the middle of each plate12A or12B.

The ribs R1, R2, R2′, R3, R4may each be delimited by straight edges, in order to define respective virtual rectangles. Besides, the ribs R1, R2, R2′, R3, R4may extend around a panel part PP of the plate12A,12B, with such panel part PP having a transverse size TL which is equal or superior to half the width T12(transverse size) of the plate12A,12B, as illustrated for example inFIG.2B. The same typically applies for embodiments with ribs110,83,84,85,86arranged around a panel part PP1or PP2, with each panel part PP1or PP2having a transverse size TL which is equal or superior to half the width T12(see for instanceFIG.5C).

Here, the length LL (longitudinal size) of the panel PP is also much greater than half the total length of the plate12A,12B. When having two panels PP1, PP2, cumulated longitudinal size of the two panels PP1, PP2may also be superior or equal to the total length of the plate12A,12B. More generally, it is of interest to have cumulated panel length(s) exceeding half of the plate length.

Still referring toFIG.14A, it is understood that the section view where such profile is obtained can correspond to a plane parallel to YZ direction, preferably away from the middle section MS. In the middle section MS, the number of longitudinal ribs portions (along X direction) can be minimized due to a clearance region, in order to not interfere with a belt effect. In some options (less preferred), the plates12A,12B may sandwich the pouch2without any belt effect, for instance if the pouch2has not to be filled at its full capacity.

In some embodiments, all or part of the longitudinal rib portions are removed and only transverse rib portions4,6, RP1, RP2are present in at least one of the plates12A,12B. These transverse rib portions4,6, RP1, RP2are already efficient to have more liquid stored in the two opposite ends adjacent to the short margin portions of the peripheral margin80. The more liquid can be stored near the corners and the short sides, the lower is the thickness of the protecting body12,112.

The following table shows impact for the size along Z direction, when using some ribbing patterns in the plates12A,12B, each time with same belt effect using a configuration of positioning members PM such as inFIG.11A or12. The size as indicated below is/reflects the maximum thickness of the protecting body, not in frozen state. In frozen state, the belly size may increase by approximately 25%.

It can be seen that the U-shaped ribs (here ribs R2, R2′ and R3, R4) are especially efficient at the end of the filling, when the pouch2sandwiched by the plates12A,12B is filled at more than 75%. For this reason, the minimum size along Z direction is obtained with this ribbing pattern. In similar embodiments, less U-shaped rib portions may be used, as illustrated inFIGS.11A-11Cfor instance. It is understood that, if compactness with a size less than 220 mm is wanted for sake of compactness, the pouch filling level will be too low (about 55 liters only for instance for a pouch of 100 L) in absence of any suitable ribbing for helping in having liquid near the edges, i.e. near the clamping areas. In contrast, the protecting body12with the ribs R1, R2, R2′ and R3, R4is typically suitable for containing at least 88 or 90 liters for a 100 L pouch before freezing.

Regarding situation with a pouch filled at lower level, for instance about 70 or 75% or less, the ribs such as shown inFIG.3are more efficient to limit bulge effect in the middle region MR. For maximal filling, the ribs of this embodiment have less added-value as it is firstly the belt effect that limits the bulge total size below 300 mm. In practice, 75% filling may be considered sufficient, as further expansion due to freezing is typically anticipated.

When analyzing the bulge effect such as shown inFIG.6, it can be seen that a relatively low angle is obtained for the sloped portions adjacent to the peripheral margin80. Indeed, these portions are close to the attachment system18, thus near clamping areas. It is here observed that the protecting body plates are more difficult to be deviated from the planar reference P, as if they were more rigid, at/near the edges because such peripheral areas are near the clamping areas (shorter lever arm).

A high part of the biopharmaceutical product mass is concentrated in the middle of the covering part8, even if the pouch2is filled only at 75% of its full capacity. Here, the plates of the protecting body212are not submitted to any belt effect on the one hand, and there is no ribbing for helping in having narrower sloped portions and/or homogeneous slope (without interfering folds) on the other hand. The solution illustrated inFIG.7or inFIG.8is of interest to have a better distribution of the biopharmaceutical composition Q relative to the whole lower surface S′ of the protecting body12,112, with such fluid more present in the corner areas.

Referring toFIGS.3,5A-5D and8, it is shown an example of a protecting body112having at least one plate12A,12B provided with two panels PP1, PP2. While embodiments ofFIGS.1,2A-2Bshow ribbing patterns, in which the ribs may be considered as peripheral ribs (all extending parallel to the peripheral margin80, i.e. along a circumferential direction), arranged around a central panel portion PP of the plates12A,12B,FIGS.3and8show that some ribs or rib portions114may be provided in a middle region MR, possibly extending transversally to separate two panels PP1, PP2of a same plate12A or12B.

The rib portions114, forming middle ribs in this embodiment, may be suitable to obtain a kind of “camel back” shape, once the pouch2is in a filled state. Some simulations have been performed to confirm this is efficient to limit total thickness of the protecting body, for pouches filled with 75 or 100 liters of liquid biopharmaceutical composition Q. Practically, the ribs of this pattern have a kind of molding effect so as to get two small off-center bellies rather than a greater mass of product in the middle section MS.

Transverse rib portions RP1, RP2mays also be formed at opposite ends of the cover part8, these rib portions possibly being interconnected to the longitudinal rib portions110by smaller corner ribs C1provided in the corner region CR. In some options, no corner rib is present. Referring toFIG.5D, The middle110aof the longitudinal rib portion110has here a minimum in height H1′ lower than a maximal height H1of the longitudinal rib portions110that is found away from the middle region MR where a belt effect can be performed thanks to early stopping positioning members PM specifically provided in middle of the corresponding margin portions8a,8b. The difference H1-H1′ may be at least equal to 2 or 3 mm.

Now referring toFIG.5A, the corner regions CR may be provided with less relief. Here, the maximal height H2in the corner regions CR may be equal or less than half the height H1that is obtained at the longitudinal rib portions110and/or at the transverse rib portions of the outermost side rib R1. With such arrangement, possible fold lines will be limited and only created in the corner regions CR, along diagonal lines DL1, DL2, thus corresponding to “desirable” fold lines, i.e. not interfering with expansion of panel part(s) parallel to the protecting body reference plane P.

In the illustrated embodiments, each of the two virtual diagonal lines DL1, DL2may intersect: a first series of corner ribs proximal to the first end side E1, and a second series of corner ribs proximal to the second end side E2and protruding outwardly. Each of the corner ribs are curved and are connecting two rib portions that are perpendicular one to each other. Typically, the first transverse rib portions4are directly connected to the corner ribs of the first series, while the second transverse rib portions6are directly connected to the corner ribs of the second series.

Besides, the first transverse rib portions4and the second transverse rib portions6may extend perpendicular to the longitudinal axis X1and belong to an intermediate region between two corner regions CR respectively adjacent to an intersection of two of the four sides. Preferably, each corner region is elastically more deformable than such intermediate region provided with transverse rib portions. Typically, each of the corner regions are more deformable than any one of the side regions provided with longitudinal rib portions110.

A symmetrical ribbing may be preferred. For instance, ribs in the lower surface S′ is distributed in two halves of the plate forming the lower surface S′, and/or the pattern of ribs in the upper surface S is distributed in two halves of the plate forming the upper surface S. While same ribbing pattern is provided in the two complementary plates12A,12B according to the illustrated drawings, some differences may be provided in variants. Optionally, one of the plates may be deprived of ribs.

The plates12A,12B form each a stiffening layer when overlapping, and preferably entirely covering, the main walls W1, W2. The thickness e of each plate12A,12B before Thermoforming may be of about 1.27 mm and thus may be lower than 2 mm, with provision that the plastic material of the plates has a density superior to 1.10 g/cm3, preferably superior to 1.15 g/cm3(typically without being above 1.5 or 1.6 g/cm3). Plate material may have a tensile strength at break, which is typically between 45 and 75 MPa, for example in the range 50-60 MPa, typically 52-59 MPA (standard test ASTM D638). Plate material may have a tensile strength at break between 45 and 60 MPA and a Young's Modulus comprised between 1250 and 1550 MPa, both along transverse direction (TD) and machine direction (MD).

Shrink Management

The flexible pouch2can inflate during filling operation, which means that the circumference of two main walls W1, W2as considered in the pouch plane is decreasing due to inward movement, also known as shrink stroke, of the different sides. Here, in horizontal configuration of the system1as illustrated inFIGS.6-9, four pouch sides can be displaced inwardly due to the vertical expansion (along Z-axis).

The holding and retaining assembly HR, which may include a rectangular frame15or at least two longitudinal covering parts31,32, is arranged to maintain two longitudinal margin portions of the peripheral margin80, and allowing the two plates112A,112B moving, extending, and shrinking in a transverse direction belonging to the protecting body reference plane P. The two longitudinal covering parts31,32may comprise two profiles93,94each delimiting an interior cavity CP. In non-limiting embodiments, the interspaces may be respective interior cavities CP of such covering parts. Each of the two longitudinal covering parts31,32may include a profile having a C-shape to delimit one of the interior cavities CP.

Now referring toFIGS.9,10A-10B,11A,11B,11C and12, it will be described exemplary embodiments for forming the positioning members PM as stoppers preventing too great inward displacement of some regions of the peripheral margin80, when the pouch2is more and more filled.

The positioning members PM may be adapted to cover the boss portions B12, B12′ such as illustrated inFIG.1or similar embossments. For instance, the positioning members may include several cavities each housing a respective pair of boss portions B12, B12′. With such arrangement, there is no need for aperture or through-hole in the margin portions8a,8bof the plates (only one hole may be provided for the at least one port24, at a front end of the protecting body).

Typically, the frame15may house the margin portions8a,8bsandwiched by a plurality of discontinuous positioning members PM. Along Z direction (seeFIG.1), the depth of each hollow delimited by a boss portion B12or B12′ (such depth defining a stroke for disengagement between the complementary boss portions B12and B12′) may be superior to maximum spacing, measured along Z direction, between the frame15and any one of the positioning members PM. In such option, the frame15thus extends above and below each of the positioning members PM and prevents disassembling of the respective pairs of boss portions B12, B12′.

Here, the frame15is provided with abutment surfaces BS1, BS2included in abutment members or rims. Each abutment members may delimit an inner access to a housing, in which the positioning members PM extend. Typically, each profile91,92,93,94, forming a side of the frame15may be provided with an open end suitable for introduction of a respective side of the protecting body12,112,212inside the housing (side chosen amongst the four sides). The inner open sides of the frame15are not used for assembling or disassembling steps, due to presence of the abutment members that prevent any possibility for the positioning members PM to be inserted inside or extracted outside the profiles91,92,93,94through the inner open sides. Indeed, at an inner face of each profile91,92,93,94, there is at least one abutment member BS1, BS2extending transversely relative to the protecting body reference plane P. Here, each profile91,92,93,94has a C-shape section, with the opening of the inner open side delimited between two vertically spaced abutment members. Each abutment member is here a continuous member elongated along length of the corresponding profile. But in variants, the abutment members may be divided into separated abutment regions or constructed in any suitable manner, without interfering with the protecting body reference plane P.

Here, as illustrated inFIGS.11A and11Bin particular, the positioning members PM are inserted by sliding insertion along a direction parallel to the long side of the profile91,92,93or94in which they are housed. The positioning members PM may thus be inserted at the rear of abutment members and remain at the rear of the abutment members (forming the surface BS1, BS2) in assembled configuration of the frame15around the protecting body12,112,212.

Referring toFIGS.11A-11C, each longitudinal supporting part, typically under the form of a profile93,94or similar piece, delimits one or more housings and is assembled with at least one adjacent supporting part (for instance two transverse supporting parts), also possibly under the form of a profile91,92. An annular housing may be included in the frame15, when the profiles91,92,93,94are assembled, possibly using lower feet115and/or upper feet116for supporting another frame15. For instance, the two profiles93,94respectively define a first housing and a second housing, in which the sliders are mounted.

Here, it can be seen that the sliders may comprise:

first sliders fitted in at least one cavity CP delimited by the first housing; and

second sliders fitted in at least one cavity CP delimited by the second housing.

Referring toFIGS.9,11A and12, it can be seen that the sliders in the first and second housings will act as stoppers, more particularly either early stoppers41if mounted in a inwardly shifted manner on the peripheral margin80, or late stoppers41′,42engaging abutment members at the surfaces BS1, BS2at a later stage during filling of a pouch2. The front surface BS of the early stoppers may possibly be already engaged, for a non-filled state of the pouch2, onto one or more of the abutment members or rims provided in the frame15, here in a middle region MR.

Referring toFIG.11A, each transverse supporting part, here formed as a profile91or92, is configured for housing additional sliders, at least a part of which is acting as early stoppers. The front surface BS' of the early stoppers (orientated toward the pouch2) may possibly be already engaged, for a non-filled state of the pouch2, onto one or more of the abutment surfaces provided in the frame15, here in transverse profiles91,92or similar transverse supporting parts of the frame15.

In the illustrated embodiments, all or part of the positioning members PM are configured to slide and thus form sliders able to be displaced inwardly with increasing filling level of the pouch2, as illustrated inFIGS.10A-10B. For a filling lever of more than 70 or 75% for the pouch2, the angle α of the slope defined at the surfaces S and S′, relative to the reference plane P, may be constant along the long sides, and possibly higher when having ribs110whose height is greater than plate thickness to provide an accordion effect; preferably maximal height H1of plate ribs may be greater than 3 mm with a rounded profile, such height being preferably lower than or equal to groove width (width of groove being width of the hollow which separates two interior edges of the corresponding rib). Here such ribs110extend longitudinally.

Typically, width of each groove G1, G2, G may be superior to 10 or 12 mm, preferably inferior or equal to 35 or 40 mm. In embodiments, any of the ribs formed along X or Y direction may have a width superior to 10 or 12 mm, while forming an elongated hollow/groove having an interior width of at least 10 mm.

Referring toFIGS.11A,11B and11C, a first group of the positioning members PM are distributed longitudinally in the frame long sides, while a second group of the positioning members PM are placed along transverse areas of the peripheral margin80and distributed in the frame short sides. When members PM, which typically form sliders housed in the profiles91,92, are mounted on transverse profiles or similar supporting parts, they are each slidably mounted and can move along direction of the longitudinal axis X1.

The frame15has here a rectangular shape thanks to the two longitudinal supporting parts and the transverse supporting parts. It is thus understood that the frame15can comprise abutment surfaces BS1, BS2included and distributed in the two longitudinal supporting parts and in at least one of the transverse supporting parts.

The positioning members PM, forming sliders in the frame15and assembled such as shown inFIG.11A-11C, are suitable to allow shrink management, while using rigid material (aluminum) compatible with low/negative temperatures.

Details of Exemplary Embodiments for Controlling Pouch Expansion

In embodiment ofFIGS.7-8, the plate dimension reduction (as considered in XY plane) may be obtained with a profile of shrink strokes, such reduction being adjusted to be different, depending on longitudinal positions of some positioning members PM that locally prevent or limit such dimension decrease, for a control of the shrink stroke.

Here, the positioning members PM (which are secured to the peripheral margin80as illustrated inFIGS.9and10A-10B) are distributed longitudinally and some of them are configured to limit shrink stroke of the longitudinal sides of the protecting body by a stopping effect due to engagement of the positioning members PM against the interior surfaces of the abutment rims.

All or parts of the positioning members PM are stoppers for providing strokes limitation between the stoppers41,41′42and the abutment surfaces BS1, BS2included in the frame15of the holding and retaining assembly HR. Referring toFIG.12, the stoppers41,41′ arranged at or near a middle section MS of the pouch2are involved to create a belt effect. In some embodiments, such belt effect is separating two bellies or bulges B1, B2.

The positioning members may act as stoppers41or41′ only in the two intermediate parts82of the protecting body12. As a result, since stroke is allowed in regions closer to the corner regions CR, here in the end parts81, the pouch2covered by the containment protecting body12,112or212cannot form a single belly or bulge in the middle thereof.

Moreover, the optional ribs R1, R2, R2′, R3, R4prevent the plate outer surface S, S′ from forming fold lines or hollows that limit good filling of the biopharmaceutical composition Q in the corner region. Such ribs, possibly with regions or portions of lower height (for instance only at the diagonal lines DL1, DL2as guiding and accordion-like effect is already obtained along the four sides of the rectangular shaped protecting body12,112), may help in expanding the protecting body12,112from the inside without creating hollows or inappropriate fold lines detrimental to filling at the corner regions CR.

It is understood that at a given level of filling, the pouch corners and protecting body corners can continue to move inwardly during filling operation, while the intermediate parts82are blocked by the stoppers41,41′. At the corner regions CR, shrink strokes are longer than in the middle and will allow storing at least the same liquid capacity than without the belly/bulge retention.

Still referring toFIG.12, the stoppers41,41′,42may be at predefined positions, in order to form positing members PM. Here, only the stoppers41,41′ that are located away from the end sides120a,120bhave a relatively closer distance to a median symmetry plane of the protecting body12, as compared to distance for the stoppers42. In such option shown inFIG.12, such stoppers41,41′,42follow displacement (shrinking) of the peripheral margin80.

During filling operation, as the stoppers41,41′ provided in intermediate parts82of the longitudinal margin portions8a,8bare (initially) shifted inwardly due to arrangement of the attachment system18, and because the abutment surfaces BS1, BS2are in alignment, parallel to the X direction, these stopper41,41′ are in abutment state against the abutment surfaces AB1, AB2well before the stoppers42adjacent to/facing a corresponding corner region CR. A belly retention effect at the middle of the protecting body12,112is obtained.

In options, ribs R1, R2, R2′ R3, R4are provided in the plates12A,12B. In such kind of option, the retention effect (decreasing bulge effect in the middle region MR, near the center C) is completed by a regular expansion of the regions around the panels PP or PP1, PP2, preventing undesirable formation of pronounced fold lines. Possibly, some corner ribs or rib portions C1, C2have a decreasing height profile toward the intersection region with the diagonals DL1, DL2.

Of course,FIG.12is only an exemplary embodiment for managing the shrink of the plates12A,12B. More generally, the protecting body12can be mounted to sandwich the flexible pouch2and may be received/hold in an interspace of any suitable holding and retaining assembly HR, which is rigid and delimits an outer circumference of the system1. Depending on level of filling of the pouch2sandwiched by the plates12A,12B, the protecting body12may comprise one or more areas of maximum thickness. In order to accommodate this thickness variation, the holding and retaining assembly HR may be of annular shape.

The one or more bulges/bellies B1, B2as illustrated inFIGS.13A-13Bcan be formed due to the expansion control and early stopping effect at the intermediate parts (thanks to the early blocking stopper41and/or41′ for instance), so that the middle section MS is much less moved as compared to complementary sections covered by parts of the protecting body12that are near the first and second end sides120a,120b.

More generally, any configuration with positioning members PM able to form stoppers away from the corner regions CR may be provided, so that a higher constraining effect can be obtained in a center of the pouch2, as illustrated inFIGS.9A-9Bin particular. This is of interest for managing freeze/thaw operations of biopharmaceutical materials contained in the pouch2. This is also of interest to better stacking the systems such as illustrated inFIGS.6-9, with higher compactness (less vertical space between two adjacent storage units10), thus offering opportunities to store more pouches2in a freezing chamber.

Dashed lines inFIG.13Bshow the kind of belly usually obtained when similarly allowing a significant stroke in each region of the peripheral margin80. It is thus of interest to limit or prevent the displacement of the middle part of the protecting body12,112,212, in order to limit accumulated mass (of important thickness) that could be difficult to be thawed.

FIG.13Ashows that the frame15or any kind of holding part of the assembly HR is suitable to allow the protecting body12,112,212to change its conformation (with decrease in body width and in body length), thus allowing reducing:

the pouch2in width (with w′<w, where w′ is the pouch width in filled state, as compared to pouch width w in empty state), and

the pouch2in length (with L′<L, where L′ is the pouch length in filled state, as compared to pouch length L in empty state).

In some variants, the positing members PM may be positioned in through slots and maintained stationary, for instance by being secured to or integral with the rigid frame15or similar holding and retaining assembly. The slots in the protecting body may be of greater size only near the end sides120a,120b, thus allowing greater shrinking only at the corner regions CR and preventing forming a too great bulge near the center C (due to belly effect/retention in the intermediate parts where the positioning members are early stopping members).

The holding and retaining assembly HR may comprise at least three positioning members PM distributed on each of the longitudinal sides120c,120d, with typically one or two central stoppers41corresponding to the positioning members PM arranged away from the corner regions CR.

Referring toFIGS.7-8, the pouch expansion is limited and controlled by the protecting body12,112, due to lower flexibility of the material of the two plates12A,12B. The protecting body is made of a freeze resistant polyester or copolyester material that is not brittle at about 25° F. or −4° C. This material is for instance PET or a robust copolyester of TRITAN™ type.

The flexible pouches2can be frozen, thawed, filled or emptied simultaneously when they are stored on stacked protecting bodies12,112, using the frames15. When the flexible pouches2are stored, the biopharmaceutical fluid can be frozen or thawed. When the flexible pouches2are shipped, most often, the biopharmaceutical fluid is thawed even if the biopharmaceutical fluid can as well be frozen.

Now referring toFIG.4, it can be seen that the two plates12A,12B may also comprise through holes25, for instance regularly arranged on the peripheral sides of the two plates. The through-holes25coincide, in the assembled state of the protecting body12, and extend in the margin portions8a,8b, in order to form protecting body through-slots that do not interfere with the covering part covering the pouch2. More generally, protecting body through-slots, any kind of reliefs, or suitable positioning members PM are provided in one or more of the margin portions8a,8b, in order to cooperate with complementary elements adapted to restrict expansion by preventing or limiting inward displacement of the longitudinal sides120c,120dof the protecting body in assembled state. Such complementary elements form positioning members PM because they are involved in determining the final position of longitudinal side sections at the end of the filling of the flexible pouch2, typically by abutting against an outer edge included in a margin portion8aor8b.

As illustrated inFIG.4, the flexible pouch2typically comprises, here along one of the transversal sides, a through-hole2cwhich can form a handle for the flexible pouch2. This is of interest when the pouch capacity is sufficiently low to permit manual carriage of the pouch2.

The plates12A,12B here have same thickness e, as illustrated inFIG.4, which is a constant thickness in the plate contact part for contact with the pouch (which here forms the covering part8). Such thickness e may be also present in the margin portions8a,8bin the regions provided with the through-slots. In some variants, the margin portions8a,8b, may be reinforced by at least one additional stiffening layer.

Length of the two opposite margin portions8a,8bis here substantially the same. Such length may be for example superior to 250 or preferably superior to 350 mm, which of interest to provide at least three through-slots regularly distributed in at least one margin portion, preferably in all of these margin portions8a,8b, while having excellent robustness. This length may correspond to more than 75% of the total length of the pouch2, before filling the pouch2.

The freeze/thaw system1may be optionally provided with clamps, here two clamps11,13in the example ofFIG.4. Each clamp11,13is located near to a corner between the front edge2aof the flexible pouch2and a long side or similar longitudinal edge. Each clamp11,13respectively pinches one hose or tube Tat a straight angle. Thus, each plate12A,12B may comprise a cut-out located at each corner between its front I edge and adjacent edge parallel to the longitudinal axis A. These cut-outs create a free space that can be occupied by the clamps11,13.

With such arrangement, the frame or similar holding assembly HR may possibly only support the two margin portions8a,8b. The frame structure may be particularly simple when the capacity of the pouch2is lower than 10 or 20 liters.

Independently of the way the positioning members PM are provided in the peripheral margin80, the protecting body12,112,212mounted to sandwich the flexible pouch2may be received in a single cavity of interior space of any suitable holding and retaining device HR, which is rigid and delimits an outer circumference of the system1. Depending on level of filling of the pouch2sandwiched by the plates12A,12B, the protecting body12may comprise one or more areas with ribbing.

In order to accommodate the corresponding thickness variation (as measured on corresponding outer surface S or S′, from the protecting body reference plane along Z axis-direction), the holding and retaining device may be of annular shape without covering the covering part8. The one or more bulges/bellies B, B1, B2can be formed due to the expansion control and early stopping effect at the intermediate parts82, so that the middle section MS illustrated inFIG.13Ais much less movable as compared to complementary sections of the protecting body12. At the middle section MS, the total thickness (or maximum in thickness) is less than 300 mm, for example around 230 or 260 mm, while total length of the protecting body is typically superior to 1400 mm. In other words, the ratio thickness:length may be kept inferior to 1:4, which is of interest for stacking efficiency and compactness.

The system1is well adapted for freezing, storing and thawing biopharmaceutical materials contained in a flexible pouch2of simple conception. A protecting device10as above described is of interest for filing the pouch2with a controlled and restricted expansion, so that expansion is restricted in one or more areas where the fluid thickness would reach a maximum if no expansion control is carried. The interior volume or cavity delimited by the main walls W1, W2is expanded with prevention of free expansion in the middle areas of these walls W1, W2. Especially expansion can be limited along one or more belt line BL that joins the two intermediate parts82, as illustrated inFIG.13A.

Depression along such belt line BL, due to the low or inexistent shrink stroke in the intermediate parts82, typically creates at least one recess. In the pouch2as filled and in containment configuration of the storage unit10, at least one recess is thus created in the filled pouch2between the two bulges B1, B2that are formed respectively in front of and at rear of the belt line BL (line crossing the at least one recess). Of course, such effect does not prevent fluid communication between the two opposite regions where a bulge B1or B2is formed. This allows a generally equal distribution of fluid. As more than one region is created with bulge formation, a more uniform thickness distribution is obtained, without decreasing the capacity of the pouch2. In other words, the decreased thickness of each region decreases the thickness at any one point in the pouch2, and thus no “belly” is formed.

The ribbing also facilitates having the belt effect without undesirable waves or folds which impair filling in the corner region CR.

The pouch2and the storage unit10may be exposed to a temperature of about −70° C. or lower to freeze the biopharmaceutical fluid. The annular shape of the shell HR is of interest to provide a recessed area where cold air can circulate and flow between systems1(even if they are staked). But other shapes and structures may be used to form a holding and retaining device for a controlled expansion, in order to eliminate or reduce the formation of too significant projections during freezing. In some options with a shell covering/contacting the covering part8, this also facilitates separation of the halves or protecting parts3,4of the shell HR.

The present invention has been described in connection with the preferred embodiments. These embodiments, however, are merely for example and the invention is not restricted thereto.

Of course, the pouches2of the present invention are not in any way limited to pouches having four sides and/or pouches that are larger than wide. The pouches2may have other shapes provided with two generally parallel sides, covered by the pair of plates12A,12B or similar protecting body including two flat portions.

In preferred embodiments as illustrated, the positioning members PM are sliding members inserted in slots or holes of the peripheral margin80or through-slots25. In variants, the protecting body through-slots may be replaced by at least one cavity or hollow included in the respective plates, for receiving a positioning member PM that prevent inward movement, locally in a margin portion8aor8b.

Variation of the clearance for the shrink stroke may be obtained by abutting members included in a shell or covering parts that are differently positioned relative to the through-holes25, as inFIG.4, of with abutting members or positioning members PM made separate from the device HR, mounted on a frame15and having a stroke limited by appropriate surfaces BS1, BS2.

It will be understood by those skilled in the art that other variations and modifications can easily be made within the scope of the invention as defined by the appended claims, thus it is only intended that the present invention be limited by the following claims.

Any reference sign in the following claims should not be construed as limiting the claim. It will be obvious that the use of the verb “to comprise” and its conjugations does not exclude the presence of any other elements besides those defined in any claim. The word “a” or “an” preceding an element does not exclude the presence of a plurality of such elements.