BLOOD BAG SYSTEM AND PROCESS FOR THE INACTIVATION OF PATHOGENS IN PLATELET CONCENTRATES BY USE OF THE BLOOD BAG SYSTEM

Abstract

The present invention relates to a blood bag system, a method for its manufacture, and a process for reducing pathogens and leucocytes in biological fluids in particular in therapeutic quantities of platelet concentrates (PC) contained in the blood bag system, using UV-light and agitation, wherein part of the plasma of the PC is optionally exchanged against a platelet additive solution.

Claims

1-32. (canceled)

33. A process for manufacturing a sealed irradiation bag partially tilled with a platelet concentrate, the process comprising at least: providing a platelet concentrate from human blood donations by apheresis techniques or by buffy-coat pooling techniques; providing an irradiation bag made from a flexible plastic material substantially transparent to UV irradiation and comprising when viewed from inside at least three rounded corners and one or more inlet tubes and optionally one or more outlet tubes; introducing the platelet concentrate into the irradiation bag via the one or more inlet tubes in order to provide a partially filled irradiation bag so that the irradiation bag when sealed is filled by less than 20 vol % with the platelet concentrate; providing a sealing thereby providing a compartment containing the platelet concentrate to be treated and a compartment separated therefrom comprising the inner end(s) of the one or more inlet tubes, wherein the sealing provided comprises a rounded corner, when viewed from inside, that is symmetrical to at least one of the other rounded corners of the irradiation bag.

34. The process according to claim 33, wherein the one or more outlet tubes are provided with means for preventing the biological fluid contained in the irradiation bag and to be treated to enter into and/or to access the outlet tubes to avoid dead areas thrmed inside the irradiation bag in or around the outlet tubes.

35. The process according to claim 33, wherein the one or more outlet tubes comprise at least one clamp-off part, plug or break-off part as a closing for the tube end extending into the irradiation bag.

36. The process according to claim 33, wherein the irradiation bag when sealed is partially filled from less than 10 vol % to 1 vol %.

37. The process according to claim 33, wherein the separated compartment comprises one inlet tubes only.

38. The process according to claim 33, wherein the platelet concentrate contained in the irradiation bag does not contain a photosensitizer having an absorption maximum in the range of 200 to 350 nm.

39. The process according to claim 33, wherein the platelet concentrate is a suspended platelet concentrate comprising plasma wherein at least 20 weight % of the plasma contained in the platelet concentrate is exchanged against a platelet storage solution to form a suspended platelet concentrate and the platelet storage solution comprises water and soluble salts.

40. The process according to claim 39, wherein greater 50 weight % of the plasma is exchanged against a platelet storage solution.

41. The process according to claim 39, wherein the platelet storage solution contains at least one of the following salts: citrate, phosphate and/or acetate.

42. The process according to claim 33, wherein the platelet concentrate comprises 0.2 to 2.5×10.sup.9 platelets per ml biological fluid contained in the irradiation bag.

43. The process according to claim 33, further comprising that the platelet concentrate is irradiated in the irradiation bag with UV-C radiation and is filled thereafter into a storage bag for storage, wherein the irradiation bag is different from the storage hag, wherein the storage bag has half or less of the volume capacity of the irradiation bag and wherein a tubing for interconnecting the irradiation bag and the storage bag, optionally detachable, is provided thereby forming a blood bag system.

44. The process according to claim 43, wherein the storage bag has 20% or less of the volume capacity of the irradiation bag.

45. The process according to claim 43, wherein the irradiation bag and the storage bag consist of the same plastic material.

46. The process according to claim 43, wherein the irradiation hag and the storage bag consist of different plastic materials.

47. The process according to claim 33, wherein at least the irradiation bag consists of EVA.

48. The process according to claim 33, wherein the storage bag is permeable for at least one gas, selected from the group consisting of air, oxygen and carbon dioxide.

49. The process according to claim 33, wherein the irradiation bag is made from material that has no adsorption maximum in the range of 200 to 350 nm.

50. The process according to claim 33, wherein the irradiation bag has a flat inside, the inside having boundaries when viewed from the top form a circle or oval when filled with the biological fluid.

51. The process according to claim 33, further comprising a leucocyte filter optionally as part of the inlet tube for the irradiation bag.

52. The process according to claim 33, wherein the at least one inlet tube is located at one corner of the irradiation bag.

53. The process according to claim 33, further comprising the following steps: irradiating the irradiation bag comprising the platelet concentrate with an irradiation source comprising UV-C radiation of a wavelength of 200 to 270 nm while keeping the irradiation bag under agitation; and inserting the irradiated platelet concentrate into a storage bag for storage or remaining the irradiated platelet concentrate in the irradiation bag for storage in the irradiation bag.

54. A process according to claim 53, comprising the following further step: exchanging at least 20 weight % or at least 50 weight %, of the plasma contained in the platelet concentrate against a platelet storage solution to form a suspended platelet concentrate, the platelet storage solution comprises water and one or more soluble salts before exposing the platelet concentrate to UV irradiation.

55. The process according to claim 53, wherein the UV-irradiation is generated by a quartz lamp, a LED- and/or flashlight lamp.

56. The process according to claim 53, wherein the irradiation bag is placed upon a stiff sheet, optionally made from glass/quartz material, while irradiated and agitated.

57. The process according to claim 53, wherein the filled irradiation bag has an average thickness of less than 5 mm, or less than 2.5 mm, when irradiated.

58. The process according to claim 53, wherein the irradiation bag is agitated to homogeneously mix the fluid content and/or to obtain a fluid profile with wave like surface areas in the irradiation bag comprising a multiplicity of moving or standing troughs and crests, wherein the troughs at their lowest spot have average film thickness of less than 2.5 mm.

59. The process according to claim 53, wherein the light dose for irradiation of the irradiation bag is between 0.01 and 2 J/cm.sup.2.

60. The process according to claim 53, wherein the platelet concentrate/suspended platelet concentrate is stored at room temperature for at least 8 days.

61. The process according to claim 53, wherein the stored platelet concentrates/suspended platelet concentrates are stored at room temperature under slight agitation for at least 8 days.

62. The process according to claim 53, wherein the irradiation bag is agitated while irradiated by means of a steady agitation using an amplitude of from 0.2 to 8 cm in the x and the y direction of the plane, wherein x and y are the same, and a frequency.sup., of the amplitude from 10 to 200 Hz.

63. The process according to claim 53, wherein the platelet concentrate contained in the irradiation bag does not contain a photosensitizer having an absorption maximum in the range of in particular 200 to 350 nm and if free of any pathogen inactivating substance added to the biological fluid or any photosensitizer.

64. The process according to claim 63, wherein the irradiation bag is irradiated and agitated while stretched out flat and horizontal on a substantially plane sheet without any clamping of the upper layer of the irradiation bag thus allowing the upper layer to freely move in reaction to the agitation of the bag.

65. The process according to claim 33, wherein the at least one inlet tube is located at one corner of the irradiation bag, the opening of the inlet tube being partially enclosed by a partial seal that can be completed to create a sealed compartment comprising the opening of the inlet tube.

Description

DESCRIPTION OF THE FIGURES

[0040] The invention is illustrated by the figures without being limited to the embodiment depicted.

[0041] FIG. 1 shows a blood bag system according to the invention.

[0042] FIG. 2 shows a further embodiment of the blood bag system of FIG. 1 additionally comprising a leucocyte filter and a sampling bag.

[0043] FIG. 3 shows an embodiment, where details of the bag size and of the inlet and outlet tube of the irradiation bag are depicted.

[0044] FIG. 4 shows a different embodiment, wherein the irradiation bag and the storage bag form one bag.

[0045] FIG. 5 shows a different embodiment of the irradiation bag of the blood bag system,

[0046] The plastic double bag system shown in FIG. 1 comprises an inlet tube 1 connected to the irradiation bag 2 to sample the incoming stream of the processed PC co uprising platelet storage solution. The irradiation bag 2 is connected through a second tube 3 to a storage bag 4, used for storage and administering the blood product to a patient in need for platelets. After irradiation of the PC in the irradiation bag 2 and transfer of its content to the storage bag 4 through the tube 3, the tube 3 is sealed off and thus the irradiation bag 2 is separated from the storage bag 4. The storage bag 4 comprises a port 6 for spikes and optionally an additional third tube 7, which may be used for sampling, under which circumstances the third tube 7 may be connected to a sampling bag 10.

[0047] A further embodiment of the blood bag system is schematically depicted in FIG. 2. Beside the elements described in FIG. 1, the blood bag system further comprises a leucocyte filter 8 included in the inlet tube 1. This leucocyte filter may be bypassed by a bypass tube 5 further allowing air venting of the irradiation bag 2.

[0048] The sampling bag 10 allows the early and late detection of contaminants in PC, as explained in the above mentioned FR 200506296. Briefly, at the time of the filling of the storage bag 4, a sample of PC is transferred into the sample bag 10. Before the storage of the PC, a first contamination test is performed on a first part of the sampled PC, the first part being taken from the sample bag 10 via a first outlet 11.

[0049] If no contamination is detected, the PC is stored. Before the transfusion of the PC to a patient, a second contamination test is performed on a second part of the sampled PC taken from the sample bag 10 via a second outlet 11.

[0050] The bags in the blood bag system as shown in FIGS. 1 and 2 further have clamps or break-off parts 13 to close or otherwise allow free flow of the platelet concentrate through the tubing.

[0051] FIG. 3 depicts a variation of the irradiation bag 2 of FIG. 1. In this figure, the inlet tube 1 is moved to the one corner of the bag, which does not show any corner cut-off inside the bag. Once the PC has been filled into the bag, this part may be sealed off along the line 16, which can be placed using a suitable heat seal or high frequency sealing system to result in cut-off corner of the bag. The reason to have the corner of the irradiation bag rounded or cut-off, is not to have dead areas during the agitation and irradiation steps described above.

[0052] This preferred embodiment shows also a break-off part 15, which closes the tube 3 and which might be opened after irradiation, thus allowing free flow of the irradiated PC through the tube 3 into the storage bag. This break-off part is constructed and placed into the bag such, that no dead areas do exist, in which PC is trapped and not agitated during the irradiation process. This break-off part may be substituted by any system suitable for closing and opening of bags, like ball valves, plugs or other systems.

[0053] The embodiment shown in FIG. 3 shows a bag having a square format, where the length and the height of the bag are almost the same. The inside foinis an octagon. Bag 2 can also be constructed as a circular bag, containing in- and outlets.

[0054] Octagon type and circular top views of the inside boundaries have advantages on agitation by reducing possible dead ends even further, especially on circular or elliptic horizontal agitation. Therefore the bag (2) is suitable for illumination, storage and transfusion of PC.

[0055] For routine use tube 1 is sterilely docked to a PC source, obtainable from blood donations by apheresis or by a buffy-coat pool procedure. For connection purposes the inlet tube 1 may contain spike (14).

[0056] Bag 2+4 shown in FIG. 4 may be used as storage bag 2 and irradiation bag 4 at the same time. In addition to the features described for the embodiment of FIG. 3, additionally comprised is a closure 17 in form of a part which allows connection with spikes of transfusion sets.

[0057] Another example of the irradiation bag is illustrated in FIG. 5. The irradiation bag 2 is provided with an inlet tube 1 for filling the bag with PC/suspended PC and an outlet tube 3 for discharging the PC/suspended PC into a storage bag.

[0058] The irradiation bag 2 comprises a partial seal 17 extending from one edge of the bag to an adjacent edge thereof. When the seal is completed, for example by using a hand held sealer, the seal creates a first sealed compartment enclosing the opening of the inlet tube 1 and a second sealed compartment comprising the PC/suspended PC. This first sealed compartment prevents the PC contained in the second sealed compartment to enter the inlet tube 1. In that way, the bag does not contain any dead area, ensuring that all PC is agitated and irradiated during the inactivation process.

[0059] Moreover, as shown in FIGS. 3 to 5, the seal 16,17 enclosing the inlet tube 1 at one edge of the irradiation bag 2 is symmetrical to at least another edge, thereby providing a symmetrical irradiation bag. This particular shape improves the agitation of the content of the bag.

[0060] Advantageously, the irradiation bag also comprises an outlet tube provided with a plug 18, ensuring that no PC/suspended PC enters the outlet tube. For discharging the PC into the storage bag, the plug 18 is simply removed from the outlet tube 3 by pressing manually the outlet tribe to expel the plug 18 into the bag.

[0061] It is apparent to the skilled reader that the blood bag system and the method described herein and in particular with reference to FIG. 1 to FIG. 5 can as well be applied to reduce pathogens in other biological fluids such as platelet lysates, stem cell suspensions, tissue culturing media, plasma, plasma and proteins solutions. For such applications the reference to PC or suspended PC in this application may be exchanged against any one of above biological fluids. Furthermore the term “blood bag system” itself is not intended to limit the bag or the method disclosed herein to a use in connection with biological fluids that ale derived from blood only. Except that the suspended PC is exchanged against the other biological fluids all features described in more detail in the general part hereinbefore are applicable as well.

[0062] For example it should be noted that the procedure and bag system as described herein and in particular with reference to any of the claims can be used for pathogen reduction of plasma alone without the presence of PC. Therefore therapeutic quantities of human plasma and plasma protein solutions (such as from 100-350 ml, and up to 700 ml) can also be pathogen reduced using UV-light and the above mentioned procedure.

Experimental Part

[0063] A preferred bag system and procedure uses a first bag with the size of an irradiation surface of 19×38 cm, consisting of a flexible EVA-sheeting with 0.25 mm thickness, with min. UV-adsorption characteristics. The irradiation bag is filled with 300 ml of suspended PC with 4×10.sup.11 platelets, ieimkodepleted to less than 10.sup.6 residual leucocytes per PC, in plasma, where 70 weight % of the plasma has been replaced by SSP+ by MacoPharma as Storage Solution for PC. The SSP+ solution comprises (in g/l): [0064] Na-Citrate 2H.sub.2O: 3.1 8; Na-Acetate 3H.sub.2O: 4.42; Na-Phosphate 2H.sub.2O: 1.05; Di-Na-Phosphate: 3.05; KCl: 0.37; MgCl.sub.26H.sub.2O: 0.3; NaCl: 4.05 and Water to 1000 ml.

[0065] The PC in bag was irradiated horizontally for a period of 2 min. from both sides at the same time, using an UVC irradiation machine with quartz tubes, VIS-light filter, under orbital agitation of the bag at 100 Hz with amplitude of 2 cm in one axis and 4 cm in the other axis at room temperature. We found that orbital mixing is preferred over circular mixing. Under these conditions a homogeneous mixing of the PC is reached. At the same time the fluid shows a profile with high and very low liquid thickness in the flexible bag with a distribution of moving and standing waves in the bag.

[0066] After the irradiation step, the treated PC was transferred into the second bag, which consisted of a 1000 to 1500 ml bag of EVA (Alternatively PVC/TOTM sheering may be used), allowing sufficient gas exchange for CO.sub.2 and O.sub.2 during up to 10 days storage, under slight horizontal agitation at room temperature.

[0067] In the practical example an irradiation and a storage bag made from EVA was used and the irradiation bag was irradiated with UV-C radiation at a rate of 0.6 J/cm.sup.2 under constant agitation.

[0068] The results of the procedure applied to PC in the blood bag system according to the invention are summarized in Table, 1. These results demonstrate that the PC quality does not change significantly by the treatment or after storage for several days.

[0069] This inactivation method does not require the addition of an inactivating substance, such as photosensitive or photodynamic active substance, in the biological fluid to be treated. No further step, e.g. removal of the inactivating substance, is necessary. It is acknowledged that UVC directly activates nucleotides of viruses and bacteria, without the need of exogenous substances.

TABLE-US-00001 TABLE 1 Platelet parameters during storage with and without treatment at 100 Hz, under orbital agitation and UVC-irradiation in SSP+ platelet storage solution Day 6* Day 8* Before (treatment) (treatment) treatment Without with without With Platelets 11.2 9.98 10.4 10.8 10.5 (10.sup.8/ml) pH 7.03 7.14 7.13 7.19 7.10 HSR (%) 54 58 62 61 61 Swirling 5 5 5 5 5 (grade) Aggreg. (%) 87 87 86 82 86 USR: Hypotonic Shock Reaction Swirling: Visual inspection, 0 no swirling, 5 max. swirling Aggregation: Aggregation of platelets, collagen-induced *storage at room teinperature