EA045773B1 - APPLICATION OF PATHOGENE-INACTIVATED CRYOPRECIPITATE COMPOSITION FOR INFUSION TO A PATIENT - Google Patents

Description

Technical field

The methods described herein generally relate to the production of cryoprecipitate from plasma. More specifically, the present invention relates to improved cryoprecipitate compositions, as well as production methods and kits associated therewith, that can be used for infusion into a patient.

Prerequisites

Blood collection and processing play an important role in healthcare around the world, and blood banks collect millions of units of whole blood donations every year. Although some units of whole blood collected from donors are stored and used for transfusion, the bulk of whole blood is instead separated into its clinically relevant therapeutic components of red blood cells, platelets and plasma, for individual storage and use in the treatment of various medical needs and conditions. which require one or more specific blood components.

Cryoprecipitate (also known as cryo) is a blood product containing a portion of plasma rich in clotting factors. Cryoprecipitate, also referred to as cryoprecipitated antihemophilic factor (AHF), cryoprecipitated AHF, is prepared by slow, controlled thawing of frozen plasma (e.g., fresh frozen whole blood plasma, or FFP), e.g., 1 to 6°C (e.g., 4 ±2°C), which leads to the formation of a white precipitate, and subsequent separation of the precipitate after separation from the liquid portion of the plasma, also referred to herein as the supernatant, for example, by refrigerated centrifugation. The cryosuppernatant residual plasma, also referred to herein as cryosuppernatant plasma (CPP), cryoprecipitate-depleted plasma, or cryosupernatant, is removed from the bag and the separated cold-insoluble precipitate is resuspended in the retained portion of the plasma and is typically refrozen within 1 hour and kept frozen until until transfusion is required.

Cryoprecipitate serves as a source of fibrinogen, factor VIII, factor XIII, vWF and fibronectin. This component is used to control bleeding associated with fibrinogen deficiency and to treat factor XIII deficiency when volume considerations prevent the use of frozen plasma and recombinant proteins are not available. It is also indicated as second-line therapy for von Willebrand disease and hemophilia A (factor VIII deficiency). Coagulation factor agents other than cryoprecipitate are generally preferred when blood component therapy is needed to control von Willebrand disease and factor VIII deficiency. Although many uses of cryoprecipitate products have been replaced by factor concentrates or recombinant factors, many hospital blood banks still routinely stock cryo for use in fibrinogen replacement in patients, such as those with acquired hypofibrinogenemia and bleeding disorders (eg, massive hemorrhage). For cryoprecipitate, blood group compatibility testing is not strictly necessary; however, transfusion of ABO-compatible cryo is generally preferred whenever possible.

Cryoprecipitate is often infused into individual unit depots (eg, 4-6 unit depot, 5-6 unit depot) rather than as a single product, with the goal of increasing the recipient's (eg, adult recipient's) fibrinogen level, e.g., by 30- 60 mg/dl. Formation of the depot is usually carried out after thawing of individual units, before transfusion. If the label states Cryoprecipitated AHF Depot, multiple units of cryoprecipitated AHF are combined into a depot. The depot volume is usually listed on the label and, if used, the volume of 0.9% sodium chloride injection (USP) may be listed separately.

As a measure of activity and/or quality for use in transfusion, units of cryoprecipitated AHF must contain specified amounts of factor VIII and fibrinogen, and typically contain approximately 5 to 20 ml of plasma. Current US standards require manufacturers to test at least four units of Cryo each month, and the products must have an average of 150 mg or more fibrinogen and 80 IU of factor VIII. Some individual products may actually have less than these amounts as long as the average remains above these minimums. Typical values for a unit are essentially higher and, with the exception of infants, only one unit is rarely transfused.

Although factor VIII measurement is now necessary for quality control, cryo is primarily used to maintain fibrinogen levels for proper hemostasis, such as in the treatment of disseminated intravascular coagulation (DIC) or large-volume hemorrhage. The use of cryoprecipitate is generally limited by the requirement that it be transfused within 6 hours of thawing or 4 hours of depot formation, a time limitation due to many considerations including, for example, a more rapid decline in factor VIII activity and the possibility of growth of pathogenic contaminants. , if present. For example, factor VIII is known to have a half-life of approximately 12 hours; in comparison, fibrinogen has a half-life of approximately 100-150 hours. Discarding unused cryoprecipitate that has elapsed 4 or 6 hours after thawing results in wasted product and increased cost. Additionally, for indications requiring rapid delivery of cryoprecipitate to the patient (eg, massive hemorrhage), the time required for thawing and formation of the cryoprecipitate depot may also be another limitation.

There remains a need for improved methods of producing cryoprecipitate and improved cryoprecipitate compositions for transfusion and other uses, including, for example, cryoprecipitate compositions with extended shelf life after thawing and/or sufficient fibrinogen content so that depot formation is not required between thawing of the cryoprecipitate and administration to the patient. Such improved compositions and methods may provide greater efficiencies in the preparation and/or use of cryoprecipitate, such as, for example, increased number of product units, less waste, more efficient processes for providing required quantities of cryoprecipitate to the clinician for use in transfusion, more time between thawing and introduction, improved product availability and/or uniformity and/or access to a larger available donor population.

The essence of the invention

The compositions, methods and kits described herein can be used to produce a cryoprecipitate with desired characteristics, including, for example, a pathogen-inactivated cryoprecipitate and a cryoprecipitate suitable for use over a longer period after thawing.

In one aspect, the present disclosure relates to a composition that contains cryoprecipitate suitable for infusion into a patient at least 1 day after thawing, wherein the cryoprecipitate is pathogen-inactivated. In some embodiments, the composition is suitable for infusion into a patient at least 3 days after thawing. In some embodiments, the composition is suitable for infusion into a patient at least 5 days after thawing. In some embodiments, the composition is suitable for infusion into a patient at least 7 days after thawing. In some embodiments, the composition contains less than 80 IU of factor VIII per unit of cryoprecipitate. In some embodiments, the composition contains less than 50 IU of factor VIII per unit of cryoprecipitate. In some embodiments, the composition contains at least 150 mg of fibrinogen per unit of cryoprecipitate. In some embodiments, the composition further comprises plasma in a volume between about 15 ml and about 20 ml. In some embodiments, the composition contains cryoprecipitate obtained from approximately 600 ml of pathogen-inactivated plasma. In some embodiments, the composition contains cryoprecipitate obtained from approximately 600 ml of plasma, and the resulting cryoprecipitate is made pathogen inactivated. In some embodiments, the composition comprises a first cryoprecipitate prepared from approximately 600 ml of pathogen-inactivated plasma and a second cryoprecipitate prepared from approximately 600 ml of pathogen-inactivated plasma, wherein the first and second cryoprecipitates are combined before being refrozen for storage. In some embodiments, the composition comprises a first cryoprecipitate prepared from about 600 mL of plasma and a second cryoprecipitate prepared from approximately 600 mL of plasma, wherein the first and second cryoprecipitates are combined before being refrozen for storage, and wherein the first and second cryoprecipitates are made pathogen-inactivated after the combination. and before re-freezing for storage. In some embodiments, the composition comprises a first cryoprecipitate prepared from about 600 mL of plasma and a second cryoprecipitate prepared from approximately 600 mL of plasma, wherein the first and second cryoprecipitates are combined before being refrozen for storage, and wherein the first and second cryoprecipitates are made pathogen-inactivated before combining and before re-freezing for storage. In some embodiments, the composition contains cryoprecipitate prepared from at least about 600 ml and less than 650 ml of pathogen-inactivated plasma. In some embodiments, the composition contains cryoprecipitate obtained from at least about 600 ml and less than 650 ml of plasma, and the resulting cryoprecipitate is made pathogen-inactivated. In some embodiments, the composition comprises a first cryoprecipitate prepared from at least about 600 ml and less than 650 ml pathogen-inactivated plasma, and a second cryoprecipitate prepared from at least about 600 ml and less than 650 ml pathogen-inactivated plasma, wherein the first and second cryoprecipitates are combined before being re-frozen for storage. In some embodiments, the composition comprises a first cryoprecipitate obtained from at least about 600 ml and less than 650 ml of plasma, and a second cryoprecipitate obtained from at least about 600 ml and less than 650 ml of plasma, wherein the first and second cryoprecipitates are combined before re-frozen for storage and where the first and second cryoprecipi

- 2 045773 tats are made pathogen-inactivated after combining and before re-frozen for storage. In some embodiments, the composition comprises a first cryoprecipitate obtained from at least about 600 ml and less than 650 ml of plasma and a second cryoprecipitate obtained from at least about 600 ml and less than 650 ml of plasma, wherein the first and second cryoprecipitates are combined before being repeated. frozen for storage and where the first and second cryoprecipitates are made pathogen-inactivated before combining and before re-frozen for storage. In some embodiments, the composition further comprises plasma in a volume between about 40 ml and about 75 ml. In some embodiments, the composition further comprises plasma in a volume between about 50 ml and about 60 ml. In some embodiments, the composition is stored at room temperature for at least 1 day after thawing. In some embodiments, the cryoprecipitate is made pathogen-inactivated by photochemical inactivation. In some embodiments, the cryoprecipitate is made pathogen-inactivated by photoinactivation using psoralen. In some embodiments, psoralen is amotosalen.

In another aspect, the present disclosure relates to a method of obtaining cryoprecipitate for infusion into a patient, comprising a) obtaining cryoprecipitate from pathogen-inactivated plasma; b) freezing cryoprecipitate; and c) thawing the frozen cryoprecipitate, wherein the resulting cryoprecipitate from step c) is suitable for infusion into a patient at least 1 day after thawing. In some embodiments, the resulting cryoprecipitate from step c) is suitable for infusion into a patient at least 5 days after thawing. In some embodiments, the method further includes testing the thawed cryoprecipitate for fibrinogen. In some embodiments, the method does not include testing the thawed cryoprecipitate for factor VIII. In some embodiments, the cryoprecipitate is prepared from approximately 600 ml of pathogen-activated plasma. In some embodiments, the method further includes combining a first cryoprecipitate obtained from approximately 600 ml of pathogen-inactivated plasma and a second cryoprecipitate obtained from approximately 600 ml of pathogen-inactivated plasma, wherein the first and second cryoprecipitates are combined prior to steps b) and c). In some embodiments, the cryoprecipitate is prepared from at least about 600 ml and less than 650 ml of pathogen-inactivated plasma. In some embodiments, the method further includes combining a first cryoprecipitate prepared from at least about 600 ml and less than 650 ml of pathogen-inactivated plasma and a second cryoprecipitate obtained from at least about 600 ml and less than 650 ml of pathogen-inactivated plasma wherein the first and second cryoprecipitates are combined before steps b) and c). In some embodiments, the resulting cryoprecipitate from step c) is suitable for infusion into a patient at least 3 days after thawing. In some embodiments, the resulting cryoprecipitate from step c) is suitable for infusion into a patient at least 5 days after thawing. In some embodiments, the resulting cryoprecipitate from step c) is suitable for infusion into a patient at least 7 days after thawing.

In yet another aspect, the present disclosure relates to a method of infusing cryoprecipitate into a patient, which comprises a) obtaining cryoprecipitate from pathogen-inactivated plasma; b) freezing cryoprecipitate; c) thawing frozen cryoprecipitate; and d) infusing the thawed cryoprecipitate into the patient, wherein the infusion occurs at least 1 day after thawing the frozen cryoprecipitate. In some embodiments, the method further includes testing the thawed cryoprecipitate for fibrinogen. In some embodiments, the method does not include testing the thawed cryoprecipitate for factor VIII prior to transfusion of the thawed cryoprecipitate. In some embodiments, the cryoprecipitate is prepared from approximately 600 ml of pathogen-inactivated plasma. In some embodiments, the method further includes combining a first cryoprecipitate obtained from approximately 600 ml of pathogen-inactivated plasma and a second cryoprecipitate obtained from approximately 600 ml of pathogen-inactivated plasma, wherein the first and second cryoprecipitates are combined prior to step b). In some embodiments, the cryoprecipitate is prepared from at least about 600 ml and less than 650 ml of pathogen-inactivated plasma. In some embodiments, the method further includes combining a first cryoprecipitate obtained from at least about 600 ml and less than 650 ml of pathogen-inactivated plasma, and a second cryoprecipitate obtained from at least about 600 ml and less than 650 ml of pathogen-inactivated plasma, wherein the first and the second cryoprecipitates are combined before step b).

In some embodiments, according to any of the above embodiments, the resulting cryoprecipitate from step c) contains less than 80 IU of factor VIII per unit of cryoprecipitate. In some embodiments, the resulting cryoprecipitate from step c) contains less than 50 IU of factor VIII per unit of cryoprecipitate. In some embodiments, according to any of the above embodiments, the resulting cryoprecipitate from step c) contains

- 3 045773 lives at least 150 mg of fibrinogen per unit of cryoprecipitate. In some embodiments, the cryoprecipitate from step a) further contains plasma in a volume between about 15 ml and about 20 ml. In some embodiments, the cryoprecipitate from step a) further contains plasma in a volume between about 40 ml and about 75 ml. In some embodiments, the cryoprecipitate from step a) further contains plasma in a volume between about 50 ml and about 60 ml. In some embodiments of any of the above embodiments, the plasma is made pathogen-inactivated by photochemical inactivation. In some embodiments, the cryoprecipitate is made pathogen-inactivated by photoinactivation using psoralen. In some embodiments, psoralen is amotosalen. In some embodiments of any of the above embodiments, the patient is a human.

In yet another aspect, the present disclosure provides a kit that includes a) a container; b) pathogen-inactivated cryoprecipitate; and c) instructions for use of the pathogen-inactivated cryoprecipitate for infusion into a patient, wherein the instructions indicate that the cryoprecipitate is suitable for infusion into a patient for up to approximately 7 days after thawing. In some embodiments, the instructions indicate that the cryoprecipitate is suitable for infusion into a patient for up to about 5 days after thawing. In some embodiments, the instructions indicate that the cryoprecipitate is suitable for infusion into a patient for up to about 3 days after thawing.

In yet another aspect, the present disclosure relates to a method of infusing cryoprecipitate into a patient, which includes infusing a composition of any of the above embodiments into the patient.

In yet another aspect, the present disclosure relates to a method of infusing cryoprecipitate into a patient, which includes infusing cryoprecipitate obtained by the method of any of the above embodiments into the patient.

In yet another aspect, the present disclosure relates to cryoprecipitate obtained by the method of any of the above embodiments.

In yet another aspect, the present disclosure relates to a composition that contains cryoprecipitate suitable for infusion into a patient at least 1 day after thawing, wherein the cryoprecipitate is pathogen-inactivated. In some embodiments, the composition is suitable for infusion into a patient at least 3 days after thawing. In some embodiments, the composition is suitable for infusion into a patient at least 5 days after thawing. In some embodiments, the composition contains cryoprecipitate prepared from at least about 550 ml and about less than 650 ml of pathogen-inactivated plasma. In some embodiments, the composition contains cryoprecipitate obtained from at least about 550 ml and less than about 650 ml of plasma, and the resulting cryoprecipitate is made pathogen-inactivated. In some embodiments, the composition contains cryoprecipitate obtained from approximately 600 ml of pathogen-inactivated plasma. In some embodiments, the composition contains cryoprecipitate obtained from approximately 600 ml of plasma, and the resulting cryoprecipitate is made pathogen inactivated. In some embodiments, the composition contains cryoprecipitate obtained from 3 units of pathogen-inactivated plasma. In some embodiments, the composition contains cryoprecipitate obtained from 3 units of plasma, and the resulting cryoprecipitate is made pathogen-inactivated. In some embodiments, the composition comprises a first cryoprecipitate prepared from at least about 550 ml and less than 650 ml pathogen-inactivated plasma, and a second cryoprecipitate prepared from at least about 550 ml and less than 650 ml pathogen-inactivated plasma, wherein the first and second cryoprecipitates are combined before being re-frozen for storage. In some embodiments, the composition comprises a first cryoprecipitate prepared from at least about 550 ml and less than 650 ml plasma, and a second cryoprecipitate prepared from at least about 550 ml and less than 650 ml plasma, wherein the first and second cryoprecipitates are combined before re-frozen for storage and wherein the first and second cryoprecipitates are made pathogen-inactivated after combining and before re-frozen for storage. In some embodiments, the composition comprises a first cryoprecipitate prepared from at least about 550 ml and less than 650 ml plasma, and a second cryoprecipitate prepared from at least about 550 ml and less than 650 ml plasma, wherein the first and second cryoprecipitates are combined before refrozen for storage and wherein the first and second cryoprecipitates are made pathogen-inactivated before combining and before refrozen for storage. In some embodiments, the composition comprises a first cryoprecipitate prepared from approximately 600 ml of pathogen-inactivated plasma and a second cryoprecipitate prepared from approximately 600 ml of pathogen-inactivated plasma, wherein the first and second cryoprecipitates are combined before being refrozen for storage. In some embodiments

- 4 045773 the composition contains a first cryoprecipitate obtained from approximately 600 ml of plasma, and a second cryoprecipitate obtained from approximately 600 ml of plasma, where the first and second cryoprecipitates are combined before being re-frozen for storage and where the first and second cryoprecipitates are made pathogen-inactivated before combining and before re-freezing for storage. In some embodiments, the composition comprises a first cryoprecipitate prepared from about 600 mL of plasma and a second cryoprecipitate prepared from approximately 600 mL of plasma, wherein the first and second cryoprecipitates are combined before being refrozen for storage, and wherein the first and second cryoprecipitates are made pathogen-inactivated after the combination. and before re-freezing for storage. In some embodiments, the composition comprises a first cryoprecipitate prepared from 3 units of pathogen-inactivated plasma and a second cryoprecipitate prepared from 3 units of pathogen-inactivated plasma, wherein the first and second cryoprecipitates are combined before being refrozen for storage. In some embodiments, the composition comprises a first cryoprecipitate prepared from 3 units of plasma and a second cryoprecipitate prepared from 3 units of plasma, wherein the first and second cryoprecipitates are combined before refreezing for storage and where the first and second cryoprecipitates are made pathogen inactivated after combination and before refreezing for storage. In some embodiments, the composition comprises a first cryoprecipitate prepared from 3 units of plasma and a second cryoprecipitate prepared from 3 units of plasma, wherein the first and second cryoprecipitates are combined before being re-frozen for storage, and wherein the first and second cryoprecipitates are made pathogen-inactivated before combining and before re-frozen for storage. In some embodiments, the composition contains cryoprecipitate obtained from 6 units of pathogen-inactivated plasma. In some embodiments, the composition contains cryoprecipitate obtained from 6 units of plasma, and the resulting cryoprecipitate is made pathogen inactivated. In some embodiments, the composition contains cryoprecipitate derived from plasma obtained from a single donor. In some embodiments, the composition contains cryoprecipitate obtained from plasma obtained from 2-6 donors. In some embodiments, the composition contains less than 80 IU of factor VIII per unit of cryoprecipitate. In some embodiments, the composition contains less than 50 IU of factor VIII per unit of cryoprecipitate. In some embodiments, the composition contains 80-100 IU of factor VIII per unit of cryoprecipitate. In some embodiments, the composition contains at least 80 IU of factor VIII. In some embodiments, the composition contains 80-240 IU of factor VIII. In some embodiments, the composition contains 80-480 IU of factor VIII. In some embodiments, the amount of Factor VIII is determined from cryoprecipitate sampled within approximately 2 hours of thawing. In some embodiments, the amount of factor VIII is determined from a cryoprecipitate sample taken approximately 1 day after thawing. In some embodiments, the amount of factor VIII is determined from a cryoprecipitate sample taken approximately 3 days after thawing. In some embodiments, the amount of factor VIII is determined from a cryoprecipitate sample taken approximately 5 days after thawing. In some embodiments, the composition contains at least 150 mg of fibrinogen per unit of cryoprecipitate. In some embodiments, the composition contains at least 250 mg of fibrinogen per unit of cryoprecipitate. In some embodiments, the composition contains at least 750 mg of fibrinogen. In some embodiments, the composition contains at least 1500 mg of fibrinogen. In some embodiments, each unit of cryoprecipitate is prepared from 180-250 ml of pathogen-inactivated plasma. In some embodiments, the composition further comprises plasma in a volume of between about 5 ml and about 20 ml per unit of cryoprecipitate. In some embodiments, the composition further comprises plasma in a volume greater than about 1 ml and less than or equal to about 75 ml. In some embodiments, the composition further comprises plasma in a volume between about 50 ml and about 60 ml. In some embodiments, the composition further comprises plasma in a volume between about 30 ml and about 120 ml. In some embodiments, the composition is stored at room temperature for at least 1 day after thawing. In some embodiments, the composition is stored between about 2°C and about 6°C for at least 1 day after thawing. In some embodiments, the cryoprecipitate is made pathogen-inactivated by photochemical inactivation. In some embodiments, the cryoprecipitate is made pathogen-inactivated by photochemical inactivation using psoralen. In some embodiments, psoralen is amotosalen. In some embodiments, the cryoprecipitate is obtained from plasma that has been made pathogen-inactivated in a first container suitable for photochemical inactivation of the plasma under sterile conditions; wherein the first container is interfaced with a compound absorption device (CAD) such that pathogen-inactivated plasma can be transferred from the first

- 5 045773 containers in CAD in sterile conditions; and wherein the cryoprecipitate is contained in one or more second containers, each of which is mated to the CAD such that the pathogen-inactivated plasma can be transferred from the CAD to the one or more second containers under sterile conditions, and each of which is suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow the formation of cryoprecipitate. In some embodiments, each of the one or more second containers is suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow the formation of cryoprecipitate and cryosupernatant, followed by removal of all or a portion of the cryosupernatant from the one or more second containers. In some embodiments, the cryoprecipitate is obtained from plasma that is made pathogen-inactivated in a first container suitable for photochemical inactivation of the plasma under sterile conditions; wherein the first container is interfaced with a compound absorption device (CAD) such that pathogen-inactivated plasma can be transferred from the first container to the CAD under sterile conditions; wherein the CAD is mated to one or more second containers, each of which is mated to the CAD so that the pathogen-inactivated plasma can be transferred from the CAD to the one or more second containers under sterile conditions; and wherein the cryoprecipitate is contained in a third container configured to interface with the one or more second containers such that the pathogen-inactivated plasma can be transferred from the CAD in the one or more second containers to the third container under sterile conditions, where the third container is suitable for freezing the pathogen inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow the formation of cryoprecipitate. In some embodiments, the third container is suitable for freezing the pathogen-inactivated plasma, followed by thawing the pathogen-inactivated plasma under conditions that allow the formation of cryoprecipitate and cryosupernatant, followed by removal of all or part of the cryosupernatant from the third container. In some embodiments, the composition is contained in a container that further includes a label indicating that the composition is suitable for use for at least about 1 day after thawing. In some embodiments, the composition is contained in a container that further includes a label indicating that the composition is suitable for use for at least about 3 days after thawing. In some embodiments, the composition is contained in a container that further includes a label indicating that the composition is suitable for use for at least about 5 days after thawing. In some embodiments, the cryoprecipitate is derived from plasma other than group O plasma.

In yet another aspect, the present disclosure relates to a method of obtaining cryoprecipitate for infusion into a patient, which includes a) obtaining cryoprecipitate from pathogen-inactivated plasma; b) freezing cryoprecipitate; and c) thawing the frozen cryoprecipitate, wherein the resulting cryoprecipitate from step c) is suitable for infusion into a patient at least 1 day after thawing. In some embodiments, the thawed cryoprecipitate contains at least about 150 mg of fibrinogen per unit of cryoprecipitate. In some embodiments, the thawed cryoprecipitate contains at least about 750 mg of fibrinogen. In some embodiments, the method does not include determining factor VIII levels prior to infusion of thawed cryoprecipitate. In some embodiments, the method further includes determining the level of factor VIII in the thawed cryoprecipitate. In some embodiments, the cryoprecipitate is prepared from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma. In some embodiments, the cryoprecipitate is prepared from approximately 600 ml of pathogen-inactivated plasma. In some embodiments, the method further includes combining a first cryoprecipitate obtained from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma and a second cryoprecipitate obtained from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma wherein the first and second cryoprecipitates are combined before steps b) and c). In some embodiments, the method further includes combining a first cryoprecipitate obtained from approximately 600 ml of pathogen-inactivated plasma and a second cryoprecipitate obtained from approximately 600 ml of pathogen-inactivated plasma, wherein the first and second cryoprecipitates are combined prior to steps b) and c). In some embodiments, the method further includes combining a first cryoprecipitate prepared from 3 units of pathogen-inactivated plasma and a second cryoprecipitate prepared from 3 units of pathogen-inactivated plasma, wherein the first and second cryoprecipitates are combined prior to steps b) and c). In some embodiments, the resulting cryoprecipitate from step c) is suitable for infusion into a patient at least 3 days after thawing. In some embodiments, the resulting cryoprecipitate from step c) is suitable for infusion into a patient at least 5 days after thawing. In another aspect, provided herein is a method of infusing cryoprecipitate into a patient, which comprises: a) obtaining

- 6 045773 cryoprecipitate from pathogen-inactivated plasma; b) freezing cryoprecipitate; c) thawing frozen cryoprecipitate; and d) infusing the thawed cryoprecipitate into the patient, wherein the infusion occurs at least 1 day after thawing the frozen cryoprecipitate. In some embodiments, the thawed cryoprecipitate contains at least about 150 mg of fibrinogen per unit of cryoprecipitate. In some embodiments, the thawed cryoprecipitate contains at least about 750 mg of fibrinogen. In some embodiments, the method does not include determining factor VIII levels prior to infusion of thawed cryoprecipitate. In some embodiments, the method further includes determining the level of factor VIII in the thawed cryoprecipitate prior to infusion of the thawed cryoprecipitate. In some embodiments, the cryoprecipitate is prepared from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma. In some embodiments, the cryoprecipitate is prepared from approximately 600 ml of pathogen-inactivated plasma. In some embodiments, the method further includes combining a first cryoprecipitate obtained from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma and a second cryoprecipitate obtained from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma. inactivated plasma, where the first and second cryoprecipitates are combined before steps b) and c). In some embodiments, the method further includes combining a first cryoprecipitate obtained from approximately 600 ml of pathogen-inactivated plasma and a second cryoprecipitate obtained from approximately 600 ml of pathogen-inactivated plasma, wherein the first and second cryoprecipitates are combined prior to steps b) and c). In some embodiments, the method further includes combining a first cryoprecipitate prepared from 3 units of pathogen-inactivated plasma and a second cryoprecipitate prepared from 3 units of pathogen-inactivated plasma, wherein the first and second cryoprecipitates are combined prior to steps b) and c). In some embodiments, the resulting cryoprecipitate from step c) contains less than 80 IU of factor VIII per unit of cryoprecipitate. In some embodiments, the resulting cryoprecipitate from step c) contains at least about 80 IU of factor VIII. In some embodiments, the resulting cryoprecipitate from step c) contains 80-240 IU of factor VIII. In some embodiments, the resulting cryoprecipitate from step c) contains 80-480 IU of factor VIII. In some embodiments, the resulting cryoprecipitate from step c) contains less than 50 IU of factor VIII per unit of cryoprecipitate. In some embodiments, according to any of the above embodiments, the resulting cryoprecipitate from step c) contains at least 150 mg of fibrinogen per unit of cryoprecipitate. In some embodiments of any of the above embodiments, the resulting cryoprecipitate from step c) contains at least 750 mg of fibrinogen. In some embodiments of any of the above embodiments, the cryoprecipitate from step a) further contains plasma in a volume of between about 5 ml and about 20 ml per unit of cryoprecipitate. In some embodiments, the cryoprecipitate from step a) further contains plasma in a volume of greater than about 1 ml and less than or equal to about 75 ml. In some embodiments, the cryoprecipitate from step a) further contains plasma in a volume between about 50 ml and about 60 ml. In some embodiments, the cryoprecipitate from step a) further contains plasma in a volume between about 30 ml and about 120 ml. In some embodiments of any of the above embodiments, the plasma is made pathogen inactivated by photochemical inactivation. In some embodiments, the cryoprecipitate is made pathogen-inactivated by photochemical inactivation using psoralen. In some embodiments, psoralen is amotosalen. In some embodiments, according to any of the above embodiments, the cryoprecipitate is obtained from plasma that is made pathogen-inactivated in a first container suitable for photochemical inactivation of plasma under sterile conditions; wherein the first container is interfaced with a compound absorption device (CAD) such that pathogen-inactivated plasma can be transferred from the first container to the CAD under sterile conditions; and wherein the cryoprecipitate is frozen and thawed in steps b) and c) in one or more second containers, each of which is interfaced with a CAD such that pathogen-inactivated plasma can be transferred from the CAD to the one or more second containers under sterile conditions, and each of which is suitable for freezing pathogen-inactivated plasma, followed by thawing of pathogen-inactivated plasma under conditions that ensure the formation of cryoprecipitate. In some embodiments, each of the one or more second containers is suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow the formation of cryoprecipitate and cryosupernatant, followed by removal of all or a portion of the cryosupernatant from the one or more second containers. In some embodiments, the cryoprecipitate is obtained from plasma that has been made pathogen inactivated in a first container suitable for photochemical inactivation of the plasma in a

- 7 045773 real conditions; wherein the first container is interfaced with a compound absorption device (CAD) such that pathogen-inactivated plasma can be transferred from the first container to the CAD under sterile conditions; and wherein the cryoprecipitate is frozen and thawed in steps b) and c) in a third container configured to interface with the one or more second containers such that the pathogen-inactivated plasma can be transferred from the CAD in the one or more second containers to the third container under sterile conditions wherein the third container is suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow the formation of cryoprecipitate. In some embodiments, the third container is suitable for freezing the pathogen-inactivated plasma, followed by thawing the pathogen-inactivated plasma under conditions that allow the formation of cryoprecipitate and cryosupernatant, followed by removal of all or part of the cryosupernatant from the third container. In some embodiments of any of the above embodiments, the patient is a human.

In yet another aspect, the present disclosure relates to a kit that includes a) a container; b) pathogen-inactivated cryoprecipitate; and c) instructions for use of the pathogen-inactivated cryoprecipitate for infusion into a patient, wherein the instructions indicate that the cryoprecipitate is suitable for infusion into a patient for up to approximately 5 days after thawing.

In yet another aspect, the present disclosure relates to a kit that includes a) a container; b) pathogen-inactivated cryoprecipitate; and c) a label indicating that the pathogen-inactivated cryoprecipitate is suitable for use for up to approximately 5 days after thawing.

In yet another aspect, the present disclosure relates to a method of infusing cryoprecipitate into a patient, which includes infusing a composition of any of the above embodiments into the patient.

In yet another aspect, the present disclosure relates to a method of infusing cryoprecipitate into a patient, which includes infusing the patient with cryoprecipitate obtained using any of the above embodiments.

In yet another aspect, the present disclosure relates to cryoprecipitate obtained using any of the above embodiments.

In yet another aspect, the present disclosure relates to a method of preparing a cryosupernatant depot for infusion into a patient, which includes a) freezing at least a first pathogen-inactivated plasma and a second pathogen-inactivated plasma, wherein each of the first and second pathogen-inactivated plasma has a volume of at least about 550 ml and about less than 650 ml; b) thawing the first pathogen-inactivated plasma under conditions that ensure the formation of a first precipitate and a first supernatant, and thawing the second pathogen-inactivated plasma under conditions that ensure the formation of a second precipitate and a second supernatant; c) separating the first and second supernatants from the first and second precipitates to form a first cryosupernatant and a second cryosupernatant; and d) combining the first and second cryosupernatants to form a cryosupernatant depot. In some embodiments, the first and second pathogen-inactivated plasma each have a volume of approximately 600 mL. In some embodiments, step a) further includes freezing at least a third pathogen-inactivated plasma and a fourth pathogen-inactivated plasma, wherein each of the third and fourth pathogen-inactivated plasma has a volume of at least about 550 ml and less than 650 ml; step b) further includes thawing the third pathogen-inactivated plasma under conditions that provide the formation of a third precipitate and a third supernatant, and thawing the fourth pathogen-inactivated plasma under conditions that provide the formation of a fourth precipitate and a fourth supernatant; step c) further includes separating the third and fourth supernatants from the third and fourth precipitates in order to form a third cryosupernatant and a fourth cryosupernatant; the cryosupernatant depot formed in step d) is a first supernatant depot, and step d) further includes combining the third and fourth cryosupernatants to form a second cryosupernatant depot; and the method further comprises e) combining the first cryosupernatant depot and the second cryosupernatant depot. In some embodiments, each of the third and fourth pathogen-inactivated plasma has a volume of approximately 600 ml. In some embodiments, the first and/or second pathogen-inactivated plasma is made pathogen-inactivated by photochemical inactivation. In some embodiments, one or more of the first, second, third and fourth pathogen-inactivated plasmas are made pathogen-inactivated using psoralen. In some embodiments, psoralen is amotosalen. In some embodiments, one or more of the first, second, third and fourth pathogen-inactivated plasmas are made pathogen-inactivated in a first container suitable for photochemical inactivation of the plasma under sterile conditions, where the first container is interfaced with a compound absorption device

- 8 045773 niy (CAD) so that the pathogen-inactivated plasma can be transferred from the first container to the CAD under sterile conditions. In some embodiments, one or more of the first, second, third and fourth pathogen-inactivated plasmas are frozen in step a) and thawed in step b) in one or more second containers, each of which is interfaced with the CAD such that the pathogen-inactivated plasma can be transferred from the CAD into one or more second containers under sterile conditions, each of which is suitable for freezing the pathogen-inactivated plasma followed by thawing the pathogen-inactivated plasma under conditions that allow cryoprecipitate to form. In some embodiments, one or more of the first, second, third and fourth pathogen-inactivated plasmas are frozen in step a) and thawed in step b) in a third container configured to interface with the one or more second containers such that the pathogen-inactivated the plasma can be transferred from the CAD in one or more second containers to a third container under sterile conditions, where the third container is suitable for freezing the pathogen-inactivated plasma, followed by thawing the pathogen-inactivated plasma under conditions that allow cryoprecipitate to form. In some embodiments, one or more of the first, second, third and fourth supernatants are separated from one or more of the first, second, third and fourth precipitates in step c) in one or more fourth containers, each of which is configured to interface with one or a plurality of second containers or with a third container so that the supernatant can be transferred from the one or more second containers or the third container to one or more fourth containers under sterile conditions to obtain the pathogen-inactivated cryosupernatant contained in the one or more fourth containers and the pathogen -inactivated cryoprecipitate contained in one or more second containers or a third container.

In yet another aspect, the present disclosure relates to a method of infusing a cryosupernatant into a patient, which comprises infusing into the patient a cryosupernatant obtained by the method of any of the above embodiments.

In yet another aspect, the present disclosure relates to a processing kit for producing pathogen-inactivated cryoprecipitate, which contains a) a first container in which one or more units of plasma can be photochemically inactivated in the presence of psoralen under sterile conditions; b) a compound absorption device (CAD) coupled to the first container such that one or more units of plasma can be transferred from the first container to the compound absorption device under sterile conditions; and c) one or more second containers, each of which is mated to a compound absorption device such that one or more units of plasma can be transferred from the compound absorption device to the one or more second containers under sterile conditions to provide pathogen-inactivated plasma, suitable for infusion into a patient, wherein one or more second containers are suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow the formation of a precipitate and a supernatant. In some embodiments, each of the one or more second containers is suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow the formation of cryoprecipitate and cryosupernatant, followed by removal of all or a portion of the cryosupernatant from the one or more second containers.

In yet another aspect, the present disclosure relates to a processing kit for producing pathogen-inactivated cryoprecipitate, which contains a) a first container in which one or more units of plasma can be photochemically inactivated in the presence of psoralen under sterile conditions; b) a compound absorption device (CAD) coupled to the first container such that one or more units of plasma can be transferred from the first container to the compound absorption device under sterile conditions; c) one or more second containers, each of which is mated to a compound absorption device such that one or more units of plasma can be transferred from the compound absorption device to one or more second containers under sterile conditions to provide pathogen-inactivated plasma suitable for infusion to the patient; and d) a third container that is configured to interface with the one or more second containers such that the pathogen-inactivated plasma can be transferred from the one or more second containers to the third container under sterile conditions, where the third container is suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that ensure the formation of a precipitate and supernatant. In some embodiments, the third container is suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow the formation of cryoprecipitate and cryosupernatant, followed by removal of all or part of the cryosupernatant from the third container. In some embodiments, the treatment kit further comprises an additional container suitable for mixing one or more units of plasma with a pathogen-inactivating compound, wherein the additional con

- 9 045773 the container is mated to the first container so that one or more units of plasma mixed with a pathogen-inactivating compound can be transferred from the additional container to the first container under sterile conditions. In some embodiments, the treatment kit further comprises one or more fourth containers, each of which is configured to interface with the one or more second containers or a third container such that the supernatant can be transferred from the one or more second containers or the third container to the one or more fourth containers under sterile conditions to provide pathogen-inactivated cryosupernatant contained in one or more fourth containers and pathogen-inactivated cryoprecipitate contained in one or more second containers or a third container. In some embodiments, the third container is interfaced with one or more second containers such that the supernatant can be transferred from the one or more second containers to the third container under sterile conditions to produce the pathogen-inactivated cryosupernatant contained in the third container and the pathogen-inactivated cryoprecipitate. contained in one or more second containers. In some embodiments, the third container is configured to interface with the one or more second containers such that the pathogen-inactivated plasma can be transferred from the one or more second containers to the third container under sterile conditions; wherein the third container is suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow the formation of a precipitate and a supernatant; and wherein each of the one or more fourth containers is configured to interface with a third container such that the supernatant can be transferred from the third container to the one or more fourth containers under sterile conditions to produce a pathogen-inactivated cryosupernatant contained in the one or more fourth containers, and pathogen-inactivated cryoprecipitate contained in a third container.

In yet another aspect, the present disclosure relates to a method of obtaining cryoprecipitate for infusion into a patient, which includes a) obtaining cryoprecipitate from pathogen-inactivated plasma; and b) freezing the cryoprecipitate; wherein the cryoprecipitate is suitable for infusion into the patient for up to approximately 5 days after thawing. In some embodiments, the cryoprecipitate is prepared from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma. In some embodiments, the cryoprecipitate is prepared from approximately 600 ml of pathogen-inactivated plasma. In some embodiments, the method further includes combining a first cryoprecipitate obtained from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma and a second cryoprecipitate obtained from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma. inactivated plasma, where the first and second cryoprecipitates are combined before step b). In some embodiments, the first cryoprecipitate is obtained from approximately 600 ml of pathogen-inactivated plasma, and wherein the second cryoprecipitate is obtained from approximately 600 ml of pathogen-inactivated plasma. In some embodiments, the method further includes combining a first cryoprecipitate obtained from 3 units of pathogen-inactivated plasma and a second cryoprecipitate obtained from 3 units of pathogen-inactivated plasma, wherein the first and second cryoprecipitates are combined prior to step b).

In yet another aspect, the present disclosure relates to a method of obtaining cryoprecipitate for infusion into a patient, which includes a) obtaining cryoprecipitate from plasma; and b) effecting inactivation of pathogens in the cryoprecipitate; wherein the pathogen-inactivated cryoprecipitate is suitable for infusion into a patient for up to about 5 days after storage between about 2°C and about 25°C. In some embodiments, the plasma is not pathogen-inactivated. In some embodiments, the method further comprises, after step b) c), freezing the pathogen-inactivated cryoprecipitate; and d) thawing the frozen pathogen-inactivated cryoprecipitate; wherein the pathogen-inactivated cryoprecipitate is suitable for infusion into the patient for up to approximately 3 days after thawing. In some embodiments, the pathogen-inactivated cryoprecipitate is suitable for infusion into a patient for up to about 5 days after thawing. In some embodiments, the cryoprecipitate is prepared from 1 unit of plasma. In some embodiments, the cryoprecipitate is prepared from at least about 180 ml and less than about 250 ml of plasma. In some embodiments, the resulting cryoprecipitate is resuspended in at least about 30 ml and less than about 70 ml of plasma. In some embodiments, the method further includes combining at least a first cryoprecipitate obtained from 1 unit of plasma and a second cryoprecipitate obtained from 1 unit of plasma, wherein the first and second cryoprecipitates are combined prior to step b). In some embodiments, the method further includes combining at least a first cryoprecipitate obtained from 1 unit of plasma and a second cryoprecipitate obtained from 1 unit of plasma, wherein the first and second cryoprecipitates are combined after step b). In some embodiments, the first cryoprecipitate

- 10045773 is prepared from at least about 180 ml and less than about 250 ml of plasma, and wherein the second cryoprecipitate is prepared from at least about 180 ml and less than about 250 ml of plasma. In some embodiments, combining at least the first cryoprecipitate and the second cryoprecipitate includes combining 2-12 cryoprecipitates. In some embodiments, the volume of the combined cryoprecipitates is at least about 500 ml and about less than 700 ml. In some embodiments, the first and second cryoprecipitates are derived from plasma of the same type of ABO. In some embodiments, the first and second cryoprecipitates are derived from plasma of different types of ABO. In some embodiments, the combined cryoprecipitates are prepared from at least 3 cryoprecipitates, and each of the cryoprecipitates is derived from a different type of ABO plasma. In some embodiments, the cryoprecipitate is derived from plasma derived from whole blood. In some embodiments, the cryoprecipitate is obtained from apheresis-collected plasma. In some embodiments, the plasma collected by apheresis is between about 200 ml and about 800 ml.

It should be understood that one, some, or all of the features of the various embodiments described herein may be combined to form other embodiments. These and other aspects will be apparent to one skilled in the art. These and other embodiments are further described in the following detailed description.

Brief description of the figures

In fig. 1A illustrates an exemplary processing set in accordance with some embodiments. The dotted components are optional.

In fig. 1B illustrates an exemplary processing set in accordance with some embodiments. The dotted components are optional.

In fig. 1C illustrates an exemplary processing set in accordance with some embodiments. The dotted components are optional.

In fig. 2A illustrates an exemplary processing set in accordance with some embodiments. The dotted components are optional.

In fig. 2B illustrates an exemplary processing set in accordance with some embodiments. The dotted components are optional.

In fig. 2C illustrates an exemplary processing set in accordance with some embodiments. The dotted components are optional.

In fig. 3A illustrates an exemplary processing set in accordance with some embodiments. The dotted components are optional.

In fig. 3B illustrates an exemplary processing set in accordance with some embodiments. The dotted components are optional.

In fig. 4 depicts the combination of two separate cryoprecipitate preparations in accordance with some embodiments.

In fig. 5 illustrates an exemplary processing set in accordance with some embodiments. The dotted components are optional.

In fig. 6 illustrates an exemplary processing set in accordance with some embodiments. The dotted components are optional.

In fig. 7 illustrates an exemplary processing set in accordance with some embodiments. The dotted components are optional.

Detailed description

The term cryoprecipitate refers to a blood product obtained by controlled thawing of frozen plasma (e.g., fresh frozen plasma obtained from whole blood obtained by plasma apheresis) to form a precipitate containing one or more clotting factors, including, but not limited to, fibrinogen, factor VIII , factor XIII, vWF and/or fibronectin. Such cryoprecipitate can be recovered from the liquid portion of the plasma, for example by refrigerated centrifugation. Once recovered, the cryoprecipitate can be resuspended in any suitable volume of plasma. Methods for preparing cryoprecipitate are well known in the art and are provided throughout this disclosure.

The term plasma refers to any blood plasma product known in the art. In some embodiments, plasma refers to fresh frozen plasma obtained from whole blood. In some embodiments, plasma refers to one or more units of plasma from a whole blood donation (eg, approximately 180-250 mL each). In some embodiments, plasma refers to one or more units of plasma from an apheresis blood donation (can be up to about 700-800 ml each). In some embodiments, plasma refers to a single unit. In some embodiments, a plasma depot can be formed from multiple units. In some embodiments, the plasma may contain one or more additional components, including, without limitation, one or more pathogen-inactivating compounds and/or by-products of the pathogen inactivation process.

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The term infusionable refers to any blood product (eg, cryoprecipitate) that can be used for infusion (eg, transfusion) into a patient (eg, human patient) in accordance with medical judgment. In some embodiments, suitability refers to the presence of sufficient biological activity for its intended use, i.e. for use where transfusion of human coagulation factors is indicated, including without limitation the control of bleeding associated with fibrinogen deficiency, treatment of factor XIII deficiency, treatment of factor VIII deficiency, treatment of von Willebrand disease, maintenance of hemostasis, treatment of disseminated intravascular coagulation (DIC) or large hemorrhage volume and/or creation of fibrin sealant. In some embodiments, suitability refers to having sufficient safety, e.g., that the product has undergone a treatment that will improve the safety of the product (e.g., pathogen inactivation), and/or demonstrates satisfactory performance on one or more safety-related measures (such as viral or bacterial titer). It is well established that photochemical inactivation of pathogens in blood product units using amotosalen and UVA light, as disclosed herein, provides a blood product (eg, cryoprecipitate) that is suitable for human transfusion. In some embodiments, suitability refers to compliance with one or more standards (eg, having a level of biological activity or biological component, a safety criterion, etc.) established by an accrediting body or regulatory body that regulates the practice of infusion, for example, AABB.

Pathogen-inactivated, as used herein, describes a blood product (eg, cryoprecipitate or plasma) that has been treated (eg, using the methods described herein) to inactivate pathogens that may be present. It is understood that the pathogen-inactivated cryoprecipitate may include cryoprecipitate that has itself undergone pathogen inactivation, or a cryoprecipitate derived from a pathogen-inactivated blood product (eg, plasma, whole blood, etc.). Moreover, it is understood that this process does not necessarily completely inactivate all pathogens that may be present, but essentially reduces the number of one or more pathogens to significantly reduce the risk of transfusion-associated disease. Pathogen inactivation can be analyzed by measuring the number of infectious pathogens (eg, viruses or bacteria) in a certain volume, and the level of inactivation is usually expressed using the logarithmic reduction in pathogen infectivity or the logarithmic reduction in titer. Methods for analyzing and measuring log titer reduction for pathogen inactivation are known in the art. Methods for analyzing and measuring log titer reduction for pathogen inactivation are described, for example, in US Pat. No. 7,655,392, the disclosure of which is therefore incorporated by reference as it relates to pathogen inactivation assays. As such, for any given pathogen, known amounts can be added to a test unit of cryoprecipitate or plasma in order to assess how much inactivation results from this process, where typically the pathogen inactivation process results in at least a log reduction in titer of approximately 1, or log , approximately equal to 2, log, approximately equal to 3, log, approximately equal to 4, or at least a logarithmic titer reduction of approximately equal to 5. Although the methods as disclosed herein are applied to any pathogen-inactivating treatment, it is desirable that the pathogen-inactivating treatment was capable of inactivating a variety of pathogens to at least a log titer reduction of 1, including a pathogen selected from the group consisting of HIV-1, HBV, HCV, HTLV-1, HTLV-2, West Nile virus, Escherichia coli, Klebsiella pneumoniae , Yersinia enterocolitica, Staphylococcus epidermidis, Staphylococcus aureus, Treponema pallidum, Borrelia burgdorferi, Plasmodium falciparum, Trypanosoma cruzi and Babesia microti.

The term pathogen-inactivating compound refers to any suitable compound, such as a small organic compound, that can be used to inactivate a pathogen that may be present in a blood product, such as cryoprecipitate or plasma. A photoactivated pathogen-inactivating compound is a suitable compound that requires some level of light (eg, ultraviolet light) in order to sufficiently inactivate the pathogen. Such compounds are preferred when inactivating pathogens in blood products such as cryoprecipitate or plasma, since they provide control over the inactivation process. Such photoactivated pathogen-inactivating compounds described herein include psoralens, isoalloxazines, alloxazines, phthalocyanines, phenothiazines and porphyrins, where these terms are understood to cover a general class of compounds, i.e. the basic compound and its suitable derivatives. For example, psoralens or psoralen in general describes the main compound psoralen and any of its derivatives (e.g., amotosalen), isoalloxazins or isoalloxazine in general describes the isoalloxazine backbone and any of its derivatives (e.g., riboflavin), and so on. Such derivatives contain the structure of the main compound, as well as additional substituents on the backbone. Descriptions of such compounds include any salts thereof.

The term amotosalen means the compound 3-(2-aminoethoxymethyl)-2,5,9-trimethylfuro[3,2-g]chromene

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7-on and any of its salts. The compound may also be referred to as 3-[(2-aminoethoxy)methyl]-2,5,9trimethyl-7H-furo[3,2-G][1]benzopyran-7-one hydrochloride. The compound may also be referred to as 4'-(4-amino-2-oxa)butyl-4,5',8-trimethylpsoralen. When inactivation of blood products, such as cryoprecipitate or plasma, involves the addition of amotosalen HCl (a salt of HCl and amotosalen) to a unit of blood product, the removal of this compound from the unit is not limited to the removal of amotosalen HCl, since amotosalen may be present in solution as other salts or as free base. As used in the methods described herein, removal of amotosalen refers to the removal of the compound in some form, for example, as a free base or as any salt, as measured by the assays described herein. Treatment of blood products by amotosalen inactivation refers to combining a blood product (eg, cryoprecipitate or plasma unit, individual unit, depot) with amotosalen and illumination with an appropriate dose of UVA light in order to inactivate pathogens that may be present. In some embodiments, the amotosalen-inactivated cryoprecipitate is made pathogen-inactivated, or the plasma from which the cryoprecipitate is derived is made pathogen-inactivated, according to commercial methods or similar methods.

The term sterile conditions, as used herein, refers to maintaining the sterility of the system, for example by connecting two bags from a blood processing kit, or refers to the means by which the process does not introduce contamination. For example, as used in the methods described herein, a blood product source unit, such as cryoprecipitate or plasma, containing tubing for connection to a treatment kit or pathogen-inactivating compound container containing similar tubing can be connected under sterile conditions known in the art methods, for example, using a sterile connecting device that operates to fuse or weld the tubes together to provide a sterile flow path between two containers. Likewise, when the methods described herein describe sealing such a tube, the sealing is performed under sterile conditions, for example, using a tube sealer.

The blood collection bag may be any bag used to collect blood from a donor, as is known in the art. Blood collected in a blood collection bag that is not attached to other bags can be centrifuged to separate the blood into its blood components. The blood collection bag is then sterilely mated to a specific number of companion bags that corresponds to the number of blood products determined to be produced from whole blood. The blood in the blood collection bag can be processed, for example, by centrifugation and/or freezing, in the blood collection bag before being separated into companion bags, or the blood can be transferred (by gravity or by pumping) from the blood collection bag to the blood processing bag.

A blood processing bag is any such bag known in the art, other than a blood collection bag, used for processing blood. The blood treatment bag can be pre-connected to the blood collection bag or attached to the blood collection bag through a sterile interface. Blood transferred to a blood processing bag can be centrifuged. Before centrifugation or immediately after centrifugation, the blood processing bag is sterilely joined to a certain number of companion bags that correspond to the number of blood products that are determined to be produced from whole blood.

Blood collection and cryoprecipitate preparation.

Whole blood for use in preparing cryoprecipitate as disclosed herein can be collected using a variety of procedures known in the art. One of the most common methods of blood collection is the manual collection of whole blood from healthy donors. As commonly understood and used herein, manual collection refers to a collection method where whole blood is allowed to flow from the donor and into a collection container without the use of external pumps or similar devices. This differs from so-called automated procedures, in which blood is collected from a donor and further processed using a device that typically contains a processing or separation device and pumps to move the blood or blood components into and out of the device. Automated cell separation systems can be used to collect plasma from a donor through an apheresis procedure (eg, plasmapheresis), while returning other blood components to the donor. Apheresis-collected plasma can also be used to produce cryoprecipitate and cryosupernatant plasma using the methods and kits provided herein.

Regardless of whether the blood collection method is manual or automated, withdrawing blood from a donor typically involves inserting a venous access device, such as a needle, into the donor's arm (and more specifically, the donor's vein), and withdrawing blood from the donor through the needle. A venipuncture needle usually has a plastic tube attached to it, which provides a flow path for the blood. The other end of the plastic tube ends in one or more pre-attached blood containers or blood collection bags. The needle, tube and containers form a blood collection kit, which is pre-sterilized and discarded after one use. A sterile blood collection container typically serves as the primary container for the initial separation of blood components (eg, separation of plasma from red blood cells and platelets).

The blood collection container and plastic tubing may also contain a specified volume of liquid anticoagulant, although an automated method may provide a separate anticoagulant container from which the anticoagulant is dispensed into the flow path and mixed with the incoming whole blood. The anticoagulant is necessary because of the tendency of blood to coagulate and stick to the walls of the plastic surfaces with which it is exposed. Exemplary anticoagulants are well known in the art and may include, but are not limited to, citrate phosphate dextrose (CPD) anticoagulant solution, double dextrose phosphate citrate anticoagulant (CP2D) solution, citrate phosphate dextrose adenine (CPDA) anticoagulant solution (e.g., CPDA-1 ), acid citrate dextrose (ACD) solution (e.g. ACD-A), and sodium citrate anticoagulant solution 4% w/v.

Blood can be identified or characterized with respect to one or more parameters, such as hematocrit, for example. Such identification or characterization typically occurs before or shortly after blood collection, but before subjecting the collected whole blood to further processing, such as in accordance with the methods provided herein. In addition, tests can be performed at or near the time of collection and before transfusion to the patient to determine the blood type and the presence of pathogens, such as virus, bacteria, and/or other foreign substances in the donor's blood. Such testing generally requires obtaining a blood sample from a donor. In general, collection of a blood sample may occur before, during, or after donation, but without compromising the sterility of the system and/or the collected blood product. For example, samples can be obtained in the usual manner by finger pricking, heel pricking or venipuncture. When blood for hemoglobin testing is collected using a capillary tube, a sterile disposable lancet can be used. Another well-known method is simply to extract or collect the blood remaining after donation in the flow path of the collection kit. This involves removing the needle from the donor, inserting the needle into a vacuum sealed sample vial or tube, and allowing the blood out of the flow path to flow into the vial. Another alternative is to remove the clamp from the flow path near the collection container and redirect the blood withdrawn from the donor into a collection vial or tube. This procedure can use a specific type of disposable tubing kit that has a pre-attached sample collection site in the main flow path. Blood at or near the sample collection site may be obtained by piercing the sample collection site with a separately provided needle or other piercing device and attaching a sample vial to it. To minimize the risk that the incoming blood may be affected by the external environment, the sample is usually collected after the blood donation has been completed. Alternatively, some collection bags or collection kits contain diverter pockets to sequester a portion (eg, the first 20 ml) of the collected blood. Another example of a blood sample collection system is described in US Pat. No. 5,167,656, which describes blood collection kits with an enlarged sample collection portion included in the flow path. Blood to obtain a sample is collected from the enlarged portion by removing the clamp from the flow path near the collection container and allowing the enlarged portion of the tube to fill with blood.

Plasma that can be used to produce cryoprecipitate as disclosed herein can be recovered from whole blood through various procedures known in the art. For example, plasma can be recovered by centrifuging whole blood at low speed (eg, about 1000-3000 rpm for about 10-20 minutes, optionally with cooling), followed by recovery of a plasma fraction. In some embodiments, the platelet content of the plasma can be reduced (e.g., by centrifugation at higher speeds and/or for longer times in the above ranges, e.g., about 2000-3000 rpm for about 15-20 minutes or about 5000xg).

Methods for obtaining cryoprecipitate from plasma are well known in the art and are described and exemplified herein. Typically, individual units of whole blood plasma used to produce cryoprecipitate are frozen within 8 hours of donation, and the frozen plasma (eg, fresh frozen whole blood plasma, or FFP) can be thawed in a temperature-controlled apparatus such as like a water bath. The present disclosure also provides that plasma obtained from whole blood frozen within 24 hours of donation and plasma obtained by apheresis (eg, frozen within 8 hours, frozen within 24 hours) may be used. For thawing, the temperature may be low enough (eg, about 4°C or between about 1°C and about 6°C) so as to lead to controlled gradual thawing. For example, thawing may occur for a total time of between about 4 hours and about 7-8, 8 and 10 hours or overnight. As discussed in more detail above, individual units (eg, 200 ml units, as defined by an accepted standard such as AABB) of plasma can be used to produce cryoprecipitate, or more than one individual unit (eg, 200 ml units) of plasma. Plasma can be pooled into a depot to produce cryoprecipitate (eg 550-650 ml plasma). For plasma depot, a larger suitable bag such as a 1000 ml PVC bag (eg Fenwal Transfer Pack) or any blood product compatible bag of sufficient volume (eg 800, 600 ml) can be used to obtain cryoprecipitate. In some embodiments, the total melting time may depend on the plasma volume; for example, a 200-250 ml unit of plasma may take approximately 4.5 hours to thaw, while a 550-650 ml plasma unit may require approximately 6.5 hours. Once thawed, the plasma can be centrifuged, for example by refrigeration (e.g. approx. 4°C) for approximately 10-15 minutes at approximately 4200 rcf (optionally with a slow stop) in order to separate the cryoprecipitate from the cryosuppernatant plasma (cryosupernatant). The cryoprecipitate can be separated from the cryosuppernatant plasma, for example, by inversion to remove the cryosupernatant plasma, or through the use of a plasma expressor to remove the cryosupernatant plasma.

In some embodiments, the cryoprecipitate may be frozen after receipt. Since cryoprecipitate can be recovered from plasma that is itself frozen, cryoprecipitate refreezing, as used herein, refers to freezing the cryoprecipitate after the cryoprecipitate has been prepared (eg, after the initial plasma freezing step, after the precipitation step). Advantageously, this allows cryoprecipitate to be stored for later use. In some embodiments, the cryoprecipitate can be stored at approximately -18°C or lower (eg, in accordance with AABB standards).

Once frozen (and optionally kept frozen), cryoprecipitate can be thawed. Methods for thawing frozen cryoprecipitate are well known in the art. As a non-limiting example, cryoprecipitate can be thawed in a plasma thawer (eg, the one commercially available from Helmer Scientific). In some embodiments, the cryoprecipitate can be thawed at approximately 35°C. In some embodiments, the cryoprecipitate may be thawed in approximately 5-10 minutes. In some embodiments, after thawing, the cryoprecipitate can be mixed, for example, by shaking. In some embodiments, the cryoprecipitate may be allowed to thaw for two or more intervals, which may optionally be separated by one or more mixing steps. In some embodiments, the cryoprecipitate may be thawed for about 5-10 minutes, mixed, and allowed to continue thawing for about 5-10 minutes.

For each of the parameters set forth in the methods provided herein, methods for determining or measuring the parameters are well known in the art.

Compositions of cryoprecipitates.

The following describes various exemplary parameters and properties that may characterize the cryoprecipitate (or a composition that contains cryoprecipitate) according to the present disclosure. One skilled in the art will appreciate that these exemplary features and embodiments may be combined in any number or combination unless the context indicates otherwise. These exemplary features and embodiments may be combined with any of the other embodiments or aspects described elsewhere herein in any number or combination unless the context indicates otherwise.

Certain aspects of the present disclosure relate to compositions containing cryoprecipitate suitable for infusion into a patient. As disclosed herein, these compositions are suitable for infusion into a patient for a longer duration after thawing (eg, thawing after storage of frozen cryoprecipitate) than currently prescribed by existing guidelines (eg, the compositions have an extended shelf life after thawing). Such compositions may find use, inter alia, in treatments (eg, infusions) associated with the control of bleeding associated with fibrinogen deficiency, treatment of factor XIII deficiency, treatment of von Willebrand disease, maintenance of hemostasis, treatment of disseminated intravascular coagulation (DIC) or major hemorrhage. volume, and/or in the creation of fibrin sealant.

In some embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) is suitable for infusion into a patient over at least 6 hours, at least 12 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least at least 60 hours, at least 72 hours, at least 84 hours, at least 96 hours, at least 108 hours, at least 120 hours, at least 132 hours, at least 144 hours, at least 156 h, or at least 168 h after thawing. In some embodiments, the cryoprecipitate is suitable for infusion into a patient within 6 hours, within 12 hours, within 24 hours, within 36 hours, within 48 hours, within 60 hours, within 72 hours, within 84 hours, in within 96 hours, within 108 hours, within 120 hours, within 132 hours, within 144 hours, within 156 hours or within 168 hours after defrost. In some embodiments, the cryoprecipitate is suitable for infusion into a patient within a specified number of hours after thawing, which is approximately less than any of the following number of hours: 168, 156, 144, 132, 120, 108, 96, 84, 72 . 0.25, 0.5, 1, 2, 3, 4, 5, 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144 or 156. the number of hours after thawing during which cryoprecipitate is suitable for infusion into a patient may be any number of hours in the range which has an upper limit of 168, 156, 144, 132, 120, 108, 96, 84, 72, 60, 48, 36 , 24 or 12 hours and independently selected lower limit 0, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144 or 156 hours, where the upper limit is greater than the lower limit. In some embodiments, the cryoprecipitate is suitable for infusion into a patient immediately after thawing and resuspension of the cryoprecipitate (eg, 0 hour after thawing). In some embodiments, the cryoprecipitate may be suitable for infusion into a patient from about 0 hour to about 168 hours, from about 0 hour to about 144 hours, from about 0 hour to about 120 hours after thawing, from about 0 hour to about 96 hours after defrost, from about 0 hours to about 72 hours after thawing, or from about 0 hours to about 48 hours after thawing. In some embodiments, the cryoprecipitate may be suitable for infusion into a patient within about 6 hours to about 168 hours, about 6 hours to about 144 hours, or about 6 hours to about 120 hours after thawing. In some embodiments, the cryoprecipitate may be suitable for infusion into a patient over a period of about 12 hours to about 168 hours, about 12 hours to about 144 hours, or about 12 hours to about 120 hours after thawing. In some embodiments, the cryoprecipitate may be suitable for infusion into a patient within about 24 hours to about 168 hours, about 24 hours to about 144 hours, or about 24 hours to about 120 hours after thawing. In some embodiments, the cryoprecipitate may be suitable for infusion into a patient within about 36 hours to about 168 hours, about 36 hours to about 144 hours, or about 36 hours to about 120 hours after thawing. In some embodiments, the cryoprecipitate may be suitable for infusion into a patient within about 48 hours to about 168 hours, about 48 hours to about 144 hours, or about 48 hours to about 120 hours after thawing.

In some embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) is suitable for infusion into a patient after at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least at least 6 days or at least 7 days after thawing. In some embodiments, the cryoprecipitate is suitable for infusion into a patient within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, or within 7 days after thawing. In some embodiments, the cryoprecipitate is suitable for infusion into a patient within a specified number of days after thawing, which is approximately the lesser of any of the following number of days: 7, 6, 5, 4, 3, or 2. In some embodiments, the cryoprecipitate is suitable for infusion into a patient for a specified number of days after thawing (for example, after thawing and resuspending the cryoprecipitate), which is approximately greater than any of the following number of days: 0, 1, 2, 3, 4, 5, or 6. In some embodiments, the cryoprecipitate is suitable for infusion into the patient immediately after thawing and resuspension of cryoprecipitate (for example, 0 days after thawing). Those. the number of days after thawing during which the cryoprecipitate is suitable for infusion into a patient may be any number of days within a range having an upper limit of 7, 6, 5, 4, 3 or 2 days and an independently selected lower limit of 0, 1, 2, 3, 4, 5 or 6 days, where the upper limit is greater than the lower limit. In some embodiments, the cryoprecipitate may be suitable for infusion into a patient for from about 0 days to about 7 days, from about 0 days to about 6 days, from about 0 days to about 5 days, from about 0 days to about 4 days, from about 0 days to approximately 3 days or from approximately 0 days to approximately 2 days after thawing. In some embodiments, the cryoprecipitate may be suitable for infusion into a patient for about 1 day to about 7 days, about 1 day to about 6 days, or about 1 day to about 5 days after thawing.

In some embodiments, the cryoprecipitate may be suitable for infusion into a patient for about 2 days to about 7 days, about 2 days to about 6 days, or about 2 days to about 5 days after thawing.

In some embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) is stored at room temperature after thawing, for example, during the interval between thawing and use (eg, for infusion). In some embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) is stored at between about 2°C and about 25°C after thawing, for example, during the interval between thawing and

- 16 045773 use (for example, for infusion). In some embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) is stored at between about 20°C and about 24°C after thawing, for example, during the interval between thawing and use (eg, for infusion). In some embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) is stored at approximately 22°C after thawing, for example, during the interval between thawing and use. In some embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) is stored at 2°C and approximately 6°C after thawing, for example, during the interval between thawing and use (eg, for infusion). In some embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) is stored after thawing, e.g., during the interval between thawing and use (e.g., for infusion) in accordance with standards established by AABB, American Red Cross, or other accrediting, regulatory, or establishment standards authority.

It is well known in the art that donations of different types of blood, including plasma, may have different associated volumes. The volume of plasma obtained from a whole blood donation may vary, for example, depending on the volume of whole blood collected, the size of the collection bag (eg, 450, 500 ml), percentage of donor hematocrit, and processing conditions (eg, centrifugation conditions). For example, in certain embodiments, a whole blood donation will typically yield a unit of plasma (e.g., plasma derived from whole blood) of approximately 180-250 mL (e.g., approximately 200 mL), whereas the volume of plasma from a single apheresis donation or sample (e.g., apheresis-collected plasma) can yield from approximately 200 ml up to approximately 700-800 ml depending on various factors including donor size (eg, body weight). In some embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) of the present disclosure can be prepared from about 180 or 200 ml to about 250 or 300 or 325 ml of plasma. For example, cryoprecipitate can be obtained from one unit of plasma with a volume of approximately 200 ml (eg, a certain AABB unit, AABB unit volume), for example, from one whole blood donation. In other embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) of the present disclosure can be prepared from at least about 300 ml, at least about 400 ml, at least about 500 ml, or at least about 600 ml or more plasma. In other embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) of the present disclosure can be prepared from at least about 550 ml and less than 650 ml of plasma. In some embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) of the present disclosure can be prepared from at least about 570 ml and about less than 620 ml of plasma. In some embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) of the present disclosure can be prepared from at least about 600 ml and about less than 650 ml of plasma. In certain embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) of the present disclosure can be prepared from approximately 600 ml of plasma. For example, cryoprecipitate can be obtained from a depot of several AABB plasma volume units (eg, to obtain 550-650 ml), a single apheresis sample (eg, having 550-650 ml or more), or from a depot of several cryoprecipitates obtained from different plasma samples.

As such, in some embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) of the present disclosure may comprise cryoprecipitate obtained from a single donor. In other embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) of the present disclosure may contain cryoprecipitate obtained from more than one donor (eg, obtained from more than one plasma donation, obtained from more than one unit of plasma). In some embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) of the present disclosure may contain cryoprecipitate obtained from 2-12 donors. In some embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) of the present disclosure may comprise cryoprecipitate derived from plasma obtained from 2-6 donors. For example, in some embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) of the present disclosure may comprise cryoprecipitate derived from plasma obtained from 1, 2, 3, 4, 5, or 6 donors. In some embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) of the present disclosure may contain cryoprecipitate obtained from 7-12 donors. For example, in some embodiments, the cryoprecipitate (or a composition that contains cryoprecipitate) of the present disclosure may comprise cryoprecipitate derived from plasma obtained from 7, 8, 9, 10, 11, or 12 donors.

In some embodiments, the cryoprecipitate composition of the present disclosure may contain more than one cryoprecipitate (eg, individual cryoprecipitate preparations). For example, in some embodiments, the cryoprecipitate composition of the present

- 17 045773 disclosure may contain a first cryoprecipitate obtained from pathogen-inactivated plasma, and a second cryoprecipitate obtained from pathogen-inactivated plasma. In some embodiments, the cryoprecipitate composition of the present disclosure may comprise a first cryoprecipitate prepared from 2 units of pathogen-inactivated plasma and a second cryoprecipitate prepared from 2 units of pathogen-inactivated plasma. In some embodiments, the cryoprecipitate composition of the present disclosure may comprise a first cryoprecipitate prepared from 3 units of pathogen-inactivated plasma and a second cryoprecipitate prepared from 3 units of pathogen-inactivated plasma. In some embodiments, the first and second cryoprecipitates are combined before being re-frozen for storage. In some embodiments, the first and second cryoprecipitates are combined before use (eg, for infusion) and/or before storage at room temperature or refrigeration. In some embodiments, the cryoprecipitate composition of the present disclosure may comprise a pathogen-inactivated plasma depot of at least 3, at least 4, at least 5, or at least 6 units of pathogen-inactivated plasma. In some embodiments, the cryoprecipitate composition of the present disclosure may comprise a pathogen-inactivated plasma depot of at least 7, at least 8, at least 9, at least 10, at least 11, or at least 12 pathogen-inactivated plasma units. plasma. In some embodiments, the cryoprecipitate composition of the present disclosure may comprise a pathogen-inactivated plasma depot of at least 7, at least 8, at least 9, at least 10, at least 11, or at least 12 units of pathogen-inactivated plasma B In certain embodiments, the cryoprecipitate composition of the present disclosure may comprise a pathogen-inactivated plasma depot of at least 3 units of pathogen-inactivated plasma. In certain embodiments, the cryoprecipitate composition of the present disclosure may comprise a pathogen-inactivated plasma depot of at least 6 units of pathogen-inactivated plasma.

In some embodiments, the cryoprecipitate composition of the present disclosure can be created from plasma that has not been pathogen inactivated, after which the cryoprecipitate itself can be pathogen inactivated (and optionally frozen for storage after pathogen inactivation). In some embodiments, the pathogen-inactivated cryoprecipitate can be stored at 2-25°C (eg, 2-6, 20-24°C) until used for infusion. In some embodiments, the cryoprecipitate can be obtained from plasma and subsequently subjected to pathogen inactivation. In some embodiments, the plasma has not been subjected to pathogen inactivation. In some embodiments, multiple cryoprecipitate preparations derived from plasma (e.g., plasma that has not been pathogen inactivated) may be pooled together in a depot and then subjected to pathogen inactivation (see, for example, 700, 702, and 704, as shown in FIG. 7). Advantageously, this makes it possible to inactivate pathogens in a large volume of cryoprecipitate (eg, a cryoprecipitate composition depot) in one step and/or in one container. In other embodiments, multiple cryoprecipitate preparations derived from plasma (eg, plasma that has not been pathogen inactivated) can be pathogen inactivated, then combined together. In some embodiments, the pathogen-inactivated cryoprecipitate (eg, cryoprecipitate depot) is frozen for storage. Any desired volume of cryoprecipitate can be subjected to pathogen inactivation and optionally formed into a depot (eg, before or after pathogen inactivation). For example, in some embodiments, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 At least 11 or at least 12 cryoprecipitate preparations or units can be combined together in a depot, for example, before or after pathogen inactivation. In some embodiments, the cryoprecipitate is prepared from at least about 550 ml and less than about 650 ml of plasma. In some embodiments, cryoprecipitate is prepared by forming a depot of two or more units of cryoprecipitate (eg, before or after inactivation of pathogens), each unit of cryoprecipitate being obtained from at least about 550 ml and about less than 650 ml of plasma. In some embodiments, cryoprecipitate is prepared by forming a depot of two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, or twelve or more units of cryoprecipitate (eg, before or after inactivation of pathogens), each unit of cryoprecipitate is obtained from at least about 150 ml and about less than 250 ml of plasma, for example, about 200 ml of plasma. In some embodiments, the cryoprecipitate is prepared by forming a depot of two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, or twelve or more units of cryoprecipitate (eg, before or after inactivation of pathogens), each unit of cryoprecipitate is obtained from a unit of plasma derived from whole blood.

- 18 045773

In some embodiments, the cryoprecipitate composition of the present disclosure may comprise a first cryoprecipitate prepared from at least about 550 ml and less than 650 ml pathogen-inactivated plasma, and a second cryoprecipitate prepared from at least about 550 ml and less than 650 ml pathogen - inactivated plasma. In some embodiments, the cryoprecipitate composition of the present disclosure may comprise a first cryoprecipitate prepared from at least about 570 ml and less than 620 ml pathogen-inactivated plasma, and a second cryoprecipitate prepared from at least about 570 ml and less than 620 ml pathogen - inactivated plasma. In some embodiments, the cryoprecipitate composition of the present disclosure may comprise a first cryoprecipitate derived from at least about 600 ml and less than 650 ml of pathogen-inactivated plasma, and a second cryoprecipitate prepared from at least about 600 ml and less than 650 ml of pathogen-inactivated plasma. plasma. In certain embodiments, the cryoprecipitate composition of the present disclosure may comprise a first cryoprecipitate prepared from approximately 600 ml of pathogen-inactivated plasma and a second cryoprecipitate prepared from approximately 600 ml of pathogen-inactivated plasma. In some embodiments, the cryoprecipitate composition of the present disclosure may comprise a first cryoprecipitate prepared from at least about 150 ml and less than about 250 ml of pathogen-inactivated plasma, and a second cryoprecipitate prepared from at least about 150 ml and less than about 250 ml of pathogen-inactivated plasma. Individual cryoprecipitates can be combined or pooled after the cryoprecipitate is prepared but before use and/or refrozen for storage, and/or individual plasma samples can be combined or pooled before cryoprecipitate is produced.

In some embodiments, the cryoprecipitate may be part of a composition containing plasma in a specific volume. For example, the cryoprecipitate is typically resuspended in a certain volume of plasma remaining after receiving the cryoprecipitate (eg, some remaining plasma after receiving the cryoprecipitate). This volume can then be used or frozen for storage as disclosed herein.

In some embodiments, the composition that contains the cryoprecipitate of the present disclosure contains a volume of plasma that is approximately less than any of the following volumes (in ml): 150, 140, 130, 120, 110, 100, 90, 80, 76. 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 45, 40, 35, 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, or 6. In some embodiments, a composition that contains The cryoprecipitate of the present disclosure contains a volume of plasma that is approximately greater than any of the following volumes (in ml): 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60. a composition that contains cryoprecipitate of the present disclosure may contain plasma in any volume within a range having an upper limit of 150, 140, 130, 120, 110, 100, 90, 80, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 45, 40, 35, 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7 or 6 ml, and independently selected lower limit 5, b, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 ml, where the upper limit is greater than the lower limit. In some embodiments, a composition that contains cryoprecipitate of the present disclosure contains between about 5 ml and about 25 ml plasma, about 5 ml and about 20 ml plasma, about 10 ml to about 20 ml plasma, or about 15 ml to about 20 ml plasma. 20 ml plasma. In other embodiments, the composition that contains the cryoprecipitate of the present disclosure contains from about 30 ml to about 150 ml, from about 75 ml to about 150 ml, from about 30 ml to about 75 ml of plasma, from about 40 ml to about 75 ml plasma, from about 50 ml to about 75 ml of plasma, from about 60 ml to about 75 ml of plasma, from about 50 ml to about 70 ml of plasma, from about 50 ml to about ml of plasma, from about 50 ml to about 60 ml of plasma , from about 55 ml to about 7 0 ml of plasma, from about 55 ml to about 65 ml of plasma, from about 55 ml to about 60 ml of plasma, or from about 60 ml to about 70 ml of plasma. In other embodiments, a composition that contains the cryoprecipitate of the present disclosure contains more than about 1 ml and less than or exactly 75 ml of plasma, or more than about 5 ml and less than or exactly 75 ml of plasma. In some embodiments, the above plasma volumes comprise plasma volumes after cryoprecipitate has been resuspended.

In some embodiments, the specific plasma volume may depend on the amount of cryoprecipitate (eg, depend on the amount of plasma used to obtain the cryoprecipitate). In some embodiments, for a cryoprecipitate prepared from one AABB unit volume of plasma (e.g., 200 mL), the volume of plasma in the composition may be approximately

- 19 045773 from 5 ml to about 25 ml, from about 5 ml to about 20 ml, from about 10 ml to about 20 ml, or from about 15 ml to about 20 ml, or some other comparable range as described above. In some embodiments, for a cryoprecipitate prepared from more than one AABB unit volume of plasma (e.g., 550-650 mL), or for a depot of multiple cryoprecipitate preparations (e.g., each obtained from approximately 200 mL of plasma), the volume of plasma in the composition may be from about 15 ml to about 75 ml, from about 15 ml to about 60 ml, from about 30 ml to about 75 ml, from about 30 ml to about 60 ml, from about 30 ml to about 40 ml, from 40 ml to about 70 ml, from about 45 ml to about 65 ml, from about 50 ml to about 60 ml, or some other comparable range as described above. In certain embodiments, the volume of plasma in the composition may be less than or exactly about 75 ml. In some embodiments, for a cryoprecipitate prepared by combining two or more cryoprecipitate preparations, each derived from more than one AABB unit volume of plasma (e.g., each is 550-650 ml, for a total of 110 0-1300 ml), the volume of plasma in the composition may be from about 30 ml to about 150 ml, from about 30 ml to about 120 ml, from about 60 ml to about 120 ml, from about 90 ml to about 120 ml, from about 50 ml to about 100 ml, from about 60 ml to about 90 ml, from about 60 ml to about 75 ml from about 50 ml to about 75 ml or about 75 ml. In certain embodiments, the volume of plasma in the composition obtained by combining two or more cryoprecipitate preparations may be less than or exactly about 75 ml.

As disclosed herein and well known in the art, the cryoprecipitate or cryoprecipitate composition of the present disclosure can be tested for the amount and/or activity of one or more components, including, without limitation, fibrinogen, factor VIII, factor XIII and/or vWF. In some embodiments, this testing refers to a measurement performed on an individual sample. In other embodiments, it refers to the average based on measurements taken across multiple samples (eg, a sufficient number of random samples to provide a statistically significant sample). Often, multiple cryoprecipitate compositions (units) can be thawed during a specific acquisition period (eg, 1 month of acquisition) and tested to obtain a measurement that is considered representative of those units not tested. Untested samples can then be used in treatments such as infusion. Therefore, testing, as used herein, refers to the testing of a particular cryoprecipitate composition, or it refers to the testing of other cryoprecipitate compositions in a defined cross-section of cryoprecipitate compositions (e.g., in which the measurement of one or more individual samples or the average of the measurements is considered representative of the cryoprecipitate composition that is not tested). In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure may be tested prior to refreezing and/or storage. In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure can be tested after thawing. In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure may be tested prior to use, for example, for infusion. As used herein, the terms testing and determination, including their grammatical derivatives, may be used interchangeably. Therefore, a definition, as used herein, refers to determining the amount of an analyte of interest (including, without limitation, fibrinogen, factor VIII, factor XIII, and/or vWF) in a particular cryoprecipitate composition, or it refers to determining the amount of an analyte of interest, in other cryoprecipitate compositions, in a particular cross-section of cryoprecipitate compositions (e.g., in which a measurement of one or more individual samples or an average of measurements is considered representative of a cryoprecipitate composition that was not tested, such as a plurality of cryoprecipitate compositions prepared by the same methods and/or prepared in the same manner same location or general time interval, for example, within 30 days).

One skilled in the art will appreciate that the cryoprecipitate or cryoprecipitate composition of the present disclosure can be tested at one or more time points (e.g., after thawing) for the amount and/or activity of one or more components, including, without limitation, fibrinogen, factor VIII, factor XIII and/or vWF. For example, the cryoprecipitate or cryoprecipitate composition of the present disclosure may be tested shortly after thawing (e.g., within 2 hours of thawing, within 6 hours of thawing) and/or the cryoprecipitate or cryoprecipitate composition of the present disclosure may be tested shortly before or at the time of infusion or the post-thaw shelf life point, which in some embodiments described herein may be after about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, or about 7 days

- 20 045773 days after thawing. It should be understood that any exemplary amounts of cryoprecipitate or cryoprecipitate composition components described herein (e.g., fibrinogen, factor VIII, factor XIII, and/or vWF) refer to amounts that were tested or determined shortly after thawing (e.g., at within 2 hours of thawing, within 6 hours of thawing), or the amount tested shortly before or at the time of infusion or expiration date after thawing (e.g., up to approximately 1 day, up to approximately 2 days, up to approximately 3 days, approximately up to 4 days, up to approximately 5 days, or up to approximately 7 days after thawing).

In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure can be tested for factor VIII. Various assays for measuring factor VIII are known in the art, including, but not limited to, chromogenic assays, one-step clotting or partial thromboplastin activation time (ARTT) assays, and two-step clotting or partial thromboplastin activation time (ARTT) assays. Without wishing to be limited by theory, it is believed that cryoprecipitate having less than a specific amount of factor VIII, for example, the AABB standard for factor VIII, such as 80 IU per unit, can be beneficially used for the treatment of many conditions, including, without limitation, the control of bleeding associated with deficiency fibrinogen, treatment of factor XIII deficiency, treatment of von Willebrand disease, maintenance of hemostasis, treatment of disseminated intravascular coagulation (DIC) or large volume hemorrhage and/or creation of fibrin sealant. Advantageously, this cryoprecipitate, preferably containing pathogen-inactivated plasma, may be suitable for infusion after a longer post-thaw duration than, for example, current AABB standards (eg, less than 6 hours) recommend.

In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains less than about 80 IU, less than about 75 IU, less than about 70 IU, less than about 65 IU, less than about 60 IU, less than about 55 IU, about less less than 50 IU, approximately less than 45 IU, approximately less than 40 IU, approximately less than 35 IU, approximately less than 30 IU, approximately less than 25 IU, approximately less than 20 IU, approximately less than 15 IU, or approximately less than 10 Factor VIII ME per unit of cryoprecipitate (eg, per unit of cryoprecipitate obtained from approximately 200 ml of plasma). In some embodiments, the composition that contains the cryoprecipitate of the present disclosure contains factor VIII in an amount that is approximately less than any of the following amounts (in ME, absolute or per cryoprecipitate unit): 480, 450, 400, 350, 300 , 250, 225, 200, 175, 150, 125, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20 or 15.V In some embodiments, a composition that contains cryoprecipitate of the present disclosure contains factor VIII in an amount that is greater than approximately any of the following amounts (in ME, absolute or per unit of cryoprecipitate): 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200 or 225. a composition which contains cryoprecipitate of the present disclosure may contain factor VIII in any amount within a range which has an upper limit of 480, 450, 400, 350, 300, 250, 225, 200, 175, 150, 125, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20 or 15 ME and independently selected lower limit of 10, 15, 20, 25, 30, 35 , 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200 or 225 ME, where the upper limit is greater than the lower limit. In other embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains at least 80 IU of factor VIII per unit (eg, 200 mL unit, per unit of cryoprecipitate obtained from approximately 200 mL of plasma) of cryoprecipitate. In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains at least 80 IU of factor VIII. In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains 80-100 IU of factor VIII per unit (eg, 200 mL unit, per unit of cryoprecipitate obtained from approximately 200 mL of plasma) cryoprecipitate. The content of factor VIII in the cryoprecipitate or cryoprecipitate composition of the present disclosure can be expressed per unit volume (eg, per unit cryoprecipitate obtained from approximately 200 ml of plasma) or as an absolute amount. In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains less than about 80 IU or less than about 50 IU of factor VIII per unit (e.g., a 200 mL unit, per unit of cryoprecipitate derived from about 200 mL of plasma) cryoprecipitate at the time of thawing ( for example, within about 1 hour or within about 2 hours after thawing). In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains less than about 80 IU or less than about 50 IU of factor VIII per unit of cryoprecipitate shortly before or at the time of infusion (e.g., up to about 1 day, up to about 3 days, up to about 5 days or up to approximately 7 days after thawing). In some embodiments, the cryoprecipitate or cry composition

- 21045773 precipitate of the present disclosure contains approximately less than 80 IU of factor VIII shortly before or at the time of infusion (eg, up to about 1 day, up to about 3 days, up to about 5 days, or up to about 7 days after thawing). In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains at least about 80 IU of factor VIII shortly before or at the time of infusion (e.g., up to about 1 day, up to about 3 days, up to about 5 days, or up to about 7 days after thawing) . In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains 80-100 IU of Factor VIII shortly before or at the time of infusion (e.g., up to about 1 day, up to about 3 days, up to about 5 days, or up to about 7 days after thawing). In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains about 80-240 IU (e.g., total IU) of factor VIII shortly before or at the time of infusion (e.g., up to about 1 day, up to about 3 days, up to about 5 days, or up to about 7 days after thawing). In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains about 80-480 IU (e.g., total IU) of factor VIII shortly before or at the time of infusion (e.g., up to about 1 day, up to about 3 days, up to about 5 days, or up to about 7 days after thawing). In some embodiments, the amount of factor VIII is determined from cryoprecipitate sampled within about 2 hours, within about 6 hours, within about 1 day, within about 2 days, within about 3 days, within about 4 days, or within approximately 5 days after thawing.

In some embodiments, the composition contains cryoprecipitate prepared from at least about 550 ml and about less than 650 ml of pathogen-inactivated plasma. In some embodiments, the composition contains two or more cryoprecipitates, each of the two or more cryoprecipitates derived from at least about 150 ml and about less than 250 ml of plasma, such as about 200 ml of plasma. In some embodiments, the cryoprecipitate prepared from at least about 550 mL and less than about 650 mL of pathogen-inactivated plasma contains between about 80 and about 200 IU of factor VIII, e.g., shortly before or at the time of infusion (e.g., up to about 1 day , up to approximately 3 days, up to approximately 5 days, or up to approximately 7 days after thawing). For example, in some embodiments, the cryoprecipitate prepared from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma contains between about 80 IU and about 200 IU factor VIII at the time of thawing (e.g., within about 1 hour or within approximately 2 hours after thawing). In some embodiments, the cryoprecipitate prepared from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma contains between about 80 IU and about 200 IU factor VIII, as determined within about 2 hours, within about 6 hours, at within about 1 day, within about 2 days, within about 3 days, within about 4 days, or within about 5 days after thawing.

In some embodiments, the composition comprises a first cryoprecipitate prepared from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma, and a second cryoprecipitate prepared from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma. In some embodiments, a composition comprising two cryoprecipitates, each derived from at least about 550 mL and less than about 650 mL of pathogen-inactivated plasma, contains between about 160 and about 400 IU of factor VIII, for example, shortly before or at the time of infusion (eg , up to approximately 1 day, up to approximately 3 days, up to approximately 5 days, or up to approximately 7 days after thawing). For example, in some embodiments, a composition comprising two cryoprecipitates, each derived from at least about 550 ml and about 650 ml of pathogen-inactivated plasma, contains between about 160 IU and about 400 IU factor VIII at the time of thawing (e.g., at within approximately 1 hour or within approximately 2 hours after thawing). In some embodiments, a composition comprising two cryoprecipitates, each derived from at least about 550 ml and about 650 ml of pathogen-inactivated plasma, contains between about 160 IU and about 400 IU factor VIII as determined within about 2 hours, in within about 6 hours, within about 1 day, within about 2 days, within about 3 days, within about 4 days, or within about 5 days after thawing.

In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure can be tested for fibrinogen. Various assays for measuring fibrinogen are known in the art, including, but not limited to, the Claus method, prothrombin-based assays

- 22 045773 of the present time, immunological tests and gravimetric tests. In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains an amount of fibrinogen that meets AABB standards. In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains at least about 100, at least about 150, at least about 200, at least about 250, or at least about 300 mg of fibrinogen per unit of cryoprecipitate (e.g., per unit of cryoprecipitate obtained from approximately 200 ml of plasma). In some embodiments, the composition that contains the cryoprecipitate of the present disclosure contains fibrinogen in an amount that is approximately less than any of the following amounts (mg, absolute, or per cryoprecipitate unit): 2500, 2000, 1800, 1500, 1200 , 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, or 150. In some embodiments, a composition that contains cryoprecipitate of the present disclosure contains fibrinogen in an amount that is approximately greater than or of the following amounts (in mg, absolute or per unit of cryoprecipitate): 140, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 70o, 750, 800, 850, 900 , 1000, 1100, 1200 or 1500. I.e. the composition which contains the cryoprecipitate of the present disclosure may contain fibrinogen in any amount within a range which has an upper limit of 2500, 2000, 1800, 1500, 1200, 750, 700, 650, 600, 550, 500, 450, 400 , 350, 300, 250, 200 or 150 mg and an independently selected lower limit of 140, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 1000, 1100, 1200 or 1500 mg, where the upper limit is greater than the lower limit. In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains at least about 250 mg or at least about 150 mg of fibrinogen per unit of cryoprecipitate (e.g., per unit of cryoprecipitate obtained from about 200 mL of plasma) at the time of thawing (e.g., at within approximately 1 hour or within approximately 2 hours after thawing). In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains at least about 250 mg or at least about 150 mg of fibrinogen per unit of cryoprecipitate (e.g., per unit of cryoprecipitate obtained from about 200 mL of plasma) shortly before or at the time of infusion (e.g. , up to approximately 1 day, up to approximately 3 days, up to approximately 5 days, or up to approximately 7 days after thawing). In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains at least about 250 mg or at least about 150 mg of fibrinogen at the time of thawing (eg, within about 1 hour or within about 2 hours after thawing). In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains at least about 750 mg of fibrinogen (e.g., mg total fibrinogen) shortly before or at the time of infusion (e.g., up to about 1 day, up to about 3 days, up to about 5 days, or about up to 7 days after thawing). In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains at least about 750 mg of fibrinogen (e.g., mg fibrinogen total) at the time of thawing (e.g., within about 1 hour or within about 2 hours after thawing). In some embodiments, the amount of fibrinogen is determined from cryoprecipitate sampled within about 2 hours, within about 6 hours, within about 1 day, within about 2 days, within about 3 days, within about 4 days, or within approximately 5 days after thawing.

In some embodiments, the composition contains cryoprecipitate prepared from at least about 550 ml and about less than 650 ml of pathogen-inactivated plasma. In some embodiments, the composition contains two or more cryoprecipitates, each of the two or more cryoprecipitates derived from at least about 150 ml and about less than 250 ml of plasma, such as about 200 ml of plasma. In some embodiments, the cryoprecipitate prepared from at least about 550 mL and less than about 650 mL of pathogen-inactivated plasma contains between about 700 mg and about 1000 mg fibrinogen, e.g., shortly before or at the time of infusion (e.g., up to about 1 day , up to approximately 3 days, up to approximately 5 days, or up to approximately 7 days after thawing). For example, in some embodiments, the cryoprecipitate prepared from at least about 550 mL and less than about 650 mL of pathogen-inactivated plasma contains between about 700 mg and about 1000 mg fibrinogen at the time of thawing (e.g., within about 1 hour or within approximately 2 hours after thawing). In some embodiments, the cryoprecipitate prepared from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma contains between about 700 mg and about 1000 mg fibrinogen, as determined within about 2 hours, within about 6 hours, within approximately 1 day, within approximately 2 days, within approximately 3 days, within

- 23 045773 approximately 4 days or within approximately 5 days after thawing.

In some embodiments, the composition comprises a first cryoprecipitate prepared from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma, and a second cryoprecipitate prepared from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma. In some embodiments, a composition comprising two cryoprecipitates, each derived from at least about 550 ml and about 650 ml of pathogen-inactivated plasma, contains between about 1400 mg and about 2000 mg fibrinogen, for example, shortly before or at the time of infusion (eg , up to approximately 1 day, up to approximately 3 days, up to approximately 5 days, or up to approximately 7 days after thawing). For example, in some embodiments, a composition comprising two cryoprecipitates, each derived from at least about 550 ml and about 650 ml of pathogen-inactivated plasma, contains between about 1400 mg and about 2000 mg fibrinogen at the time of thawing (e.g., within approximately 1 hour or within approximately 2 hours after thawing). In some embodiments, a composition comprising two cryoprecipitates, each derived from at least about 550 ml and about 650 ml of pathogen-inactivated plasma, contains between about 1400 mg and about 2000 mg fibrinogen, as determined within about 2 hours, in within about 6 hours, within about 1 day, within about 2 days, within about 3 days, within about 4 days, or within about 5 days after thawing.

In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure can be tested for vWF. Various assays for measuring vWF (such as vWF:RCo and vWF:Ag assays) are known in the art, including, but not limited to, vWF ELISA, platelet agglutination, flow cytometry, and latex immunoassays. In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains an amount of vWF that meets AABB standards. In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains at least about 80 IU, at least about 90 IU, at least about 100 IU, at least about 110 IU, at least about 120 IU, at least about 130 IU, at least about 140 IU, or at least about 150 IU vWF per unit of cryoprecipitate (eg, per unit of cryoprecipitate obtained from approximately 200 ml of plasma). In some embodiments, a composition that contains cryoprecipitate of the present disclosure contains vWF in an amount that is approximately less than any of the following amounts (in ME, absolute, or per cryoprecipitate unit): 450, 400, 350, 300, 250, 200, 150, 140, 130, 120, 110, 100 or 9o. In some embodiments, a composition that contains the cryoprecipitate of the present disclosure contains vWF in an amount that is approximately greater than any of the following amounts (in ME, absolute, or per cryoprecipitate unit): 80, 90, 100, 110, 120, 130, 140, 150, 200, 250, 300, 350 or 400. i.e. a composition that contains cryoprecipitate of the present disclosure may contain vWF in any amount within a range that has an upper limit of 450, 400, 350, 300, 250, 200, 150, 140, 130, 120, 110, 1θ0 or 90 ME and an independently selected lower limit of 80, 90, 100, 110, 120, 130, 140, 150, 200, 250, 300, 350 or 400 ME, where the upper limit is greater than the lower limit. In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains at least about 100 IU or at least about 150 IU vWF per unit of cryoprecipitate at the time of thawing (e.g., within about 1 hour or within about 2 hours after thawing). In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains at least about 100 IU or at least about 150 IU vWF per unit of cryoprecipitate shortly before or at the time of infusion (e.g., up to about 1 day, up to about 3 days, up to about 5 days or up to approximately 7 days after thawing).

In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure can be tested for factor XIII. Various assays are known in the art to measure factor XIII, including, but not limited to, the Berichrom assay, clot solubility assay, and factor XIII ELISA. In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains an amount of factor XIII that meets AABB standards. In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, or at least at least approximately 100 IU factor XIII per unit of cryoprecipitate (eg, per unit of cryoprecipitate obtained from approximately 200 ml of plasma). In some embodiments, the composition that contains the cryoprecipitate of the present disclosure contains factor XIII in an amount that is approximately less than

- 24 045773 or one of the following amounts (in ME, in absolute terms or per unit of cryoprecipitate): 300, 275, 250, 225, 200, 175, 150, 125, 100, 90, 80, 70, 60 or 50. In some In embodiments, the composition that contains the cryoprecipitate of the present disclosure contains factor XIII in an amount that is greater than approximately any of the following amounts (in ME, absolute or per cryoprecipitate unit): 40, 50, 60, 70, 80, 90 , 100, 125, 150, 175, 200, 225, 250 or 275. i.e. a composition which contains cryoprecipitate of the present disclosure may contain factor XIII in any amount within a range which has an upper limit of 300, 275, 250, 225, 200, 175, 150, 125, 100, 90, 80, 70, 60 or 50 ME and an independently selected lower limit of 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250 or 275 ME, where the upper limit is greater than the lower limit. In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains at least about 100 IU or at least about 150 IU of factor XIII per unit of cryoprecipitate at the time of thawing (e.g., within about 1 hour or within about 2 hours after thawing) . In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains at least about 100 IU or at least about 150 IU of factor XIII per unit of cryoprecipitate shortly before or at the time of infusion (e.g., up to about 1 day, up to about 3 days, up to about 5 days or up to approximately 7 days after thawing).

Any of the above amounts of cryoprecipitate components can be combined in any number or combination described herein. For example, in some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains less than about 80 IU or less than about 50 IU factor VIII per unit of cryoprecipitate and at least about 250 mg or at least about 150 mg of fibrinogen per unit of cryoprecipitate at the time defrosting (eg, within about 1 hour or within about 2 hours after thawing). In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure contains less than about 80 IU or less than about 50 IU of factor VIII per unit of cryoprecipitate and at least about 250 mg or at least about 150 mg of fibrinogen per unit of cryoprecipitate shortly before or at infusion (eg, up to about 1 day, up to about 3 days, up to about 5 days, or up to about 7 days after thawing).

In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure can be obtained from plasma other than group O plasma, such as group A, B, and/or AB plasma. In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure can be prepared from plasma of more than one type of ABO. In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure can be prepared from type A, B, and AB plasma.

In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure may be contained in a container of the present disclosure. In some embodiments, the container further includes a label indicating that the composition is suitable for use (eg, suitable for infusion) for up to about 1, 2, 3, 4, 5, 6, or 7 days after thawing.

Also provided herein is a cryoprecipitate produced by any of the methods of the present disclosure, for example, including one or more of the aspects and features described above in any order or combination.

Kits or industrial products of cryoprecipitates.

In some embodiments, the cryoprecipitate or cryoprecipitate composition of the present disclosure, or the cryoprecipitate or cryoprecipitate composition produced by the methods of the present disclosure, can be packaged in a kit or manufactured article. In some embodiments, the kit or article of manufacture may comprise a container, pathogen-inactivated cryoprecipitate, and instructions for using the pathogen-inactivated cryoprecipitate. In some embodiments, the kit or article of manufacture may comprise a container, a pathogen-inactivated cryoprecipitate, and a label indicating that the pathogen-inactivated cryoprecipitate is suitable for use for up to about 1 day, up to about 2 days, up to about 3 days, up to about 4 days, up to approximately 5 days, up to approximately 6 days, or up to approximately 7 days after thawing. In some embodiments, the kit or article of manufacture may further comprise any other material or device that can be used in treatment (eg, transfusion), including, without limitation, one or more containers, tubing, sterilants or equipment, cannulas, syringes, etc. .P.

In some embodiments, instructions may be for use of the pathogen-inactivated cryoprecipitate when infused into a patient. In some embodiments, the instructions may specify an expiration date for the cryoprecipitate, such as a date by which the cryoprecipitate should be used in a treatment (eg, infusion) after thawing. In some variants

- 25 045773 implementation instructions may indicate that cryoprecipitate is suitable for infusion into a patient for up to about 1 day, up to about 2 days, up to about 3 days, up to about 4 days, up to about 5 days, up to about 6 days or up to approximately 7 days after thawing. In some embodiments, the instructions may indicate that the cryoprecipitate is suitable for infusion into a patient over a period of up to about 6 hours, up to about 12 hours, up to about 24 hours, up to about 36 hours, up to about 48 hours, up to about 60 hours, up to about 72 hours, up to about 84 hours, up to about 96 hours, up to about 108 hours, up to about 120 hours, up to about 132 hours, up to about 144 hours, up to about 156 hours, or up to approximately 168 hours after thawing.

Cryoprecipitate methods.

Certain aspects of the present disclosure relate to methods of preparing cryoprecipitate for infusion into a patient. Certain aspects of the present disclosure relate to methods of infusing cryoprecipitate into a patient. It should be understood that any of the cryoprecipitate or cryoprecipitate compositions of the present disclosure may find use in any of the methods described herein. It should be understood that any of the features or aspects of the cryoprecipitate or cryoprecipitate compositions of the present disclosure described herein may find use in any of the methods described herein in any combination.

In some embodiments, methods of producing cryoprecipitate for infusion into a patient and/or methods of infusing cryoprecipitate into a patient may include producing cryoprecipitate or a cryoprecipitate composition of the present disclosure from pathogen-inactivated plasma. Any of the exemplary methods for producing cryoprecipitate from plasma (eg, pathogen-inactivated plasma) described herein (eg, above) or any methods for producing cryoprecipitate from plasma known in the art may be used. Any of the exemplary methods for inactivating pathogens in plasma described herein (eg, below) or any methods for inactivating pathogens in plasma known in the art can be used to create pathogen-inactivated plasma.

In some embodiments, methods of preparing cryoprecipitate for infusion into a patient and/or methods of infusing cryoprecipitate into a patient may involve freezing the cryoprecipitate or cryoprecipitate composition of the present disclosure, for example, as described above or as known in the art.

In some embodiments, methods of preparing cryoprecipitate for infusion into a patient and/or methods of infusing cryoprecipitate into a patient may involve thawing frozen cryoprecipitate or a cryoprecipitate composition of the present disclosure, for example, as described above or as known in the art. In some embodiments, the thawed cryoprecipitate or cryoprecipitate composition may be suitable for infusion into a patient as disclosed herein for at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days , at least about 5 days, at least about 6 days, or at least about 7 days after thawing. In some embodiments, the thawed cryoprecipitate or cryoprecipitate composition may be suitable for infusion into a patient as disclosed herein over at least about 6 hours, at least about 12 hours, at least about 24 hours, at least about 36 hours , at least about 48 hours, at least about 60 hours, at least about 72 hours, at least about 84 hours, at least about 96 hours, at least about 108 hours, at least about 120 hours, at least about 132 hours, at least about 144 hours, at least about 156 hours, or at least about 168 hours after thawing.

In some embodiments, methods of preparing cryoprecipitate for infusion into a patient and/or methods of infusing cryoprecipitate into a patient may include testing thawed cryoprecipitate (e.g., testing one or more representative random cryoprecipitate preparations) for factor VIII, for example, as disclosed herein or known in the art . In some embodiments, thawed cryoprecipitate may be tested for factor VIII prior to infusion. In some embodiments, the thawed cryoprecipitate may be tested for factor VIII before freezing. In other embodiments, methods of preparing cryoprecipitate for infusion into a patient and/or methods of infusing cryoprecipitate into a patient may avoid testing the thawed cryoprecipitate for factor VIII. In some embodiments, methods of preparing cryoprecipitate for infusion into a patient and/or methods of infusing cryoprecipitate into a patient may include testing the thawed cryoprecipitate for fibrinogen but not testing for factor VIII.

In some embodiments, methods of producing cryoprecipitate for infusion into a patient and/or methods of infusing cryoprecipitate into a patient may include testing thawed cryoprecipitate

- 26 045773 cipitate (eg, testing one or more representative random cryoprecipitate preparations) for fibrinogen, for example, as disclosed herein or known in the art. In some embodiments, thawed cryoprecipitate may be tested for fibrinogen prior to infusion. In some embodiments, the thawed cryoprecipitate may be tested for fibrinogen before freezing. In other embodiments, methods of preparing cryoprecipitate for infusion into a patient and/or methods of infusing cryoprecipitate into a patient may eliminate testing of thawed cryoprecipitate for fibrinogen.

In some embodiments, methods of producing cryoprecipitate for infusion into a patient and/or methods of infusing cryoprecipitate into a patient may comprise cryoprecipitate prepared from about 600 mL of pathogen-inactivated plasma, at least about 550 mL, and less than 650 mL of pathogen-inactivated plasma of at least from at least about 570 ml and less than 620 ml of pathogen-inactivated plasma or from at least about 600 ml and less than 650 ml of pathogen-inactivated plasma. Such cryoprecipitate can be obtained, for example, by forming a depot of several plasma volume units (eg, 200 ml volume unit, AABB volume unit to obtain 550-650 ml) or by forming a depot of several cryoprecipitates obtained from different plasma samples. Individual cryoprecipitates can be combined or pooled into a depot after the cryoprecipitate is prepared but before use, stored at room temperature or refrigerated and/or refrozen for storage; and/or individual plasma samples can be combined or pooled before receiving cryoprecipitate. In some embodiments, two or more cryoprecipitates can be combined before using, storing, and/or freezing the cryoprecipitate. In some embodiments, two or more cryoprecipitates can be combined after the cryoprecipitate has been frozen but before infusion.

In some embodiments, the methods of the present disclosure may further comprise infusion of the cryoprecipitate or cryoprecipitate composition of the present disclosure into a patient. Methods for infusing cryoprecipitate into a patient are well known in the art. In some embodiments, cryoprecipitate may be infused at a rate of about 1 mL, about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, or about 10 mL/min. or for a total duration of about 30 minutes to about 4 hours. In some embodiments, a cryoprecipitate depot (eg, equivalent to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 units) may be infused. In some embodiments, the infusion is sufficient to increase the patient's fibrinogen level by an amount from about 30 mg/dL to about 60 mg/dL, such as about 40 mg/dL. In some embodiments, the infusion is a transfusion. In addition, a description of cryoprecipitate infusion dosing, response, indications and preparation can be found, for example, in the American Red Cross Compendium of Transfusion Practice Guidelines, the disclosure of which is therefore incorporated by reference as it relates to cryoprecipitate infusion dosing, response, indications and preparation.

Also described herein are methods of preparing cryoprecipitate for infusion into a patient. In some embodiments, the methods include obtaining cryoprecipitate from pathogen-inactivated plasma (eg, as disclosed herein) and freezing the cryoprecipitate. In some embodiments, the methods include obtaining cryoprecipitate from pathogen-inactivated plasma (eg, as disclosed herein) and storing the cryoprecipitate at room temperature or refrigerated prior to use for infusion. In some embodiments, the cryoprecipitate is suitable for infusion into a patient for up to about 1, 2, 3, 4, 5, 6, or 7 days after thawing, as disclosed herein. In some embodiments, the cryoprecipitate is prepared from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma of the present disclosure. In certain embodiments, the cryoprecipitate is prepared from approximately 600 ml of pathogen-inactivated plasma of the present disclosure.

In some embodiments, the methods further comprise combining a first cryoprecipitate prepared from at least about 150 ml and less than about 250 ml (e.g., about 200 ml) of the pathogen-inactivated plasma of the present disclosure and a second cryoprecipitate prepared from at least about 150 ml and less than about 250 ml (eg, about 200 ml) of pathogen-inactivated plasma according to the present disclosure. In some embodiments, the methods further comprise combining a first cryoprecipitate prepared from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma of the present disclosure and a second cryoprecipitate prepared from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma according to the present disclosure. In some embodiments, the first and second cryoprecipitates are combined before freezing the cryoprecipitate. In certain embodiments, the first cryoprecipitate is obtained from approximately 600 ml of pathogen-inactivated plasma of the present disclosure, and wherein the second cryoprecipitate is obtained

- 27 045773 from approximately 600 ml of pathogen-inactivated plasma according to the present disclosure.

In some embodiments, the methods further comprise combining a first cryoprecipitate prepared from 1-3 (e.g., 3) units of pathogen-inactivated plasma of the present disclosure and a second cryoprecipitate prepared from 1-3 (e.g., 3) units of pathogen-inactivated plasma of the present disclosure . In some embodiments, the first and second cryoprecipitates are combined before freezing the cryoprecipitate.

In any of the methods of the present disclosure, the patient may be a human. In other embodiments, the patient may be a veterinary patient.

Cryoprecipitate processing.

Processing of cryoprecipitate and handling of blood products typically involves the use of blood-compatible bag systems that are well known in the art, as described, for example, in US Pat. opening blood bags and systems. In general, a blood handling system contains more than one plastic container, usually plastic bags, where the bags are integrally connected to a plastic tube. Some of the containers described herein include those plastic bags that are known for storing and handling blood products, including cryoprecipitates. Blood handling bags can typically be designed to hold various volumes of fluid, including but not limited to volumes ranging from 50 ml to 2 L, such as having a capacity of up to 1 L, a capacity of up to 1.5 L, or a capacity of up to 2 l. Examples of conventional blood collection bags include those with capacities of 350, 450 and 500 ml, among others. It is understood that when the method refers to a bag, it includes any such plastic bags used in handling blood. When such bags are referred to as a disposal bag, product bag, transfer bag, collection bag, or illumination bag, it is understood that these bags are typical blood handling bags or have similar properties to such bags. Plastic bags suitable for use in accordance with the present disclosure include, for example, those containing PL2410, as well as other suitable plastics known in the art. Plastic bag materials include polyvinyl chloride, polyolefins, ethylene vinyl acetate, ethylene vinyl acetate mixed with other plastics, and the like.

As disclosed herein, when a tube is described as connecting, for example, two bags of a treatment kit, it is understood that the tube may be connected at some point between them by another connection component between the two bags. For example, a disposal bag connected to a product bag by a tube includes where the tube contains a filter between the two bags, i.e. the tube is divided by a filter so that the fluid flows from one bag to the other through the tube and filter. In one example, the conduit connecting the disposal bag and the product bag may include a filter to remove any loose particles from the fluid flowing from the disposal device into the product bag, i.e. the tube divides or interrupts the filter between the bags. These filters are designed to remove any small particles that may exit the removal device while still allowing platelets to pass through the filter. The tube between the bags allows fluid to flow from one bag to another, which can be blocked to prevent flow until needed, for example, as part of the treatment, fluid in one bag can be prevented from flowing into the next bag until it does. will be needed for the next stage of the process. Essentially, an openable seal, such as a clip, stopper, valve, or the like, is contained in or on a tube connecting the bags, where the clip, stopper, valve, or the like can be selectively opened as needed, for example, to transfer fluid from one bag to another. next. In certain preferred embodiments, the tube between the bags contains a rupture seal, such as a rupture valve, and then breaking the rupture seal allows the blood solution to flow between the bags through the tube. It is understood that the breakable seal is within the connection between the containers, so that the sterility of the system is maintained. It is also understood that the tube containing the filter or seal includes where the tube may be interrupted by the filter or seal, for example, the tube extends from one bag and connects to the filter or seal (the inlet portion of the tube), and the tube extends from another portion of the filter or seal to to another bag (the exiting part of the tube). In this configuration, fluid flows from the first bag, through the inlet portion of the tube, through the filter or seal, and through the outlet portion of the tube and into the other bag.

Different bags within a blood bag system can be used for different stages of the process. For example, a bag system to be used to inactivate pathogens in a unit of cryoprecipitate or plasma may comprise a container with a pathogen-inactivating compound contained within, a bag for receiving the cryoprecipitate or plasma unit and a pathogen-inactivating compound (e.g., an illumination bag), a bag for illuminating the unit cryoprecipitate or plasma, when the method of inactivating pathogens involves illumination (for example, a bag for illumination and usually the same bag to contain the unit of cryoprecipitate or plasma and

- 28 045773 pathogen-inactivating compound), a bag for removing pathogen-inactivating compounds and/or their by-products from a processed unit of cryoprecipitate or plasma (for example, designated as a removal bag) and one or more bags for containing the final cryoprecipitate or plasma product , i.e. pathogen-inactivated cryoprecipitate or plasma unit having a concentration of the inactivating compound and/or its by-products reduced below the desired concentration, which is ready for use, can be stored for later use (for example, designated as a product bag) or in the case of plasma can be used for in order to create cryoprecipitate. Each bag in the system is typically made of plastic material. For example, the container containing the pathogen-inactivating compound solution may be made of a suitable plastic such as PL2411 (Baxter Healthcare) or other plastics such as polyvinyl chloride, polyolefins, ethylene vinyl acetate, ethylene vinyl acetate mixed with other plastics, and the like. This container is also wrapped in a material that is impermeable to light of the wavelength that activates the photoactive pathogen-inactivating compound (eg, a suitable plastic such as PL2420, Baxter Healthcare). The photoactivated pathogen-inactivating compound illumination bag requires a clean, durable thermoplastic material that transmits light of the selected wavelength. Suitable plastics that transmit light in the UVA wavelength range include polyvinyl chloride, polyolefins, ethylene vinyl acetate, ethylene vinyl acetate mixed with other plastics, or other mixtures of thermoplastic polymers. Such suitable plastics include PL2410 (Baxter Healthcare) and PL732 (Baxter Healthcare). Similar materials can be used to create a disposal bag and a product bag. Product bags include those made from PL2410. Suitable bag materials are discussed, for example, in PCT Publication No. WO 2003078023 and US Pat. No. 7,025,877, the disclosures of which are therefore incorporated by reference as they relate to such bag materials and related materials. In all cases, the materials used in preparing the treatment kit must be sterilizable by known methods, such as steam and gamma or electron beam irradiation, which are used to ensure the sterility of the treatment kit. Although these are exemplary materials for making bags, the methods described herein are applicable to processes using any suitable bag material as would be readily apparent to one skilled in the art, and can also be used with containers other than bags. Bags used for illumination, removal and storage are also designed to allow the passage of gases such as oxygen and carbon dioxide into and out of the blood bag so that the blood products within them have sufficient oxygen supply and carbon dioxide levels during processing and storage time.

Inactivation of pathogens.

Blood products, including cryoprecipitate or blood plasma products, may contain pathogens or may be contaminated with pathogens during processing. As such, it is desirable to subject such blood products to a specific process in order to reduce the risk of transfusion-transmitted diseases. In some embodiments, the plasma may be subjected to one or more treatments to inactivate pathogens (ie, pathogen inactivation). In some embodiments, the pathogen-inactivated plasma can then be used to produce cryoprecipitate, as disclosed herein. In some embodiments, the cryoprecipitate itself may be subjected to one or more treatments to inactivate pathogens (ie, pathogen inactivation).

Various methods are available to reduce the risk of transmission of transfusion-associated diseases in cryoprecipitate or blood products containing plasma. In addition to screening and detection of pathogens and subsequent elimination of contaminated blood products, processes are available that include treatments to inactivate pathogens (ie, pathogen inactivation) that may be present. Ideally, this process will result in the inactivation of a wide range of pathogens, such as viruses, bacteria and parasites, that may be present in blood products. In certain preferred embodiments, the pathogen inactivation method requires the addition of a specified amount of a pathogen-inactivating compound per unit of cryoprecipitate or plasma. For example, pathogen inactivation may involve the addition of a small molecule compound that inactivates various pathogens.

In some embodiments, inactivation of pathogens may involve photochemical inactivation (eg, photoinactivation), which involves adding a photosensitizer that, when activated by illumination using light of suitable wavelengths, inactivates various pathogens that may be present. Two such methods involve adding amotosalen or riboflavin to blood products followed by exposure to UV light. Other methods include illumination with UV light without the addition of a photosensitizer, as well as illumination using other photoactive compounds, including psoralen derivatives other than amotosalen, isoalloxazines other than riboflavin, alloxazines, dyes such as phthalocyanines, phenothiazine dyes (eg, methylene blue, azure B, azure C, thionine, toluidine blue), porphyrin derivatives (e.g., dihematoporphyrin ether, hematoporphyrin derivatives, benzoporphyrin derivatives, alkyl-substituted sapphirin), and merocyanine 540 (Prodouz et al.,

Blood Cells 1992, 18(1):101-14; Sofer, Gail, BioPharm, August 2002).

In some embodiments, pathogen inactivation is performed using the INTERCEPT® Blood System (Cerus), such as the INTERCEPT® Blood System for Plasma. The INTERCEPT® Blood System is well known in the art as a pathogen inactivation system that is widely available in European blood centers and has FDA approval in the United States. A more detailed description of the INTERCEPT® Blood System and methods for inactivating pathogens and compositions related thereto; see, for example, US Pat. Nos. 5399719, 5556993, 5578736, 5585503, 5593823, 5625079, 5654443, 5712085, 5871900, 5972593, 6004741, 6004742, 60176 91, 6194139, 6218100, 6503699, 6544727, 6951713, 7037642 and 7611831; and PCT Publications No. WO 1995000141, WO 1996014739, WO 1997021346, WO 1998030327, WO 1999034914 and WO1999034915, the disclosures of each of which are hereby incorporated by reference as they relate to the inactivation of pathogens in blood products.

As described above, plasma or cryoprecipitate can be subjected to pathogen inactivation. An exemplary process for using the INTERCEPT® Blood System to inactivate pathogens in plasma is as follows. A plasma sample (eg, containing one or more plasma units, AABB units) in an illumination container can be brought into contact with amotosalen from the amotosalen container (eg, by connecting through a tube and breaking the cannula of the amotosalen container to release amotosalen). Once the lighting container is sealed, it can be illuminated using UV according to the manufacturer's protocols. Once illuminated, the plasma can be transferred through a tube to one or more storage containers via a compound adsorption device (CAD). Optionally, if more than one plasma storage container is to be formed into a depot, they can be formed into a depot in a larger blood bag (e.g., a 600-650 ml bag for three plasma units, e.g., 200 ml units, AABB plasma units; such as 600 ml PVC transfer bag). The cryoprecipitate can then be prepared (eg, in a larger blood bag) as disclosed herein. The liquid plasma can then be removed, for example by pouring it into one or more bags. Optionally, more than one cryoprecipitate sample can be obtained; if so, individual cryoprecipitate samples can be combined in a single container using a sterile coupling/tube. The cryoprecipitate can then be frozen and stored. One skilled in the art will appreciate that alternative steps, combinations of steps, and order of steps can be followed.

In some embodiments, the plasma or cryoprecipitate may be pathogen inactivated in a container (eg, a blood bag or other container described herein) suitable for photochemical inactivation of the plasma under sterile conditions. This container may be interfaced with the CAD (eg, as described and/or mentioned above) such that plasma can be transferred from the container to the CAD under sterile conditions. In some embodiments, the CAD may further be interfaced with one or more second containers such that plasma can be transferred from the CAD to the one or more second containers under sterile conditions. For example, one 600 ml PVC transfer bag or another larger sized blood bag can be used for one second container, or more than one (e.g., three) smaller sized blood bags (e.g., the size of one AABB unit) can be used as second containers. One or more second containers may be suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow cryoprecipitate to form. In some embodiments, the third container may be interfaced with one or more second containers such that the pathogen-inactivated plasma can be transferred from the CAD in the one or more second containers to the third container under sterile conditions. The third container may be suitable for freezing the pathogen-inactivated plasma, followed by thawing the pathogen-inactivated plasma under conditions that allow cryoprecipitate to form. For example, pathogen-inactivated plasma from multiple (eg, three) second containers can be transferred to and combined within a larger third container (eg, 600-650 ml bag) to subsequently produce cryoprecipitate.

Other pathogen inactivation systems include, for example, those described in PCT publication No. WO 2012071135; WO 2012018484; WO 2003090794; WO 2003049784; WO 1998018908; WO 1998030327; WO 1996008965; WO 1996039815; WO 1996039820; WO 1996040857; WO 1993000005; US Patent Application No. US 20050202395; and US Pat. Nos. 8,296,071 and 6,548,242, the disclosures of which are therefore incorporated by reference as they relate to the inactivation of pathogens in blood products. When adding a compound to a blood product is used to inactivate pathogens, whether the method requires illumination or not, in some cases it is desirable to remove any residual pathogen-inactivating compound or by-products thereof.

Some pathogen inactivation methods may require the use of a removal device, i.e. devices for reducing the concentration of a pathogen-inactivating compound, such as a small organic compound, and its by-products in a unit of cryoprecipitate or plasma, while substantially maintaining the desired biological activity of the cryoprecipitate or plasma. In some cases, the removal device contains porous adsorbent particles in an amount sufficient to reduce the pathogen-inactivating compound below a desired concentration, where the adsorbent particles have an affinity for the pathogen-inactivating compound, where it is understood that such adsorbent particles can be selected to best manner to adsorb the compound or compounds to be removed with minimal effect on components that are not intended to be removed or damaged through contact with the adsorbent particles. Various adsorbent particles are known, generally including particles made from any natural or synthetic material capable of reacting with the compounds to be removed, including solid particles made from natural materials such as activated carbon, silica, diatomaceous earth and cellulose, and synthetic materials such as hydrophobic resins, hydrophilic resins or ion exchange resins. Such synthetic resins include, for example, carbonaceous materials, polystyrene, polyacrylic, polyacrylic ester, cation exchange resin and polystyrene-divinylbenzene. A detailed description of such removal devices suitable for use in the methods as disclosed herein can be found in PCT Publication Nos. WO 1996040857, WO 1998030327, WO 1999034914 and WO 2003078023, the disclosures of which are hereby incorporated by reference with respect to the discussion of such devices for removing and adsorbent particles and other materials used to obtain such devices. Exemplary adsorbent particles include, but are not limited to, Amberlite (Rohm and Haas) XAD-2, XAD-4, XAD-7, XAD-16, XAD-18, XAD-1180, XAD-1600, XAD-2000, XAD- 2010; Amberchrom (Toso Haas) CG-71m, CG-71c, CG-161m, CG161c; Diaion Sepabeads (Mitsubishi Chemicals) HP20, SP206, SP207, SP850, HP2MG, HP20SS, SP20MS; Dowex (Dow Chemical) XUS-40285, XUS-40323, XUS43493 (also referred to as Optipore V493 (dry form) or Optipore L493 (hydrated form)), Optipore V503, Optipore SD-2; Hypersol Macronet (Purolite) MN-100, MN-102, MN-150, MN-152, MN170, MN-200, MN-202, MN-250, MN-252, MN-270, MN-300, MN-400 , MN-500, MN-502, Purosorb (Purolite) PAD 350, PAD 400, PAD 428, PAD 500, PAD 550, PAD 600, PAD 700, PAD 900 and PAD 950. Material used to form the immobilized matrix , contains a low melting polymer such as nylon, polyester, polyethylene, polyamide, polyolefin, polyvinyl alcohol, ethylene vinyl acetate or polysulfone. In one example, the adsorbent particles immobilized in the matrix are in the form of a sintered medium. While it is understood that the methods and devices described herein include removal devices as known in the art, examples of such methods and devices include a removal device for amotosalen-inactivated blood product that is commercially available. Some such removal devices contain Hypersol Macronet MN-200 adsorbent contained within a sintered matrix, where the sintered matrix contains PL2410 plastic as a binder. In one embodiment, the removal device contains Hypersol Macronet MN-200 adsorbent in a sintered matrix containing PL2410, where Hypersol Macronet MN-200 is present in an amount of approximately 5 g dry weight equivalent.

Because different resins may require different processing when used to create removal devices that can be used in the methods and devices as disclosed herein, comparisons of amounts of adsorbent resins described herein, unless otherwise indicated, are comparisons of resins by dry mass. For example, resins are dried to <5% water before processing, and the dry weight equivalent of the adsorbent is used when comparing amounts of resin used. For example, Hypersol Macronet MN-200 is treated to stabilize the adsorbent, or what is commonly referred to as wetting the adsorbent, so that it can be directly used in contact with a unit of blood product. Such a wetted sample may contain, for example, approximately 50% glycerol or other suitable wetting agent. In some embodiments, the adsorbent resin is a polystyrene divinyl benzene resin. In some embodiments, the polystyrene-divinylbenzene resin is Hypersol Macronet MN-200. In some embodiments, the adsorbent is contained within a sintered matrix, where the sintered matrix contains a PL2410 binder. In some embodiments, Hypersol Macronet MN-200 adsorbent is contained within a sintered matrix to provide a removal device.

Preparation of cryosupernatant.

One skilled in the art will appreciate that in the process of creating the cryoprecipitate or cryoprecipitate composition of the present disclosure, a cryosupernatant is also produced or formed. Such cryosupernatant may have medical uses of interest, such as infusion into a patient.

As such, the present disclosure describes methods for preparing a cryosupernatant depot for infusion into a patient. In some embodiments, the methods include freezing at least the first pathogen-inactivated plasma and the second pathogen-inactivated plasma. In some

- 31 045773 embodiments, the first and second pathogen-inactivated plasmas have a combined volume of at least about 550 ml and about less than 650 ml. In some embodiments, each of the first and second pathogen-inactivated plasma has a volume of at least about 550 ml and about less than 650 ml. In some embodiments, the first and second pathogen-inactivated plasmas have a combined volume of approximately 600 mL. In some embodiments, the first and second pathogen-inactivated plasma each have a volume of approximately 600 mL. In some embodiments, three units (eg, AABB plasma units) may be used.

In some embodiments, the first and second pathogen-inactivated plasmas may then be thawed under conditions that allow the formation of cryoprecipitates (eg, as disclosed herein). In some embodiments, each cryoprecipitate may then be separated from its corresponding cryosupernatant. In some embodiments, the two cryosupernatants can then be combined to form a cryosupernatant depot.

In some embodiments, two cryosupernatant depots (obtained, for example, as described above) can be combined. For example, two cryosupernatant depots can be combined, wherein each cryosupernatant depot is prepared by combining a depot of cryosupernatants derived from pathogen-inactivated plasmas totaling at least about 550 ml and less than about 650 ml, for example, as described above. As such, in some embodiments, a cryosupernatant depot can be prepared from 1100-1300 ml of pathogen-inactivated plasma.

In some embodiments, the plasma or cryoprecipitate may be pathogen inactivated in a container (eg, a blood bag or other container described herein) suitable for photochemical inactivation of the plasma under sterile conditions. This container can be interfaced with the CAD (eg, as described and/or mentioned above) so that plasma can be transferred from the container to the CAD under sterile conditions. In some embodiments, this container may be interfaced with an additional (eg, upstream) container suitable for mixing one or more units of plasma with a pathogen-inactivating compound (eg, as described and/or mentioned herein). In some embodiments, the additional container is mated to the first container such that one or more units of plasma mixed with a pathogen-inactivating compound can be transferred from the additional container to the first container under sterile conditions. In some embodiments, the CAD may further be interfaced with one or more second containers such that plasma can be transferred from the CAD to the one or more second containers under sterile conditions. For example, one 600 ml PVC transfer bag or another larger sized blood bag can be used for one second container, or more than one (e.g., three) smaller sized blood bags (e.g., the size of one AABB unit) can be used as second containers. containers. One or more second containers may be suitable for freezing the pathogen-inactivated plasma, followed by thawing the pathogen-inactivated plasma under conditions that allow cryoprecipitate to form. In some embodiments, the third container may be interfaced with one or more second containers such that pathogen-inactivated plasma can be transferred from the CAD in the one or more second containers to the third container under sterile conditions. The third container may be suitable for freezing the pathogen-inactivated plasma, followed by thawing the pathogen-inactivated plasma under conditions that allow cryoprecipitate to form. For example, pathogen-inactivated plasma from several (eg, three) second containers can be transferred to a larger third container (eg, 600-650 ml bag) and pooled within it for subsequent cryoprecipitate production. In some embodiments, the cryosupernatant can be separated from the cryoprecipitate in one or more fourth containers (eg, one or more 600-650 ml bags). In some embodiments, the one or more fourth containers may be configured to interface with the one or more second containers or a third container, as described above, such that the supernatant can be transferred from the one or more second containers or the third container to the one or more fourth containers in sterile conditions to obtain a pathogen-inactivated cryosupernatant contained in one or more fourth containers and a pathogen-inactivated cryoprecipitate contained in one or more second containers or a third container.

Additionally, methods of infusing the cryosupernatant of the present disclosure into a patient are described herein.

Processing kits.

Certain aspects of the present disclosure apply to processing packages. The processing kits of the present disclosure may find use, inter alia, in the production of pathogen-inactivated cryoprecipitate, for example, as disclosed herein.

In some embodiments, the processing kit of the present disclosure comprises

- 32 045773 the first container in which the psoralen of the present disclosure can be photoactivated in the presence of one or more units of plasma under sterile conditions (for example, as described and/or mentioned in the present description). In some embodiments, the treatment kit further comprises a compound absorption device (CAD) coupled to the first container so that one or more units of plasma can be transferred from the first container to the compound absorption device under sterile conditions. In some embodiments, the processing kit further comprises one or more second containers. In some embodiments, each of the one or more second containers is interfaced with a compound absorption device such that one or more units of plasma can be transferred from the compound absorption device to the one or more second containers under sterile conditions, for example, to provide pathogen-inactivated plasma suitable for infusion to the patient. As non-limiting examples, the one or more second containers may include one 600 ml PVC transfer bag or another larger sized blood bag, or more than one (e.g., three) smaller sized blood bags (e.g., the size of one AABB unit) . In some embodiments, the one or more second containers are suitable for freezing the pathogen-inactivated plasma, followed by thawing the pathogen-inactivated plasma under conditions that allow the formation of a precipitate and supernatant.

In some embodiments, the treatment kit of the present disclosure further comprises a third container. In some embodiments, the third container is configured to interface with the one or more second containers such that the pathogen-inactivated plasma can be transferred from the one or more second containers to the third container under sterile conditions. In some embodiments, the third container is suitable for freezing the pathogen-inactivated plasma, followed by thawing the pathogen-inactivated plasma under conditions that allow the formation of a precipitate and supernatant. In some embodiments, the third container may be, for example, a 600-650 ml bag.

In some embodiments, the processing kit of the present disclosure further comprises one or more fourth containers. In some embodiments, the one or more fourth containers are configured to interface with one or more second containers, as described above, or with a third container, as described above, such that the supernatant can be transferred from the one or more second containers or the third container to one or more multiple fourth containers under sterile conditions, for example, to obtain the pathogen-inactivated cryosupernatant of the present disclosure contained in one or more fourth containers and the pathogen-inactivated cryoprecipitate of the present disclosure contained in one or more second containers or a third container. In some embodiments, the fourth container is suitable for storing the pathogen-inactivated cryoprecipitate of the present disclosure under conditions in which the pathogen-inactivated cryoprecipitate is frozen. In some embodiments, two or more fourth containers are used. Two or more fourth containers may be configured to interface with each other, wherein each of the two or more fourth containers contains pathogen-inactivated cryoprecipitate such that the cryoprecipitate contained in the two or more fourth containers can be combined in one of the two or more fourth containers. In some embodiments, the fourth container may be, for example, a 600-650 ml bag. Non-limiting examples of processing kits of the present disclosure are as follows.

In some embodiments, the treatment kit comprises a first container in which psoralen can be photoactivated in the presence of one or more units of plasma under sterile conditions; a compound absorption device (CAD) coupled to the first container such that plasma can be transferred from the first container to the compound absorption device under sterile conditions; one or more second containers, each of which is mated to a compound absorption device such that plasma can be transferred from the compound absorption device to the one or more second containers under sterile conditions to provide pathogen-inactivated plasma suitable for infusion into a patient; and a third container that is configured to interface with the one or more second containers such that the pathogen-inactivated plasma can be transferred from the one or more second containers to the third container under sterile conditions. In some embodiments, the one or more second containers are suitable for freezing the pathogen-inactivated plasma, followed by thawing the pathogen-inactivated plasma under conditions that allow the formation of a precipitate and a supernatant. In some embodiments, the third container is interfaced with one or more second containers such that the supernatant can be transferred from the one or more second containers to the third container under sterile conditions to produce a pathogen-inactivated cryosupernatant contained in the third container and a pathogen-inactivated cryoprecipitate contained in od

- 33 045773 number or several second containers.

In other embodiments, the treatment kit comprises a first container in which psoralen can be photoactivated in the presence of one or more units of plasma under sterile conditions; a compound absorption device (CAD) coupled to the first container such that plasma can be transferred from the first container to the compound absorption device under sterile conditions; one or more second containers, each of which is mated to a compound absorption device such that plasma can be transferred from the compound absorption device to the one or more second containers under sterile conditions to provide pathogen-inactivated plasma suitable for infusion into a patient; a third container that is configured to interface with the one or more second containers such that the pathogen-inactivated plasma can be transferred from the one or more second containers to the third container under sterile conditions; and one or more fourth containers, each configured to interface with the third container such that the supernatant can be transferred from the third container to the one or more fourth containers under sterile conditions to produce a pathogen-inactivated cryosupernatant contained in the one or more fourth containers , and pathogen-inactivated cryoprecipitate contained in the third container. In some embodiments, the third container is suitable for freezing the pathogen-inactivated plasma, followed by thawing the pathogen-inactivated plasma under conditions that allow the formation of a precipitate and supernatant.

Additional non-limiting examples of processing packages are illustrated in FIGS. 1A-3B. An exemplary processing set 100 shown in FIG. 1A includes an optional plasma bag 102 containing donor plasma to be pathogen inactivated, a container 104 that contains a pathogen inactivating compound (PIC, e.g., psoralen), and a plasma photoactivation bag 106 (e.g., the first container of the present disclosure). The photoactivation bag 106 interfaces with the CAD 108 via a tube 110 that allows the photoactivation plasma to be transferred to the CAD. The CAD 108 in turn interfaces with three smaller blood bags 112, 114 and 116 (e.g., the second containers of the present disclosure) via a tube 118 that allows plasma to pass through the CAD (e.g., to remove free photoproducts and/or pathogen-inactivating compound , unreacted) before collection in smaller blood bags. Also depicted are an optional larger plasma freezing bag 122 for forming cryoprecipitate (e.g., the third container of the present disclosure) and an optional larger bag 124 for separating the cryoprecipitate from the cryosupernatant (e.g., the fourth container of the present disclosure), which can be sterilely docked (e.g., using a sterile connection 126) with tubing between CAD 108 and tee entry 120 of tubing 118 after collecting PI plasma in three bags.

An alternative configuration of processing kit 100 is shown in FIG. 1B, wherein the cryoprecipitate is separated from the cryosupernatant by flowing the cryosupernatant from the sterile-stacked third container 122 back into three smaller blood bags 112, 114 and 116 (e.g., the second containers of the present disclosure) rather than into the optional fourth container 124.

Another alternative configuration of processing kit 100 is shown in FIG. 1C. This configuration includes an optional container 128 that is sterilely connected or docked to a third container 122 via a sterile connection 130. This configuration allows two cryosupernatant preparations derived from pathogen-inactivated plasma (eg, those obtained in 122 and 128) to be combined.

An exemplary processing set 200 shown in FIG. 2A, includes an optional plasma bag 202 containing donor plasma to be inactivated for pathogens, a container 204 that contains a pathogen inactivating compound (PIC), a photoactivation bag 206, and a CAD 208 coupled to the photoactivation bag 206 using tubing 210 as described. above, and an additional pre-attached (e.g., built-in) third container 222. After collecting pathogen-inactivated plasma in three bags 212, 214, and 216, the three units of PI plasma are pooled into the depot by transferring to a larger bag 222 (e.g., third container at present disclosure) for freezing to form cryoprecipitate, and for separating the cryoprecipitate from the cryosupernatant. As shown in FIG. 2B, a cryosupernatant bag 224 (eg, the fourth container of the present disclosure) can be used to collect the cryosupernatant after freezing (this is depicted as an optional component in FIG. 2A). This cryosupernatant bag can be connected to a larger freezing bag via 226 tubing with a common tubing clamp. An alternative configuration is shown in FIG. 2C, wherein the cryoprecipitate is separated from the cryosupernatant by flowing the cryosupernatant back into three smaller blood bags 212, 214 and 216 (e.g., the second containers of the present disclosure) using tubing 228 rather than into the fourth container 224 shown in FIG. 2B.

The exemplary processing set 300 shown in FIG. 3A, includes an optional plasma bag 302 containing donated plasma to be inactivated for pathogens.

- 34 045773 ner 304, which contains a pathogen inactivating compound (PIC), a photoactivation bag 306, and a CAD 308 coupled to the photoactivation bag 306 using a tube 310 as described above. However, in this example, one larger (eg, 800 ml) bag 312 (eg, the third container of the present disclosure) replaces three smaller bags (eg, 212, 214, and 216). This bag 312 can be used to collect pathogen-inactivated plasma after photoactivation and freeze/thaw to produce cryoprecipitate. The optional cryosupernatant bag (e.g., 314), also depicted, may be a pre-attached (e.g., built-in) portion of the kit with a clamp 316, or alternatively, it may be sterilely docked after collection of the PI plasma. In fig. 3B, this cryosupernatant bag 314 (eg, the fourth container of the present disclosure) is an integral part of the kit 300 interfaced with the cryoprecipitate bag 312 (eg, via tubing and tubing clamp 316) and used to collect the cryosupernatant.

In any of the processing kits of the present disclosure, the first container (eg, 106, 206 and/or 306) and CAD (eg, 108, 208 and/or 308) can be sterilely separated from the remaining components, such as PI plasma and cryoprecipitate containers ( e.g. 112, 114, 116, 212, 214, 216 and/or 312), e.g. before freezing.

As disclosed herein, in some embodiments, two or more cryoprecipitate preparations of the present disclosure can be combined or pooled into a depot. An exemplary method 400 for this depot formation is shown in FIG. 4. Containers 402 and 404 contain first and second cryoprecipitate preparations, respectively. They are combined in Fig. 4 via sterile joining, for example using a sterile connection 406. The method illustrated in FIG. 4 can be applied to any of the cryoprecipitate preparations described herein, for example, cryoprecipitate preparations obtained from pathogen-inactivated plasma contained in containers 122, 222 and/or 312.

An exemplary processing set 500 is shown in FIG. 5. The integrated processing kit 500 makes it possible to prepare and combine or depot two larger size cryoprecipitate preparations, for example, as disclosed herein. Treatment kit 500 includes one or more optional plasma containers (eg, as illustrated by optional plasma container 502). Container(s) 502 are mated to container 504 that contains a pathogen inactivating compound (PIC). The pathogen-inactivated plasma is then divided between first and second photoactivation bags 506 and 508 (respectively), which in turn are coupled to first and second CADs 510 and 512 (respectively). CADs 510 and 512 are then coupled to first and second bags 514 and 516 (respectively), which are used to collect pathogen-inactivated plasma after photoactivation and freeze/thaw to produce cryoprecipitate. For example, in some embodiments, 514 and/or 516 are larger sized bags (eg, 800 ml) (eg, third containers of the present disclosure) similar to bag 312 described above. Bag 514 is connected (eg, via tubing 518) to cryosuppernatant bags 520, 522 and 524 (eg, the fourth containers of the present disclosure) to collect cryosuppernatant plasma. Likewise, bag 516 is connected (eg, via tubing 528) to cryosuppernatant bags 530, 532, and 534 (eg, the fourth containers of the present disclosure) to collect cryosuppernatant plasma. In some embodiments, bags 514 and 516 are themselves connected via tubing 526, for example, to allow combination or depot of pathogen-inactivated cryoprecipitate preparations contained therein.

An exemplary processing set 600 is shown in FIG. 6. Integrated processing kit 600 is another configuration that allows two larger size cryoprecipitate preparations to be prepared and combined or depoted, for example, as disclosed herein. Treatment kit 600 includes one or more optional plasma containers (eg, as illustrated by optional plasma container 602). Container(s) 602 are mated to container 604 that contains a pathogen inactivating compound (PIC). The container 604 is then mated to a mixing container 606, which is used to contain the plasma/PIC mixture (optionally, as depicted in FIG. 6, the container 602 can be mated directly to the mixing container 606 without 604 as an intermediary). The plasma/PIC mixture is then divided between the first and second bags 608 and 610 for photoactivation (respectively). After photoactivation, the separated plasma/PIC mixtures are then passed through CAD 612 and into a bag 614, which is used to collect pathogen-inactivated plasma after photoactivation and freeze/thaw to produce cryoprecipitate. In some embodiments, pouch 614 is a larger (eg, 800 ml) pouch (eg, the third container of the present disclosure) similar to pouch 312 described above. One or more cryosupernatant bags (eg, bags 616, 618, 620, 622, 624 and 626) are connected to bag 614 to collect cryosupernatant plasma.

An exemplary processing set 700 is shown in FIG. 7. The integrated processing kit 700 allows multiple cryoprecipitate preparations to be combined or depoted into

- 35 045773 one cryoprecipitate depot, which can then be subjected to pathogen inactivation to obtain a pathogen-inactivated cryoprecipitate depot.

Advantageously, this allows multiple cryoprecipitate preparations to undergo pathogen inactivation at the same stage. As shown in FIG. 7, multiple cryoprecipitate preparations 702 are combined into a cryoprecipitate depot 704. In some embodiments, 702 contains 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 separate cryoprecipitate preparations. In some embodiments, each cryoprecipitate preparation of 702 is between about 40 ml and about 60 ml. The cryoprecipitate depot 704 is then paired with a container 706 that contains a pathogen inactivating compound (PIC). Container 706 is interfaced with a photoactivation bag 708, which is interfaced with a CAD 710. After the cryoprecipitate is mixed with the PIC, photoactivated, and passed through the CAD 710, the pathogen-inactivated cryoprecipitate depot enters the container 712. In some embodiments, the pathogen-inactivated cryoprecipitate depot is frozen and/or or stored in container 712.

It should be understood that any of the treatment kits of the present disclosure may be used in any of the methods of the present disclosure or used to accommodate and/or process any of the cryoprecipitates, cryoprecipitate compositions, and/or cryosupernatants of the present disclosure. .

The disclosure is further illustrated by the following examples, which should not be construed as limiting the scope and spirit of the disclosure to the specific procedures described therein.

Examples

Example 1. Preparation of pathogen-inactivated cryoprecipitate.

Several units of blood group O negative liquid plasma from the collection day were pooled into a depot and divided to obtain multiple units of plasma for processing, each with a final volume of 585 to 650 mL. Inactivation of pathogens and production of cryoprecipitate was carried out using depot plasma units. Plasma was photochemically inactivated for pathogens using the commercially available INTERCEPT Blood System for Plasma (Cerus Corporation). When a depot of four units was treated with INTERCEPT, the pathogen-inactivated plasma collected in 3 storage bags from the INTERCEPT treatment kit was transferred to one 1000 mL transfer bag as large volume unit preparations. A depot of two additional units that was treated with INTERCEPT was stored in 3 storage bags as individual preparations of individual smaller units. Pathogen-inactivated plasma units were then frozen at 30°C for use in cryoprecipitate preparation.

To obtain cryoprecipitate, units were thawed in a temperature-controlled water bath of 4°C, with a total melting time of approximately 6 hours 30 minutes for large cryo units and 4 hours 30 minutes for individual cryo units. Thawed units were centrifuged for 12 min at 4°C at 4200 rcf, with slow deceleration. Cryosupernatants were removed from cryoprecipitates while retaining a small amount of plasma for resuspension. After resuspension, cryoprecipitate units were frozen for storage at -30°C.

Frozen stored units of cryoprecipitate were thawed in a Helmer plasma thawer set at 35°C until the cryoprecipitate was completely dissolved with no visible particles of material. Thawed units were stored in a temperature-controlled room at 22°C, with samples removed at specified intervals of <2, 6, 24 h, and 5 days for analytical testing. Samples were tested for factor VIII (FVIII) and fibrinogen (FIB), the results are shown below in table. 1.

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Table 1

Fibrinogen and factor VIII in cryoprecipitate preparations

Large volume (n=4), 60.2+4.9 ml 2 hours 6 hours 24 hours day 5 FIB in cryo (mg) 492.7+70.7 498.7+74.0 501.3 +61.46 482.9+74.8 FIB in cryo (mg/unit*) 181.2+24.3 18 3.5+2 6.6 184.4+21.22 17 7.6 +26.7 FVIII in cryo (ME) 182.6+37.9 176, 3+26, 9 177.6+73.4 145.7+37.5 FVIII in cryo (IU/unit*) 67.2+13.7 64.9+9.6 65.2+26.6 53.6+13.5 Single unit (n=2), 24.1+11.5 ml 2 hours 6 hours 24 hours 5 days FIB in cryo (mg) 315.4+49.1 315.5+ 38.8 301.2 +35.4 274.2+55.3 FIB in cryo (mg/unit*) 192.6+4.2 183.5+26.6 184.4+3.1 167.0 +11.4 FVIII in cryo (ME) 94.5+32.5 89.2+40.0 82.4+33.0 69.3+40.0 FVIII in cryo (IU/unit*) 57.0+12.2 53.4+17.3 49.5+13.5 41.1+19.0

*Based on the volume of an AABB unit of 200 ml.

Example 2. Preparation of pathogen-inactivated cryoprecipitate.

Several units of plasma obtained from group A blood donors were pooled into depots to produce plasma preparations with volumes of approximately 650 mL each (eg, large volume). Inactivation of pathogens and production of cryoprecipitate was carried out using depot plasma units. Plasma was photochemically inactivated for pathogens using the commercially available INTERCEPT Blood System for Plasma (Cerus Corporation) to obtain three individual units of pathogen-inactivated plasma (PI plasma) from each depot. Three units of PI plasma (3 containers, see, for example, 112, 114 and 116 in Fig. 1B) that were created from each INTERCEPT treatment kit were combined by transfer into one 600 ml transfer bag and frozen at 30°C for use in obtaining cryoprecipitate.

To obtain cryoprecipitate, depot units were thawed in a temperature-controlled water bath of 4°C for a total melting time of approximately 6 h 15 min. Thawed units were centrifuged for 12 min at 4°C at 4200 rcf, with slow deceleration. Cryosuppernatant plasma supernatants were removed from the cryoprecipitates by transfer to three previous containers, 60 ml of plasma was added back to the cryoprecipitate for resuspension, and cryoprecipitate units were frozen for storage at -30°C.

Frozen stored units of cryoprecipitate were thawed in a Helmer plasma thawing system at 37°C, with the cryoprecipitate completely dissolved without visible particles of material. Thawed units were stored in a temperature-controlled room at 22°C, with samples removed at specified intervals at least 5 days after thawing for analytical testing of factor VIII (FVTII) and fibrinogen (FIB), the results of which are presented below in table. 2.

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table 2

Fibrinogen and factor VIII in cryoprecipitate preparations

< 2 h 6 hours 24 hours 48 h FIB in cryo (mg) Rev. cryo 1 960.5 926.5 942.0 937.8 Rev. cryo 2 661.4 676.0 670.0 683.3 FVIII in cryo (ME) Rev. cryo 1 273, 8 277, 6 277.9 188.1 Rev. cryo 2 252.9 260, 8 248.9 174.2

Example 3. Preparation of PI cryoprecipitate and cryosupernatant plasma.

Pathogen inactivated (PI) cryoprecipitate and cryosuppernatant plasma supernatant were obtained in the form of three incoming large-volume depots (647 + 2 ml) from 2-3 units of ABO-matched plasma, which was obtained from whole blood, in CPD anticoagulant within 8 hours of collection .

Plasma depots were subjected to photochemical pathogen inactivation using amotosalen and UVA in the commercially available INTERCEPT Blood System for Plasma. Baseline samples were collected prior to INTERCEPT treatment and pathogen inactivation was performed according to the manufacturer's package insert. Three PI units of plasma (3 containers; see, for example, 112, 114 and 116 in Fig. 1B) that were created from each INTERCEPT treatment kit were combined by sealing over the connection, sterile connection of the 600 ml transfer bag and electric current transfer gravity. After sample collection, pathogen-inactivated plasma preparations were flash frozen and stored at -30°C for use in cryoprecipitate preparation.

To obtain cryoprecipitate, frozen plasma was thawed in a water bath at 4°C for approximately 12 hours and centrifuged at 4000xg for 12 minutes to pellet the cryoprecipitate. Cryosuppernatant plasma was removed using a plasma expressor and transferred back into three plasma bags from the INTERCEPT treatment kit, leaving approximately 60 mL of plasma to resuspend the cryoprecipitate. The cryoprecipitate bag and CPP bags were separated and sealed using a tube sealant and frozen at -30°C for storage.

For characterization, frozen cryoprecipitate and cryosupernatants were thawed at 37°C in a QuickThaw™ Plasma Thawing System (Helmer, Noblesville, IN) and left at room temperature (22°C, 2 units) or refrigerated (4°C, 1 unit) for sterile collection of samples at time points 0, 6, 24 hours, days 3 and 5 after thawing for analytical testing. In vitro assays to characterize cryoprecipitate and cryosuppernatant plasma included total fibrinogen and factor VIII as measured in diluted samples using an AMAX coagulation analyzer. In table Table 3 shows the total content of fibrinogen and FVTII factor for each of the three cryoprecipitate preparations.

Table 3

Fibrinogen and factor VIII in cryoprecipitate preparations

0 h 6 hours 24 hours D3 D5 FIB in cryo (mg) Rev. cryo 1 (22°C) 901 857 887 ND 887 Rev. cryo 2 (22°C) 788 908 ND 771 995 Rev. cryo 3 (4°C) 772 896 969 ND 907 FVIII in cryo (ME) Rev. cryo 1 (22°C) 278 319 280 ND 286 Rev. cryo 2 (22°C) 319 347 ND 268 229 Rev. cryo 3 (4°C) 316 307 322 ND 218

ND: not defined.

Fibrinogen and factor VIII were also determined in cryosuppernatant plasma using the same method. At time 0 h, fibrinogen levels were 772, 746, and 736 mg total for formulations 1, 2, and 3, respectively. Also, at time 0 h, the FVTII content was 54, 46 and 70 IU total for drugs 1, 2 and 3, respectively.

Example 4. Preparation of PI cryoprecipitate and cryosupernatant plasma.

Pathogen-inactivated (PI) cryoprecipitate and cryosupernatant plasma were obtained as a large volume (585 to 650 ml) of whole blood-derived FFP input, PF24, according to

- 38 045773 obtained from whole blood, or apheresis plasma (apheresis FFP), obtained from blood donors of groups A, B and/or O. Six repetitions were obtained from a depot of 5-6 units of plasma of one group, obtained from whole blood, which was collected in anticoagulant CP2D to obtain approximately 1700 ml. The plasma depot was divided into two components (target 625+25 ml, FFP and PF24) and stored at room temperature for up to 8 hours (FFP) or 24 hours (PF24) before subjecting the plasma to photochemical pathogen inactivation using commercially available INTERCEPT Blood System and freezing. Two units were retained as untreated controls without pathogen inactivation (target 215-235 ml, FFP and PF24). Additionally, six replicates of apheresis plasma were collected in ACD anticoagulant from a maximum of two donors per group and divided into two components: one (target 625+25 ml), which was stored at room temperature for up to 8 hours before subjecting the plasma to pathogen inactivation and freezing, and the other, which was kept as an untreated control. Baseline samples were collected prior to INTERCEPT treatment and pathogen inactivation was performed according to the manufacturer's package insert. Three units of PI plasma (3 containers, see, for example, Fig. 1B) that were created from each INTERCEPT treatment kit were combined by transfer into one 800 ml transfer bag (Terumo) and frozen for use in the preparation of cryoprecipitate. Controls were frozen without treatment to inactivate pathogens.

To obtain the cryoprecipitate, the combined frozen plasma was thawed in a temperature-controlled refrigerator of 2-6°C, with a total thawing time of approximately 24 hours. The thawed plasma was centrifuged to pellet the cryoprecipitate, and the supernatants of the cryoprecipitate were removed from the cryoprecipitate using a plasma expressor and transferred to three previous containers, leaving enough plasma to obtain approximately 60 ml of resuspended cryoprecipitate, the cryoprecipitate bag was separated from the three cryosupernatant plasma bags using a tube sealer, and the cryoprecipitate and CPP units were frozen for storage.

For characterization, frozen cryoprecipitate and cryosupernatants were thawed at 37°C in a QuickThaw™ Plasma Thawing System (Helmer, Noblesville, IN) and left at room temperature (20–24°C) for sterile sampling at time points 0, 24, and 120 h. after thawing for analytical testing. In vitro assays for cryoprecipitate and/or cryosupernatant include a panel of coagulation parameters (e.g., PT, aPTT, thrombin generation), coagulation factors, and hemostatic proteins (e.g., fibrinogen, factors II, V, VII, VIII (VIII:C), IX, X, XI, XIII, vWF, ADAMTS-13) and other proteins and markers and/or functions (eg, antithrombin III, protein C, protein S, a-2-PI, thrombin-antithrombin complexes, factor VIIa, NAPTT , C3a, Ig, ROTEM).

FVIII, FXIII and fibrinogen were analyzed using an AMAX Destiny Plus coagulation analyzer and Stago Diagnostic reagents. The following tables. 4 and 5 contain total fibrinogen and FVIII at time points 0, 24 and 120 hours after thawing cryoprecipitate product containers derived from whole blood derived FFP, whole blood derived PF24 and apheresis derived FFP with ABO blood types. as listed, and confirm the extended shelf life after thawing for cryoprecipitate as disclosed herein.

Table 4

Total fibrinogen content (mg) after storage after thawing

Plasma unit t=0 t=24 h t=120 h WBD FFP group 0 Average 758 786 793 SD 192.4 229, 8 183, 8 WBD FFP group A Average 767 827 794 SD 91.0 52.7 81, 6 WBD FFP all groups Average 762 806 794 SD 134.7 150, 8 127.2 PF24 group 0 Average 762 768 775 SD 150.5 183, 1 196, 7 PF24 group A Average 693 682 695 SD 77.0 97.3 64.5 PF24 all groups Average 728 725 735 SD 113.5 139.5 138.1

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Aph FFP group O Average 923 914 963 SD 195, 3 281.2 239, 1 Aph FFP group A and B Average 954 1041 1052 SD 17.2 93, 4 100.7 Aph FFP All groups Average 942 978 1008 SD 99, 9 186, 1 158.3

Table 5

Total factor VIII content (ME) after storage after thawing

Plasma unit t=0 t=24 h t=120 h WBD FFP group 0 Average 178 158 138 SD 50, 7 46.8 5, 1 WBD FFP group A Average 226 195 204 SD 30, 7 34.9 45.5 WBD FFP all groups Average 202 176 171 SD 45, 7 42.2 46, 2 PF24 group O Average 197 175 168 SD 14.7 12, 6 6, 5 PF24 group A Average 197 211 243 SD 14.7 14, 1 32.7 PF24 all groups Average 197 193 206 SD 13.2 23.3 45, 9 Aph FFP group 0 Average 184 72 67 SD 52.4 16.8 18.8 Aph FFP group A and B Average 269 110 100 SD 65, 9 48.8 29, 0 Aph FFP All groups Average 235 91 83 SD 70, 8 37.0 27, 6

Example 5. PI cryoprecipitate from two cryo preparations.

The pathogen-inactivated cryoprecipitate compositions of the present disclosure can be combined to produce a cryoprecipitate composition with higher levels of desired factors, such as, for example, fibrinogen and factor VIII. More specifically, the first cryoprecipitate is prepared from a large input volume of approximately 600 ml FFP (eg, 2-3 units, depot) that is subjected to pathogen inactivation (eg, INTERCEPT Blood System) as described above in Example 2 and illustrated in FIG. 1B. After precipitation of the cryoprecipitate, the cryosupernatant is transferred back to three storage containers, leaving enough plasma to resuspend the cryoprecipitate in approximately 35 ml. In addition, a second cryoprecipitate is prepared from a large input volume of approximately 600 ml FFP (eg, 2-3 units, depot) of the same type of ABO as the first cryoprecipitate and is processed to inactivate pathogens in a similar manner. The second cryoprecipitate container is separated from the three cryosupernatant plasma bags using a tube seal before combining with the first cryoprecipitate (Figure 1C). The second cryoprecipitate (labeled cryoprecipitate #2) is connected using a sterile coupling device to the first cryoprecipitate container, which is also separated from its corresponding three cryosupernatant plasma bags, and the two cryoprecipitate preparations are combined by transfer before being re-frozen or stored at room temperature for use .

Example 6. Preparation of a depot of pathogen-inactivated cryoprecipitate.

In another method for producing the improved cryoprecipitate of the present disclosure, pathogen-inactivated (PI) cryoprecipitate is obtained from cryoprecipitate depot units. For example, in one embodiment, ten cryoprecipitate units are individually prepared from frozen FFP units derived from whole blood of the same ABO type. Plasma units are thawed for

- 40 045773 temperature-controlled water bath at 4°C and centrifuge for 12 minutes at 4°C at 4200 rcf, with slow deceleration. Cryosuppernatant plasma supernatants are removed from the cryoprecipitate using a plasma expressor, leaving enough plasma to completely resuspend the cryoprecipitate in approximately 50 ml units. The extruded cryosuppernatant plasma is transferred to a separate container and stored frozen for use such as plasma fractionation. Containers containing cryoprecipitate units are connected using a sterile connecting device to ensure aseptic transfer and integration of the contained cryoprecipitate into the depot. After pooling in the depot, approximately 500 ml of cryoprecipitate is subjected to photochemical inactivation of pathogens using amotosalen and UVA in the treatment kit (eg, Fig. 7, INTERCEPT Blood System for Plasma). Pathogen-inactivated cryo (PI cryo) is stored frozen at -30°C until use.

Example 7. Preparation of pathogen-inactivated cryoprecipitate.

Several units of plasma obtained from blood donors were pooled into a depot to produce plasma preparations of approximately 650 mL each. Inactivation of pathogens and production of cryoprecipitate was carried out using depot plasma units. Plasma is subjected to photochemical inactivation of pathogens using the commercially available INTERCEPT Blood System for Plasma (Cerus Corporation). The PI plasma generated in the INTERCEPT processing kit is transferred into one large container (see, for example, 800 ml bag 312 in FIG. 3B), which is frozen at -30°C for use in preparing cryoprecipitate.

To obtain cryoprecipitate, frozen PI plasma is thawed in a temperature-controlled water bath at 4°C, with a total melting time of approximately 6 h 30 min for a large cryo unit. The thawed product is centrifuged for 12 minutes at 4°C at 4200 rcf, with a slow deceleration. The cryosupernatant is removed from the cryoprecipitate (see, for example, bag 314 in FIG. 3B), leaving a small amount of plasma for resuspension. After resuspension, the cryoprecipitate is frozen for storage at -30°C.

All sources, including publications, patent applications and patents cited herein, are hereby incorporated by reference to the same extent as if each source had been individually and specifically indicated for inclusion by reference and set forth herein in its entirety.

The use of the singular number (particularly in the context of the following claims) should be understood to refer to both the singular and the plural unless otherwise indicated in the specification or clearly inconsistent with the context. The terms containing, having, and including are to be construed as open-ended terms (i.e., including by way of non-limiting examples) unless otherwise noted. Wherever an open term is used to describe a feature or element, it is specifically contemplated that a closed term may be used in place of an open term without departing from the spirit and scope of the disclosure. The listing of ranges of values in this specification is intended only to serve as a shorthand way of individually indicating each individual value falling within the range unless otherwise stated herein, and each individual value is included in the specification as if it were individually listed in the present description. All methods described herein can be performed in any suitable order unless otherwise stated herein or otherwise clearly inconsistent with the context. The use of any and all examples or exemplary language (eg, such as) set forth herein is intended to further illuminate the description and does not constitute a limitation on the scope of the description unless otherwise stated. Nothing in the specification should be construed as indicating any element not claimed as being necessary for the practice of the compositions, methods and kits described herein.

Preferred embodiments are described herein. Variations of these preferred embodiments may be apparent to those skilled in the art after reading the foregoing description. It is expected that those skilled in the art will be able to use such variations as appropriate and practice the compositions, methods, and kits described herein other than as specifically described herein. Accordingly, the compositions, methods and kits described herein include all modifications and equivalents of the subject matter that are set forth in the claims appended to this specification, as permitted by applicable law. In addition, the description covers any combination of the elements described above in all possible variations thereof, unless otherwise indicated in the present description or otherwise clearly inconsistent with the context.

List of embodiments

Embodiment 1. A composition that contains cryoprecipitate suitable for infusion into a patient at least 1 day after thawing, where the cryoprecipitate is pathogen-inactivated.

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Embodiment 2. The composition of Embodiment 1, wherein the composition is suitable for infusion into a patient at least 3 days after thawing.

Embodiment 3. The composition of embodiment 2, wherein the composition is suitable for infusion into a patient at least 5 days after thawing.

Embodiment 4. The composition of any one of embodiments 1-3, wherein the composition comprises cryoprecipitate prepared from at least about 550 ml and about less than 650 ml of pathogen-inactivated plasma.

Embodiment 5. The composition according to any one of embodiments 1-4, wherein the composition contains cryoprecipitate obtained from approximately 600 ml of pathogen-inactivated plasma.

Embodiment 6. The composition of any one of embodiments 1-3, wherein the composition comprises cryoprecipitate obtained from at least about 550 ml and about less than about 650 ml of plasma, and where the resulting cryoprecipitate is made pathogen-inactivated.

Embodiment 7. The composition according to any one of embodiments 1-3 and 6, wherein the composition contains cryoprecipitate obtained from approximately 600 ml of plasma, and where the resulting cryoprecipitate is made pathogen-inactivated.

Embodiment 8. The composition according to any one of embodiments 1-5, wherein the composition contains cryoprecipitate obtained from 3 units of pathogen-inactivated plasma.

Embodiment 9. The composition according to any one of embodiments 1-3, 6 and 7, wherein the composition contains cryoprecipitate obtained from 3 units of plasma, and where the resulting cryoprecipitate is made pathogen-inactivated.

Embodiment 10. The composition as in any one of Embodiments 1-3, wherein the composition comprises a first cryoprecipitate prepared from at least about 550 ml and less than 650 ml of pathogen-inactivated plasma, and a second cryoprecipitate prepared from at least about 550 ml and less than 650 ml of pathogen-inactivated plasma, where the first and second cryoprecipitates are combined before being re-frozen for storage.

Embodiment 11. The composition of any one of Embodiments 1-3 and 10, wherein the composition comprises a first cryoprecipitate prepared from approximately 600 ml of pathogen-inactivated plasma and a second cryoprecipitate prepared from approximately 600 ml of pathogen-inactivated plasma, wherein the first and second cryoprecipitates are combined before frozen for storage.

Embodiment 12. The composition as in any one of embodiments 1-3, wherein the composition comprises a first cryoprecipitate obtained from at least about 550 ml and less than 650 ml of plasma, and a second cryoprecipitate obtained from at least about 550 ml and less than 650 ml of plasma, wherein the first and second cryoprecipitates are combined before being re-frozen for storage and where the first and second cryoprecipitates are made pathogen-inactivated after combining and before being re-frozen for storage.

Embodiment 13. The composition as in any one of Embodiments 1-3 and 10, wherein the composition comprises a first cryoprecipitate prepared from approximately 600 mL of plasma and a second cryoprecipitate prepared from approximately 600 mL of plasma, wherein the first and second cryoprecipitates are combined before being re-frozen to storage and where the first and second cryoprecipitates are made pathogen-inactivated after combining and before being re-frozen for storage.

Embodiment 14. The composition according to any one of embodiments 1-3, wherein the composition comprises a first cryoprecipitate obtained from at least about 550 ml and less than 650 ml of plasma, and a second cryoprecipitate obtained from at least about 550 ml and less than 650 ml of plasma, where the first and second cryoprecipitates are combined before being re-frozen for storage and where the first and second cryoprecipitates are made pathogen-inactivated before combining and before being re-frozen for storage.

Embodiment 15. The composition as in any one of Embodiments 1-3 and 10, wherein the composition comprises a first cryoprecipitate prepared from approximately 600 mL of plasma and a second cryoprecipitate prepared from approximately 600 mL of plasma, wherein the first and second cryoprecipitates are combined before being re-frozen to storage and where the first and second cryoprecipitates are made pathogen-inactivated before combining and before re-frozen for storage.

Embodiment 16. The composition as in any one of embodiments 1-3, wherein the composition comprises a first cryoprecipitate prepared from at least about 550 ml and less than 650 ml of pathogen-inactivated plasma, and a second cryoprecipitate prepared from at least about 550 ml and less than 650 ml of pathogen-inactivated plasma, where the first and second cryoprecipitates are combined before being re-frozen for storage.

Embodiment 17. The composition as in any one of Embodiments 1-3 and 10, wherein the composition comprises a first cryoprecipitate prepared from approximately 600 ml of pathogen-inactivated plasma and a second cryoprecipitate prepared from approximately 600 ml of pathogen-inactivated plasma, wherein the first and second cryoprecipitates are combined before frozen for storage.

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Embodiment 18. The composition as in any one of Embodiments 1-3, wherein the composition comprises a first cryoprecipitate prepared from 3 units of pathogen-inactivated plasma and a second cryoprecipitate prepared from 3 units of pathogen-inactivated plasma, wherein the first and second cryoprecipitates are combined before being repeated. frozen for storage.

Embodiment 19. The composition according to any one of embodiments 1-3 and 10-18, wherein the composition contains cryoprecipitate obtained from 6 units of pathogen-inactivated plasma.

Embodiment 20. The composition according to any one of embodiments 1-19, wherein the composition contains cryoprecipitate obtained from plasma obtained from a single donor.

Embodiment 21. The composition according to any one of embodiments 1-19, wherein the composition contains cryoprecipitate obtained from plasma obtained from 2-6 donors.

Embodiment 22. The composition of any one of embodiments 1-21, wherein the composition contains less than 80 IU of factor VIII per unit of cryoprecipitate.

Embodiment 23. The composition of Embodiment 22, wherein the composition contains less than 50 IU of factor VIII per unit of cryoprecipitate.

Embodiment 24. The composition of any one of embodiments 1-21, wherein the composition contains 80-100 IU of factor VIII per unit of cryoprecipitate.

Embodiment 25. The composition of any one of embodiments 1-21, wherein the composition contains at least 80 IU of factor VIII.

Embodiment 26. The composition of embodiment 25, wherein the composition contains 80-240 IU of factor VIII.

Embodiment 27. The composition of embodiment 25, wherein the composition contains 80-480 IU of factor VIII.

Embodiment 29. The composition of any one of embodiments 1-27, wherein the amount of factor VIII is determined from a cryoprecipitate sample taken approximately 1 day after thawing.

Embodiment 30. The composition of any one of embodiments 2-27, wherein the amount of factor VIII is determined from a cryoprecipitate sample taken approximately 3 days after thawing.

Embodiment 31. The composition of any one of embodiments 3-27, wherein the amount of factor VIII is determined from a cryoprecipitate sample taken approximately 5 days after thawing.

Embodiment 32. The composition of any one of embodiments 1-31, wherein the composition contains at least 150 mg of fibrinogen per unit of cryoprecipitate.

Embodiment 33. The composition of any one of embodiments 1-32, wherein the composition contains at least 250 mg of fibrinogen per unit of cryoprecipitate.

Embodiment 34. The composition of any one of embodiments 4-33, wherein the composition contains at least 750 mg of fibrinogen.

Embodiment 35. The composition of any one of embodiments 10-33, wherein the composition contains at least 1500 mg of fibrinogen.

Embodiment 36. The composition of any one of embodiments 8-35, wherein each unit of cryoprecipitate is obtained from 180-250 ml of pathogen-inactivated plasma.

Embodiment 37. The composition of any one of embodiments 1-36, wherein the composition further comprises plasma in a volume of between about 5 ml and about 20 ml per unit of cryoprecipitate.

Embodiment 38. The composition of any one of embodiments 4-37, wherein the composition further comprises plasma in a volume of greater than about 1 ml and less than or equal to about 75 ml.

Embodiment 39. The composition of any one of embodiments 4-38, wherein the composition further comprises plasma in a volume between about 40 ml and about 75 ml.

Embodiment 40. The composition of any one of embodiments 4-38, wherein the composition further comprises plasma in a volume between about 50 ml and about 60 ml.

Embodiment 41. The composition of any one of embodiments 10-37, wherein the composition further comprises plasma in a volume between about 30 ml and about 120 ml.

Embodiment 42. The composition of any one of embodiments 1-41, wherein the composition is stored at room temperature for at least 1 day after thawing.

Embodiment 43. The composition of any one of embodiments 1-41, wherein the composition is stored at between about 2°C and about 6°C for at least 1 day after thawing.

Embodiment 44. The composition according to any one of embodiments 1-43, wherein the cryoprecipitate is pathogen-inactivated by photochemical inactivation.

Embodiment 45. The composition of Embodiment 44, wherein the cryoprecipitate is pathogen-inactivated by photochemical inactivation using psoralen.

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Embodiment 46. The composition of Embodiment 45, wherein psoralen is amotosalen.

Embodiment 47. The composition of any one of embodiments 44-46, wherein the cryoprecipitate is obtained from plasma that has been pathogen-inactivated in a first container suitable for photochemical inactivation of the plasma under sterile conditions;

wherein the first container is interfaced with a compound absorption device (CAD) such that the pathogen-inactivated plasma can be transferred from the first container to the CAD under sterile conditions; and wherein the cryoprecipitate is contained in one or more second containers, each of which is mated to the CAD such that the pathogen-inactivated plasma can be transferred from the CAD to the one or more second containers under sterile conditions, and each of which is suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow the formation of cryoprecipitate.

Embodiment 48. The composition of Embodiment 47, wherein each of the one or more second containers is suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow the formation of cryoprecipitate and cryosupernatant, followed by removal of all or parts of the cryosupernatant from one or more second containers.

Embodiment 49. The composition of Embodiment 47 or Embodiment 48, wherein the cryoprecipitate is obtained from plasma that has been pathogen-inactivated in a first container suitable for photochemical inactivation of the plasma under sterile conditions;

wherein the first container is interfaced with a compound absorption device (CAD) such that the pathogen-inactivated plasma can be transferred from the first container to the CAD under sterile conditions;

wherein the CAD is mated to one or more second containers, each of which is mated to the CAD so that the pathogen-inactivated plasma can be transferred from the CAD to the one or more second containers under sterile conditions; and wherein the cryoprecipitate is contained in a third container configured to interface with the one or more second containers such that the pathogen-inactivated plasma can be transferred from the CAD in the one or more second containers to the third container under sterile conditions, where the third container is suitable for freezing the pathogen inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow the formation of cryoprecipitate.

Embodiment 50. The composition of Embodiment 49, wherein the third container is suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow the formation of cryoprecipitate and cryosupernatant, followed by removal of all or part of the cryosupernatant from the third container.

Embodiment 51. The composition of any one of embodiments 1-50, wherein the composition is contained in a container that further includes a label indicating that the composition is suitable for use for at least about 1 day after thawing.

Embodiment 52. The composition as in any one of embodiments 2-50, wherein the composition is contained in a container that further includes a label indicating that the composition is suitable for use for at least about 3 days after thawing.

Embodiment 53. The composition of any one of embodiments 3-50, wherein the composition is contained in a container that further includes a label indicating that the composition is suitable for use for at least about 5 days after thawing.

Embodiment 54. The composition of any one of embodiments 1-53, wherein the cryoprecipitate is derived from plasma other than group O plasma.

Embodiment 55. A method of producing cryoprecipitate for infusion into a patient, which comprises:

a) obtaining cryoprecipitate from pathogen-inactivated plasma;

b) freezing cryoprecipitate; And

c) thawing the frozen cryoprecipitate, where the resulting cryoprecipitate from step c) is suitable for infusion into the patient at least 1 day after thawing.

Embodiment 56. The method of embodiment 55, wherein the resulting cryoprecipitate from step c) is suitable for infusion into a patient at least 5 days after thawing.

Embodiment 57. The method of Embodiment 55 or Embodiment 56, wherein the thawed cryoprecipitate contains at least about 150 mg of fibrinogen per unit of cryoprecipitate.

Embodiment 58. The method of Embodiment 55, wherein the thawed cryoprecipitate contains at least about 750 mg of fibrinogen.

Embodiment 59. The method of any one of embodiments 55-58, wherein the method does not include determining factor VIII levels prior to infusion of thawed cryoprecipitate.

Embodiment 60. The method of any one of embodiments 55-58, which further includes determining the level of factor VIII in the thawed cryoprecipitate.

Embodiment 61. The method of any one of embodiments 55-60, wherein the cryoprecipitate is prepared from at least about 550 ml and about less than 650 ml of pathogen-inactivated plasma.

Embodiment 62. The method of any one of embodiments 55-61, wherein the cryoprecipitate is obtained from approximately 600 ml of pathogen-inactivated plasma.

Embodiment 63. The method of any one of Embodiments 55-60, which further comprises combining a first cryoprecipitate prepared from at least about 550 mL and less than about 650 mL of pathogen-inactivated plasma and a second cryoprecipitate prepared from at least about 550 ml and approximately less than 650 ml of pathogen-inactivated plasma, where the first and second cryoprecipitates are combined before steps b) and c).

Embodiment 64. The method of any one of Embodiments 55-60, which further comprises combining a first cryoprecipitate obtained from approximately 600 ml of pathogen-inactivated plasma and a second cryoprecipitate obtained from approximately 600 ml of pathogen-inactivated plasma, wherein the first and second cryoprecipitates combine before steps b) and c).

Embodiment 65. The method as in any one of Embodiments 55-60, which further comprises combining a first cryoprecipitate obtained from 3 units of pathogen-inactivated plasma and a second cryoprecipitate obtained from 3 units of pathogen-inactivated plasma, wherein the first and second cryoprecipitates are combined before steps b ) and c).

Embodiment 66. The method of any one of embodiments 55-65, wherein the resulting cryoprecipitate from step c) is suitable for infusion into a patient at least 3 days after thawing.

Embodiment 67. The method of Embodiment 66, wherein the resulting cryoprecipitate from step c) is suitable for infusion into a patient at least 5 days after thawing.

Embodiment 68. A method of infusing cryoprecipitate into a patient, which comprises:

a) obtaining cryoprecipitate from pathogen-inactivated plasma;

b) freezing cryoprecipitate;

c) thawing frozen cryoprecipitate; And

d) infusion of thawed cryoprecipitate into the patient, wherein the infusion occurs at least 1 day after thawing of the frozen cryoprecipitate.

Embodiment 69. The method of Embodiment 68, wherein the thawed cryoprecipitate contains at least about 150 mg of fibrinogen per unit of cryoprecipitate.

Embodiment 70. The method of Embodiment 68, wherein the thawed cryoprecipitate contains at least about 750 mg of fibrinogen.

Embodiment 71. The method of any one of embodiments 68-70, wherein the method does not include determining factor VIII levels prior to infusion of thawed cryoprecipitate.

Embodiment 72. The method of any one of embodiments 68-70, which further comprises determining the level of factor VIII in the thawed cryoprecipitate prior to infusion of the thawed cryoprecipitate.

Embodiment 73. The method of any one of embodiments 68-72, wherein the cryoprecipitate is prepared from at least about 550 ml and about less than 650 ml of pathogen-inactivated plasma.

Embodiment 74. The method of any one of embodiments 68-73, wherein the cryoprecipitate is obtained from approximately 600 ml of pathogen-inactivated plasma.

Embodiment 75. The method of any one of embodiments 68-72, which further comprises combining a first cryoprecipitate prepared from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma and a second cryoprecipitate obtained from at least about 550 ml and approximately less than 650 ml of pathogen-inactivated plasma, where the first and second cryoprecipitates are combined before steps b) and c).

Embodiment 76. The method of any one of Embodiments 68-72, which further comprises combining a first cryoprecipitate obtained from approximately 600 ml of pathogen-inactivated plasma and a second cryoprecipitate obtained from approximately 600 ml of pathogen-inactivated plasma, wherein the first and second cryoprecipitates combine before steps b) and c).

Embodiment 77. The method of any one of embodiments 68-72, which further includes combining a first cryoprecipitate obtained from 3 units of pathogen-inactivated plasma and a second cryoprecipitate obtained from 3 units of pathogen-inactivated plasma, wherein the first and second cryoprecipitates are combined before steps b) and With).

Embodiment 78. The method of any one of embodiments 55-77, wherein the resulting cryoprecipitate from step c) contains less than 80 IU of factor VIII per unit of cryoprecipitate.

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Embodiment 79. The method of any one of embodiments 55-77, wherein the resulting cryoprecipitate from step c) contains at least about 80 IU of factor VIII.

Embodiment 80. The method of embodiment 79, wherein the resulting cryoprecipitate from step c) contains 80-240 IU of factor VIII.

Embodiment 81. The method of embodiment 79, wherein the resulting cryoprecipitate from step c) contains 80-480 IU of factor VIII.

Embodiment 82. The method of Embodiment 79, wherein the resulting cryoprecipitate from step c) contains less than 50 IU of factor VIII per unit of cryoprecipitate.

Embodiment 83. The method of any one of embodiments 55-82, wherein the resulting cryoprecipitate from step c) contains at least 150 mg of fibrinogen per unit of cryoprecipitate.

Embodiment 84. The method of any one of embodiments 55-82, wherein the resulting cryoprecipitate from step c) contains at least 750 mg of fibrinogen.

Embodiment 85. The method of any one of embodiments 55-82, wherein the resulting cryoprecipitate from step c) contains at least 1500 mg of fibrinogen.

Embodiment 86. The method of any one of embodiments 55-85, wherein the cryoprecipitate from step a) further contains plasma in a volume of between about 5 ml and about 20 ml per unit of cryoprecipitate.

Embodiment 87. The method of any one of Embodiments 61, 62, 75, 76, and 79-86, wherein the cryoprecipitate from step a) further contains plasma in a volume of greater than about 1 ml and less than or equal to about 75 ml.

Embodiment 88. The method of any one of Embodiments 61, 62, 75, 76, and 79-86, wherein the cryoprecipitate from step a) further contains plasma in a volume between about 40 ml and about 75 ml.

Embodiment 89. The method of any one of embodiments 61, 62, 75, 76, and 79-86, wherein the cryoprecipitate from step a) further contains plasma in a volume between about 50 ml and about 60 ml.

Embodiment 90. The method of any one of embodiments 63, 64, and 75-86, wherein the cryoprecipitate from step a) further contains plasma in a volume between about 30 ml and about 120 ml.

Embodiment 91. The method of any one of embodiments 55-90, wherein the plasma is made pathogen-inactivated by photochemical inactivation.

Embodiment 92. The method of Embodiment 91, wherein the cryoprecipitate is pathogen-inactivated by photochemical inactivation using psoralen.

Embodiment 93. The method of Embodiment 92, wherein the psoralen is amotosalen.

Embodiment 94. The method of any one of embodiments 55-93, wherein the cryoprecipitate is obtained from plasma that has been pathogen-inactivated in a first container suitable for photochemical inactivation of the plasma under sterile conditions;

wherein the first container is interfaced with a compound absorption device (CAD) such that the pathogen-inactivated plasma can be transferred from the first container to the CAD under sterile conditions; and wherein the cryoprecipitate is frozen and thawed in steps b) and c) in one or more second containers, each of which is interfaced with a CAD such that the pathogen-inactivated plasma can be transferred from the CAD to the one or more second containers under sterile conditions, and each of which is suitable for freezing pathogen-inactivated plasma, followed by thawing of pathogen-inactivated plasma under conditions that ensure the formation of cryoprecipitate.

Embodiment 95. The method of Embodiment 94, wherein each of the one or more second containers is suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow the formation of cryoprecipitate and cryosupernatant, followed by removal of all or a portion of the cryosupernatant from one or more second containers.

Embodiment 96. The method of Embodiment 94 or Embodiment 95, wherein the cryoprecipitate is obtained from plasma that has been pathogen-inactivated in a first container suitable for photochemical inactivation of the plasma under sterile conditions;

wherein the first container is interfaced with a compound absorption device (CAD) such that the pathogen-inactivated plasma can be transferred from the first container to the CAD under sterile conditions; and wherein the cryoprecipitate is frozen and thawed in steps b) and c) in a third container configured to interface with the one or more second containers such that the pathogen-inactivated plasma can be transferred from the CAD in the one or more second containers to the third container in sterile conditions where the third container is suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow the formation of cryoprecipitate.

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Embodiment 97. The method of Embodiment 96, wherein the third container is suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow the formation of cryoprecipitate and cryosupernatant, followed by removal of all or part of the cryosupernatant from the third container.

Embodiment 98. The method of any one of embodiments 55-97, wherein the patient is a human.

Embodiment 99: A kit that contains

a) container;

b) pathogen-inactivated cryoprecipitate; And

c) instructions for use of pathogen-inactivated cryoprecipitate for infusion into a patient, wherein the instructions indicate that the cryoprecipitate is suitable for infusion into a patient for up to approximately 5 days after thawing.

Embodiment 100: A kit that contains

a) container;

b) pathogen-inactivated cryoprecipitate; And

c) a label indicating that the pathogen-inactivated cryoprecipitate is suitable for use for up to approximately 5 days after thawing.

Embodiment 101. A method of infusing cryoprecipitate into a patient, which comprises infusing the patient with a composition according to any one of embodiments 1-54.

Embodiment 102. A method of infusing cryoprecipitate into a patient, which comprises infusing the patient with cryoprecipitate obtained by the method of any one of embodiments 55-98.

Embodiment 104. Cryoprecipitate obtained by the method of any one of embodiments 55-98.

Embodiment 105. A method for preparing a cryosupernatant depot for infusion into a patient, which comprises:

a) freezing at least the first pathogen-inactivated plasma and the second pathogen-inactivated plasma, wherein each of the first and second pathogen-inactivated plasma has a volume of at least about 550 ml and less than about 650 ml;

b) thawing the first pathogen-inactivated plasma under conditions that ensure the formation of a first precipitate and a first supernatant, and thawing the second pathogen-inactivated plasma under conditions that ensure the formation of a second precipitate and a second supernatant;

c) separating the first and second supernatants from the first and second precipitates to form a first cryosupernatant and a second cryosupernatant; And

d) combining the first and second cryosupernatants to form a cryosupernatant depot.

Embodiment 106. The method of Embodiment 105, wherein each of the first and second pathogen-inactivated plasma has a volume of approximately 600 ml.

Embodiment 107. The method of Embodiment 105 or Embodiment 106, wherein step a) further comprises freezing at least a third pathogen-inactivated plasma and a fourth pathogen-inactivated plasma, wherein each of the third and fourth pathogen-inactivated plasma has a volume of at least approximately 550 ml and less than 650 ml;

where step b) further includes thawing the third pathogen-inactivated plasma under conditions that provide the formation of a third precipitate and a third supernatant, and thawing the fourth pathogen-inactivated plasma under conditions that provide the formation of a fourth precipitate and a fourth supernatant;

where step c) further includes separating the third and fourth supernatants from the third and fourth precipitates in order to form a third cryosupernatant and a fourth cryosupernatant;

wherein the cryosupernatant depot formed in step d) is a first supernatant depot, and step d) further includes combining the third and fourth cryosupernatants to form a second cryosupernatant depot; and wherein the method further includes:

f) combining the first cryosupernatant depot and the second cryosupernatant depot.

Embodiment 108. The method of Embodiment 107, wherein each of the third and fourth pathogen-inactivated plasma has a volume of approximately 600 ml.

Embodiment 109. The method of any one of embodiments 105-108, wherein the first and/or second pathogen-inactivated plasma is made pathogen-inactivated by photochemical inactivation.

Embodiment 110. The method of Embodiment 109, wherein one or more of the first, second, third and fourth pathogen-inactivated plasmas are made pathogen-inactivated using psoralen.

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Embodiment 111. The method of Embodiment 110, wherein the psoralen is amotosalen.

Embodiment 112. The method of any one of embodiments 109-111, wherein one or more of the first, second, third and fourth pathogen-inactivated plasmas are made pathogen-inactivated in a first container suitable for photochemical inactivation of the plasma under sterile conditions, wherein the first the container is interfaced with a compound absorption device (CAD) so that the pathogen-inactivated plasma can be transferred from the first container to the CAD under sterile conditions.

Embodiment 113. The method of Embodiment 112, wherein one or more of the first, second, third and fourth pathogen-inactivated plasmas are frozen in step a) and thawed in step b) in one or more second containers, each of which is mated with CAD such that the pathogen-inactivated plasma can be transferred from the CAD to one or more second containers under sterile conditions, each of which is suitable for freezing the pathogen-inactivated plasma followed by thawing the pathogen-inactivated plasma under conditions that allow cryoprecipitate to form.

Embodiment 114. The method of Embodiment 113, wherein one or more of the first, second, third and fourth pathogen-inactivated plasmas are frozen in step a) and thawed in step b) in a third container configured to interface with one or more second containers so that the pathogen-inactivated plasma can be transferred from the CAD in one or more second containers to a third container under sterile conditions, where the third container is suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that ensure formation of cryoprecipitate.

Embodiment 115. The method of Embodiment 114, wherein one or more of the first, second, third and fourth supernatants are separated from one or more of the first, second, third and fourth precipitates in step c) in one or more fourth containers, each of which is configured to interface with one or more second containers or a third container so that the supernatant can be transferred from the one or more second containers or the third container to one or more fourth containers under sterile conditions in order to obtain a pathogen-inactivated cryosupernatant, contained in one or more fourth containers; and pathogen-inactivated cryoprecipitate contained in one or more second containers or a third container.

Embodiment 116. A method of infusing a cryosupernatant into a patient, which comprises infusing into the patient a cryosupernatant obtained by the method of any one of embodiments 105-115.

Embodiment 117. A processing kit for producing pathogen-inactivated cryoprecipitate, which contains

a) a first container in which one or more units of plasma can be photochemically inactivated in the presence of psoralen under sterile conditions;

b) a compound absorption device (CAD) coupled to the first container such that one or more units of plasma can be transferred from the first container to the compound absorption device under sterile conditions; And

c) one or more second containers, each of which is mated to a compound absorption device such that one or more units of plasma can be transferred from the compound absorption device to one or more second containers under sterile conditions to provide pathogen-inactivated plasma suitable for infusion into a patient, wherein one or more second containers are suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow the formation of a precipitate and a supernatant.

Embodiment 118. The treatment kit of Embodiment 117, wherein each of the one or more second containers is suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow the formation of cryoprecipitate and cryosupernatant, followed by disposal all or part of the cryosupernatant from one or more second containers.

Embodiment 119. A processing kit for producing pathogen-inactivated cryoprecipitate, which contains

a) a first container in which one or more units of plasma can be photochemically inactivated in the presence of psoralen under sterile conditions;

b) a compound absorption device (CAD) coupled to the first container such that one or more units of plasma can be transferred from the first container to the compound absorption device under sterile conditions;

c) one or more second containers, each of which is mated to a compound absorption device such that one or more units of plasma can be transferred from the compound absorption device to one or more second containers under sterile conditions to ensure

- 48 045773 supply pathogen-inactivated plasma suitable for infusion to the patient; And

d) a third container that is configured to interface with one or more second containers such that the pathogen-inactivated plasma can be transferred from the one or more second containers to the third container under sterile conditions, in which the third container is suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow the formation of a precipitate and supernatant.

Embodiment 120. The treatment kit of Embodiment 119, wherein the third container is suitable for freezing the pathogen-inactivated plasma, followed by thawing of the pathogen-inactivated plasma under conditions that allow the formation of cryoprecipitate and cryosupernatant, followed by removal of all or part of the cryosupernatant from the third container.

Embodiment 121. The treatment kit of any one of embodiments 117-120, which further comprises an additional container suitable for mixing one or more units of plasma with a pathogen-inactivating compound, wherein the additional container is mated to the first container such that the one or more units of plasma in mixtures containing the pathogenic activating compound can be transferred from the additional container to the first container under sterile conditions.

Embodiment 122. The treatment kit of any one of embodiments 117-121, which further comprises one or more fourth containers, each of which is configured to interface with one or more second containers or with a third container so that the supernatant can be transferred from one or more several second containers or a third container into one or more fourth containers under sterile conditions to provide pathogen-inactivated cryosupernatant contained in one or more fourth containers and pathogen-inactivated cryoprecipitate contained in one or more second containers or a third container.

Embodiment 123. The treatment kit of any one of embodiments 119-122, wherein the third container is mated to the one or more second containers such that the supernatant can be transferred from the one or more second containers to the third container under sterile conditions to obtain the pathogen -inactivated cryosupernatant contained in a third container, and pathogen-inactivated cryoprecipitate contained in one or more second containers.

Embodiment 124. The treatment kit of Embodiment 122 or Embodiment 123, wherein the third container is configured to interface with one or more second containers such that pathogen-inactivated plasma can be transferred from the one or more second containers to the third container under sterile conditions. ;

wherein the third container is suitable for freezing the pathogen-inactivated plasma, followed by thawing the pathogen-inactivated plasma under conditions that allow the formation of a precipitate and a supernatant; and wherein each of the one or more fourth containers is configured to interface with the third container such that the supernatant can be transferred from the third container to the one or more fourth containers under sterile conditions to produce a pathogen-inactivated cryosupernatant contained in the one or more fourth containers , and pathogen-inactivated cryoprecipitate contained in the third container.

Embodiment 125: A method of preparing cryoprecipitate for infusion into a patient, which comprises:

a) obtaining cryoprecipitate from pathogen-inactivated plasma; And

b) freezing cryoprecipitate;

wherein the cryoprecipitate is suitable for infusion into the patient for up to approximately 5 days after thawing.

Embodiment 126. The method of Embodiment 125, wherein the cryoprecipitate is prepared from at least about 550 ml and about less than 650 ml of pathogen-inactivated plasma.

Embodiment 127. The method of Embodiment 126, wherein the cryoprecipitate is prepared from approximately 600 ml of pathogen-inactivated plasma.

Embodiment 128. The method of Embodiment 125, which further comprises combining a first cryoprecipitate prepared from at least about 550 ml and less than about 650 ml of pathogen-inactivated plasma and a second cryoprecipitate obtained from at least about 550 ml and about 650 ml of pathogen-inactivated plasma. less than 650 ml of pathogen-inactivated plasma, where the first and second cryoprecipitates are combined before step b).

Embodiment 129. The method of Embodiment 128, wherein the first cryoprecipitate is obtained from approximately 600 ml of pathogen-inactivated plasma and wherein the second cryoprecipitate is obtained from approximately 600 ml of pathogen-inactivated plasma.

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Embodiment 130. The method of Embodiment 125, which further includes combining a first cryoprecipitate obtained from 3 units of pathogen-inactivated plasma and a second cryoprecipitate obtained from 3 units of pathogen-inactivated plasma, wherein the first and second cryoprecipitates are combined before step b).

Embodiment 131: A method of producing cryoprecipitate for infusion into a patient, which comprises:

a) obtaining cryoprecipitate from plasma; And

b) carrying out inactivation of pathogens in cryoprecipitate;

wherein the pathogen-inactivated cryoprecipitate is suitable for infusion into a patient for up to about 5 days after storage at between about 2°C and about 25°C.

Embodiment 132. The method of Embodiment 126, which further includes after step b)

c) freezing the pathogen-inactivated cryoprecipitate; And

d) thawing the frozen pathogen-inactivated cryoprecipitate;

wherein the pathogen-inactivated cryoprecipitate is suitable for infusion into the patient for up to approximately 3 days after thawing.

Embodiment 133. The method of Embodiment 132, wherein the pathogen-inactivated cryoprecipitate is suitable for infusion into a patient for up to about 5 days after thawing.

Embodiment 134. The method of any one of embodiments 131-133, wherein the cryoprecipitate is obtained from 1 unit of plasma.

Embodiment 135 The method of Embodiment 134, wherein the cryoprecipitate is prepared from at least about 180 ml and about less than 250 ml of plasma.

Embodiment 136. The method of Embodiment 135, wherein the resulting cryoprecipitate is resuspended in at least about 30 ml and less than about 70 ml of plasma.

Embodiment 137. The method as in any one of embodiments 131-133, which further includes combining at least a first cryoprecipitate obtained from 1 unit of plasma and a second cryoprecipitate obtained from 1 unit of plasma, wherein the first and second cryoprecipitates are combined before step b) .

Embodiment 138. The method as in any one of embodiments 131-133, which further comprises combining at least a first cryoprecipitate obtained from 1 unit of plasma and a second cryoprecipitate obtained from 1 unit of plasma, wherein the first and second cryoprecipitates are combined after step b) .

Embodiment 139. The method of Embodiment 137 or Embodiment 138, wherein the first cryoprecipitate is prepared from at least about 180 ml and less than about 250 ml of plasma and wherein the second cryoprecipitate is obtained from at least about 180 ml and less than about 250 ml. 250 ml plasma.

Embodiment 140. The method of any one of embodiments 137-139, wherein combining at least the first cryoprecipitate and the second cryoprecipitate includes combining 2-12 cryoprecipitates.

Embodiment 141. The method of any one of embodiments 137-140, wherein the volume of the combined cryoprecipitates is at least about 500 mL and less than about 700 mL.

Embodiment 142. The method of any one of embodiments 137-140, wherein the first and second cryoprecipitates are derived from plasma of the same type of ABO.

Embodiment 143. The method of any one of embodiments 137-140, wherein the first and second cryoprecipitates are obtained from plasma of different types of ABO.

Embodiment 144. The method according to any one of claims 137-140, wherein the combined cryoprecipitates are prepared from at least 3 cryoprecipitates, wherein each of the cryoprecipitates is obtained from a different type of ABO plasma.

Embodiment 145. The method of any one of embodiments 134-144, wherein the cryoprecipitate is obtained from plasma derived from whole blood.

Embodiment 146. The method of any one of embodiments 131-133, 136-138, and 140-143, wherein the cryoprecipitate is obtained from apheresis-collected plasma.

Embodiment 147. The method of Embodiment 146, wherein the plasma collected by apheresis is from about 200 ml to about 800 ml.

Claims (11)

1. The use of a pathogen-inactivated cryoprecipitate composition containing fibrinogen for infusion into a patient, wherein the pathogen-inactivated cryoprecipitate has been thawed at least 1 day prior to infusion into the patient, wherein the pathogen-inactivated cryoprecipitate has been prepared by a method comprising: a) obtaining cryoprecipitate from pathogen-inactivated plasma, the composition containing cryoprecipitate obtained from at least 550 ml and less than 650 ml of pathogen-inactivated plasma; b) freezing cryoprecipitate; And c) thawing the frozen cryoprecipitate, wherein the resulting cryoprecipitate composition from step c) contains at least 750 mg of fibrinogen when tested at least 3 days and within 5 days after thawing. 2. Use according to claim 1, wherein the production method further comprises a combination of a first cryoprecipitate obtained from at least 550 ml and less than 650 ml of pathogen-inactivated plasma, and a second cryoprecipitate obtained from at least 550 ml and less than 650 ml pathogen-inactivated plasma, wherein the first and second cryoprecipitates are combined prior to steps b) and c). 3. Use according to claim 2, wherein the thawed cryoprecipitate contains at least about 1500 mg of fibrinogen. 4. Use according to any one of claims 1 to 3, wherein the plasma is pathogen-inactivated by photochemical inactivation. 5. Use according to claim 4, wherein the cryoprecipitate is pathogen-inactivated by photochemical inactivation using psoralen. 6. Use according to claim 5, wherein psoralen is amotosalen. 7. Use according to any one of claims 4-6, wherein the cryoprecipitate is obtained from plasma that has been pathogen-inactivated in a first container configured to photochemically inactivate the plasma under sterile conditions; wherein the first container is interfaced with a compound absorption device (CAD) and configured to transfer pathogen-inactivated plasma from the first container to the CAD under sterile conditions; and wherein the cryoprecipitate is contained in a third container configured to interface with one or more second containers configured to transfer the pathogen-inactivated plasma from the CAD to the third container under sterile conditions, where the third container is configured to freeze the pathogen-inactivated plasma and then thaw the pathogen-inactivated plasma. inactivated plasma under conditions ensuring the formation of cryoprecipitate and cryosupernatant, followed by removal of all or part of the cryosupernatant from the third container. 8. Use according to any one of claims 1 to 7, where after thawing, the pathogen-inactivated cryoprecipitate is stored at a temperature of 2 to 25 ° C until infusion. 9. Use according to any one of claims 2 to 8, wherein the production method of the combination of at least the first cryoprecipitate and the second cryoprecipitate includes a combination of 2 to 12 cryoprecipitates. 10. Use according to any one of claims 1 to 9, wherein the cryoprecipitate composition includes cryoprecipitate obtained from plasma frozen within 24 hours after blood donation. 11. Use according to any one of claims 1 to 10, wherein the cryoprecipitate composition includes cryoprecipitate that is obtained from pathogen-inactivated plasma obtained from whole blood.