Improvements in and relating to biomanufacturing apparatus
FIELD OF THE INVENTION
The present invention relates to biomanufacturing apparatus, for example for cell culturing.
5 In particular, the invention relates to bioreactor apparatus in the form of single instruments, and
plural instruments arranged into a biomanufacturing system for optimising the usage of laboratory
and cell culturing space for biomanufacturing.
BACKGROUND OF THE INVENTION
I 0 Cell culture, for example the culture of mammalian, bacterial or fungal cells, may be
carried out to harvest the living cells for therapeutic purposes and/or to harvest biomolecules, such
as proteins or chemicals (e.g. pharmaceuticals) produced by the cells. As used herein, the term
"biomolecule" can mean any molecule, such as a protein, peptide, nucleic acid, metabolite,
antigen, chemical or biopharmaceutical that is produced by a cell or a virus. Herein, the term
15 biomanufacturing is intended to encompass the culturing or multiplication of cells, and the
production of biomolecules. The term bioreactor is intended to encompass a generally enclosed
volume capable of being used for biomanufacturing.
The cells are generally grown in large scale (I 0,000 to 25,000 litre capacity) bioreactors
which are sterilisable vessels designed to provide the necessary nutrients and environmental
20 conditions required for cell growth and expansion. Conventional bioreactors have glass or metal
growth chambers which can be sterilized and then inoculated with selected cells for subsequent
culture and expansion. Media within the gro\\1h chambers are often agitated or stirred by the use
of mechanical or magnetic impellers to improve aeration, nutrient dispersal and \vaste removal.
In recent years, there has been a move towards 'single use' bioreactors which offer smaller
25 batch sizes, greatecpro.duction flexibility, ease of use, reduced capital cost investment and reduced
risk of cross-contamination. These systems can also improve the efficiency of aeration, feeding
and waste removal to increase cell densities and product yields. Examples include WAVE TM bags
(GE Healthcare) mounted on rocking platforms for mixing, or stirred-tank single-use vessels such
as those available from Xcellerex Inc (GE Healthcare). With the advent of 'personalised
30 medicine', autologous cell therapies requiring many small batches of cells to treat patients with
unique cell therapies has become important.
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Manufacturing facilities, such as tissue culture laboratories, for the production of cells and
biomolccules, have traditionally been custom designed and carried out in clean environments to
reduce the risk of contamination. Such facilities are costly to run and maintain and also to modify
if priorities or work demands change. Work stations for maintaining or harvesting the cells within
5 the biorcactors require a specific 'footprint' which occupies a significant floor space in the culture
laboratory. As the workstations spend much of their time unattended, while the cells are growing
in the bioreactors, the laboratory space is not efficiently or effectively used.
An improvement is proposed in WO 2014122307, wherein the laboratory space required
for cell culture is reduced by the provision of customised workstations and storage bays for
10 bioreactors, on which, conventional WAVE type bioreactors and ancillary equipment can be
supported. Large supporting frameworks are required for that equipment.
US6475776 is an example of an incubator for cell culture dishes, which has a single
incubator housing and multiple shelves, however this type of equipment is not suitable for housing
bioreactors.
I 5 What is needed is the ability to stack multiple bioreactors one on top of another, closely
spaced side by side, in a system that is simple to load, operate and maintain. Ideally such
bioreactors should be capable of tradition fed batch manufacturing where cells are cultured
typically over 7 to 21 days, as well as perfusion type manufacturing where cells can be cultured for
longer periods, but waste products are continually or regularly removed, and biomolecules may be
20 harvested.
A solution to the above mentioned needs has been proposed in unpublished and co-pending
patent application GB1518426.0, the contents of which are incorporated herein by reference.
Therein, a stackable bioreactor was proposed, which saved on floor space, was capable of
providing small batch sizes used in autologous therapies, and did not require clean room
25 conditions. One important ~sp~ct of that prior design was a removable rocking platform on which
a cell culture bag could be supported during culturing. However, the inventors of the present
invention realised that in stacking bioreactors, that platform requires careful design to make it
easier to use (removing and loading whilst suppotting a bag containing, essentially, liquids in a
confined area) and easier to dismantle for cleaning.
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SUMMARY OF THE INVENTION
The invention provides an arrangement according to claim I having preferred features defined by
claims dependent on claim I.
The invention extends to any combination of features disclosed herein, whether or not such a
combination is mentioned explicitly herein. Further, where two or more features are mentioned in
combination, it is intended that such features may be claimed separately without extending the
scope of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention can be put into effect in numerous ways, illustrative embodiments of which are
described below with reference to the drawings, wherein:
Figure Ia shows a pictorial view of an embodiment of biomanufacturing apparatus;
15 Figure lb shows the apparatus of Fig Ia stacked to form a biomanufacturing system 2;
Figure 2 shows a different pictorial view of the apparatus shown in Fig I;
Figure 3 shows another pictorial view of the apparatus shown in Fig I, including a bioreactor
loaded inside the apparatus;
Figures 4 and 5 show two pictorial views of a further embodiment of biomanufacturing apparatus,
20 in different configurations;
Figures 6a, 6b, 6c and 6d show a pat1ial sectional view of the apparatus shown in Figs land 2;
Figures 7 to shows an enlarged partial view of the apparatus shown in Figures I and 2; and
Figure 8 to 14 shows detailed views of a modified tray and tray support.
25 The invention, together with its objects and the advantages thereof, may be understood better by
reference to the following description taken in conjunction with the accompanying drawings, in
which like reference numerals identify like elements in the Figures.
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Referring to Figure Ia there is shown biomanufacturing apparatus I including a generally selfcontained
instrument 10 which includes a generally cuboid or box-shaped housing 20 having
generally flat upper and bottom sides 22 and 24. The bottom side includes four adjustable height
feet 26, only two of which are visible in Figure Ia. The box shaped housing allows stacking of
5 plural instruments to form a biomanufacturing system. In practice, for convenience, the stack will
be two or three high on a benchtop 5, as schematically illustrated in Figure lb, although there is no
reason why the stack could not be higher. The instrument also includes a door 25, shown open and
cut away for in order to shown the remaining patis of the instrument more clearly. The door is
hinged at hinges 28 to the front vertical edge of the housing, so that it opens about a v~tiical hinge
10 axis to expose or enclose an insulated chamber 30 inside the housing 20. The chamber 30 is sealed
when the door is closed by an elastomeric seal 32 extending around the whole periphery of the
inner face of the door and cooperating with a seal face 31 extending in a complementary manner
around the front edges of the housing 20. No light enters the chamber 30 when the door 25 is
closed. This negates light effects on the cell culture.
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The chamber 30 has a main chamber 35 and an antechamber 33 leading to the main chamber 35.
The main chamber includes a bioreactor tray 40 for example for suppotiing a cell culture bag- a
cell bag herein, suppotied by a rocking tray suppoti 45 described in more detail below. The
rocking mechanism is protected by a cover plate 21. The antechamber 33 includes a panel 34
20 supporting two peristaltic pumps only the fluid handling heads 48 and 49 of which extend into the
antechamber 33, the electrical parts of which are behind the panel 34. The panel also includes
connections 43 described in more detail below. The antechamber 33 includes openings 46 defining
a route for conduits extending to an external storage area which includes a bag hanging rack 50.
25 Figure 2 is a differentxiew of the instrument 10 shown in Figure I, with the door 25 and bag rack
removed 50, in order to show the remaining parts of the instrument more clearly.
Figure 3 shows the instrument I 0 of figures I and 2, but loaded with a bioreactor I 00, in this
instance, in the form of a flexible bag I 00, as well as various paths linking the bioreactor to the
30 instrument, including: a fluid supply conduit I 02 feeding the bioreactor with a known mixture of
fluids to promote cell growth via the peristaltic pump head 48, a fluid removal conduit 104 for
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drawing off fluids ft·om the reactor for the purpose of removing waste components expressed by
cells in the bioreactor via a filter incorporated in the bag I 00 and via the peristaltic pump head 49;
a gas feed conduit I 06; and paths, for example electrically conductive paths I 06, I 08 and II 0 for
example electrical wires, for various sensors within or adjacent the bioreactor, for example a pH
5 sensor, and a dissolved oxygen (DO) sensor. The conduits and paths can be kept in place by one or
more hangers 23.
Figures 4 and 5 show an embodiment of the instrument 10 including the door 25. The tray 40 in
this embodiment is removable from the tray support 45 by sliding motion and can rested on a
10 collapsible stand 120, in turn hung on the hinged door 25. In use, the door 25 can be opened, the
stand 120 can be dropped down, and the tray 40 (without or without a bioreactor in place) can be
slid away from the suppmt 45 and manually moved onto the stand. It will be noted that the tray 40
has an open mid-section. This open section accommodates a bioreactor, which has clips that clip
onto the tray 40 sides so that the bioreactor does not fall through the middle of the tray. Returning
15 the tray full or empty back into the chamber 30, allows the frame 120 to be folded away and the
door 25 to be closed shut.
Figures 6a, 6b, 6c and 6d each show a sectional view of the main chamber 35 illustrated in Figures
I to 3, and the components housed therein. Those components include the removable tray 40 and
20 the rocking tray suppmt 45. The tray support 45 is formed from an electrically heated plate 42
which is in direct contact with the bottom of a bioreactor in use, a pivotable plate holder 44 which
releasably holds the heated plate and an electrical stepper motor driving rocking mechanism 47
which moves the plate holder 44 back and forth about a pivot axis P below the tray 40 through a
predefined angle of about 25-35 degrees. The suppmt 45 is controllable in use so that it stops in
25 any position, but iJ,l.p!lrticular in the forward slopping position shown in Fig 6b, which enables the
tray 40 and plate 42 to be slid forward together whilst the plate holder 44 stays in position, to a
new position as illustrated in Figure 6c, where the tray is more readily accessible for loading or
unloading rather than having to remove it as shown in the embodiment of Figure 4 and 5. In the
positon shown in Figure 6c the conduits and paths between the bioreactor and the instrument, as
30 mentioned above, can be connected or disconnected more easily. The tray 40 and plate 42 can be
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removed completely as shown in Fig 6d, for example, for cleaning purposes. A cover plate 21
protects the motor and other electrical parts.
Figure 7 shows the rocking mechanism in more detail view from the front, door, side of the
5 instrument looking into the main chamber 35 with the cover plate 21 removed. A stepper motor 51
of the rocking mechanism 47 is shown as well as a reduction pinion gear pair 52 driven by the
stepper motor and driving the plate support 44 to rotate back and fmth. In this view a load sensor,
in the form of a load cell 41 is visible which in use is used to measure the quantity of fluid added
or removed from the bioreactor, and cell culture control.
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Figures 8 to 14 show details of a modified cell bag bioreactor tray 240 and its support 245 which
have similar functionality to the tray and support 40/45 described above and where like parts have
like reference numerals but in the latter embodiment the reference numerals are additionally
preceded by the number 2.
In the embodiment, shown in Figure 8, there are three main parts: the tray frame 240 which holds a
cell bag; a tray heating plate 242, which is in direct contact with a cell bag resting in the tray
frame; and the suppmt 245 in turn rigidly connected to a rocking and drive system 247 & 244, the
support 245 including electrical connections to power the heating plate 242. The suppott 245 has a
20 female vee slot 250 which cooperates with a complementary male vee slot 252 on the heating plate
242 to hold the two components 242 and 245 in removable sliding engagement, together providing
complementary formations which allow easier access to a cell bag mounted on the tray 245. A
spring biased pin 254 extends through both components and, together with the complementary vee
slots, holds these two components together. The pin 254 can be manually urged out of engagement
25 of with the heatetpl(lt~; 242 in the direction of arrow A to allow the heater plate to slide relative
the support 245 in the vee slot 250. In an alternative embodiment the pin 254 can be
electromechanically operable.
Figure 9 shows more details of the tray 240, and the heater plate 242, and more clearly shows two
30 additional sprung pins 264. Additionally, tray 240 includes at opposed ends cell bag securing
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cleats 268 which hold the crimped ends of a cell bag in place to stop it falling through the open
bottomed tray 240 when the tray 240 is removed from the heater plate 242 in use.
Figure I 0 shows an end view of the parts shown in of Figure 9, and Figure II shows the parts in
5 Figure 9 but in a partially dismantled condition. Tray 240 can be slid in the direction of arrow B
by manually pulling the pins 264 downwardly in the direction of arrows A. Where an automatic
configuration is envisaged the pins 264 may be electromechanically actuated. In this embodiment,
·the tray 240 includes two separable parts: an upper frame 271 and a lower frame 270- on which are
supported the pins 264. The lower frame supports the upper frame during disassembly and
10 reassembly.
Siding of the tray 240 (including the upper and lower fi·ames 270/271) on the heater plate 242 is
permitted by means of a tee formation 280 and a complementary tee slot 281, one mounted to the
heater plate 242 and one mounted to the lower frame 270, which together allow sliding in the
15 direction of arrow B and the opposing direction. Stops associated with the tee slots prevent
complete removal of the lower frame 270 from the heater plate 242, in use.
Figures 12 and 13a/b show fmther details oftray features. In Figure 12, the upper frame 271 is
shown removed completely from the lower frame 270. In Figure 13a and 13b a sectional view is
20 shown which illustrates the features which enable that complete removal. In particular, the upper
frame 271 has opposed pmtial grooves 283 which cooperate with opposed pattial tongues 284
fanned in the heater plate. Once the tray upper frame 240 has reached substantially its complete
sliding extremity, these tongues and grooves no longer cooperate, and allow the upper frame 271
to be lifted away from its suppmting lower frame 270. The position of the grooves 283 and
25 tongues. may b.e re¥er.s~d),84.
Figure 14 is a sectional view showing the various parts discussed above in more detail.
Reassembly of the upper frame to the lower frame, and the sliding of the resulting tray assembly,
30 is brought about by reversing the motions described above.
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In this way a rocking cell bag suppm1 is conceived which is easy to use, allowing convenient
insertion and removal of a cell bag, as well as being readily dismantleable for cleaning. For more
convenient use a frame position sensor is employed to check alignment of the upper frame 271
with the heater plate 242 in use.
Although embodiments have been described and illustrated, it will be apparent to the skilled
addressee that additions, omissions and modifications are possible to those embodiments without
departing from the scope of the invention claimed.
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CLAIMS
!. Biomanufacturing apparatus (I) comprising a housing (20) including top (22) and bottom
(24) faces which allow stacking of plural housings,, an access door (25) at a front side of the
housing, a substantially enclosed bioreactor chamber (30) inside the housing accessible via the,
5 door, and a further substantially enclosed region (36) inside the housing containing electrical parts
and/or electronic control components, the chamber (30) including: a tray ( 40/240) for supporting a
bioreactor, a tray support (45/245) including a mechanism (44,47/244,247) for rocking the tray in
use; the tray having complementary formations allowing movement of tray relative to the tray
support toward the front side to allow more convenient access to the bioreactor.
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2. Biomanufacturing apparatus as claimed in claim I, wherein the complementary formations
include a tee slot and a tee formation and/or said movement is sliding movement.
3. Biomanufacturing apparatus as claimed in claim I or 2, wherein the tray is separable from
15 the tray support once the tray support has been moved toward the front side.
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4. Biomanufacturing apparatus as claimed in claim I ,2 or 3, wherein the tray support includes
a heater plate mounted to a rocking mechanism (47/247), by means of complementary
demountable formations, for example a dovetail and dovetail slot (205,251)
5. Biomanufacturing apparatus as claimed in claim 4, wherein the heater plate forms the
underside of the tray such that a bioreactor is suppmted directly on its underside by the heater
plate in use.
25 6. Biomanufacturing apparatus as claimed in any· one of the preceding claims, wherein the
relative movement of said complementary formations and/or complementary demountable
formations is inhibited by at least one sprung locking pin.