Pretreatment of plasma for spray drying and storage

Abstract

A method of treating plasma with a pretreatment solution having a physiologically compatible spray-drying stable acidic substance (SDSAS) and an amino acid prior to or simultaneously with spray-drying the plasma, which results in greater recovery and greater long-term stabilization of dried plasma proteins compared to spray-dried plasma that has not been subjected to the formulation method of the present invention, and compositions related to plasma dried by the method of the present invention.

Description

[Technical Field]

[0001] Related Applications This application is a continuation-in-part of U.S. Patent Application No. 17,945,126, entitled "Pretreatment Of Plasma For Spray Drying And Storage," by Qiyong Peter Liu et al., filed September 15, 2022.

[0002] The entire teachings of the above application are incorporated herein by reference.

[0003] government support This invention was made with government support under Contract Nos. HHSO100201200005C and 75A50121C00059 awarded by the Biomedical Advanced Research and Development Authority (BARDA). The government has certain rights in this invention. [Background technology]

[0004] Plasma, which accounts for approximately 55% of the total volume of whole blood, is a component of whole blood in which blood cells and other components of whole blood are suspended. Plasma also contains a mixture of over 700 proteins and additional substances that perform functions necessary for the body's health, including clotting, protein storage, and electrolyte balance, among others. When extracted from whole blood, plasma can be used to replace body fluids, antibodies, and clotting factors. Therefore, plasma is widely used in medical treatments.

[0005] To facilitate storage and transportation of plasma until use, plasma is typically preserved by freezing immediately after collection from the donor. Fresh-frozen plasma (FFP) is obtained through a series of steps, including centrifuging whole blood to separate the plasma and then freezing the collected plasma within eight hours of collecting the whole blood. In the United States, the American Association of Blood Banks (AABB) standard for storing FFP is up to 12 months from collection when stored at temperatures below -18°C. FFP can also be stored for up to seven years from collection when maintained at temperatures below -65°C. In Europe, the shelf life of FFP is only three months when stored between -18°C and -25°C, and up to 36 months when stored below -25°C. When thawed, European standards stipulate that the plasma must be transfused immediately or stored at 1°C to 6°C and transfused within 24 hours. If stored for longer than 24 hours, the plasma must be relabeled for other uses or discarded. Summary of the Invention [Problem to be solved by the invention]

[0006] Notably, however, FFP must be kept in a temperature-controlled environment at or below -18°C throughout its shelf life to prevent degradation of certain plasma proteins and maintain its efficacy, which increases the cost and difficulty of storage and transportation. Furthermore, FFP must be thawed before use, resulting in a delay of 30 to 80 minutes before it can be used after removal from refrigerated storage.

[0007] Therefore, there is a need to develop alternative technologies for the processing and storage of plasma. [Means for solving the problem]

[0008] A long-standing need and challenge for the blood industry has been to provide safe, reliable, and convenient blood products while maintaining the efficacy and safety of those products when stored and used in infusions or as a source for medical treatments. The present invention involves the preservation of clotting factors in plasma in a manner that provides efficacy preservation and does not otherwise harm the plasma or the transfusion patient. During spray drying, some plasma proteins degrade to some extent due to shear stress, surface stress (e.g., air-liquid interface stress), exposure to extremes of pH, thermal stress, dehydration stress, and other environmental stresses.

[0009] The methods and compositions of the present invention recognize that pH and associated stresses can be reduced or their effects improved by using novel formulations of liquid plasma prior to or simultaneously with spray drying. Formulation of liquid plasma with glycine HCl or a similar spray-drying stable acidic substance (SDSAS) and novel concentrations of one or more amino acids maintains the pH of the plasma at a non-alkaline level during the spray-drying process. This results in higher recovery of active plasma proteins and better subsequent storage stability compared to unformulated plasma. Described herein are methods for adding (formulating) a pretreatment solution of the present invention (e.g., SDSAS and one or more amino acids) simultaneously or otherwise with plasma during the spray-drying process.

[0010] The term "recovery" is defined herein to refer to the percentage of an analyte retained after spray drying compared to the analyte in a sample of the same native plasma (the same sample before spray drying), which may have been frozen, where the analyte is analyzed in native plasma and / or rehydrated plasma at the same protein concentration. The analyte may be any known plasma substance, such as a plasma protein (e.g., vWF antigen or fibrinogen), as described herein, and may be measured by the concentration or activity of the analyte (e.g., vWF:RCo activity), as described herein. The amount of the analyte may be compared to its corresponding clinical reference range.

[0011] As used herein, a spray-dried stable acidic substance (SDSAS) is any substance, such as an acid or acid salt or other pH-improving substance, that is physiologically suitable for addition to plasma being spray-dried and physiologically suitable for the subject (human or non-human) to whom the reconstituted plasma is administered (transfused). The SDSAS remains sufficiently stable (e.g., does not physically evaporate or chemically degrade) during the spray-drying process. The SDSAS provides the pH adjustment described herein, which results in the maintenance or improvement of von Willebrand factor recovery or functionality in the reconstituted plasma described herein, compared to, for example, non-pretreated spray-dried plasma. Specific examples of spray-dried stable acidic substances include glycine HCl, HCl, citric acid, lactic acid, monosodium citrate, and other SDSAS described herein. Other SDSAS may be known in the art or may be determinable by direct experimentation.

[0012] In one embodiment, the pretreatment solution of the present invention used to obtain the spray-dried formulation comprises one or more SDSAS and one or more amino acids. The addition of the amino acids allows for the protection of plasma proteins during spray drying without lowering the pH of the pretreatment solution. The addition of the amino acids increases the pH of the pretreatment solution, but surprisingly does not affect the pH of the pretreated spray-dried plasma or the rehydrated spray-dried plasma. Furthermore, in one embodiment, the use of amino acids together with SDSAS provides spray-dried plasma with reduced levels of C5a, anaphylatoxins, or C5a upon rehydration, which are similar to levels of never-frozen plasma (NFP) or FDA-approved apheresis plasma products. In one embodiment, complement activation is associated with inflammation and should be kept low within a clinically acceptable range. In particular, the pH of the pretreatment solution ranges from about 2.0 to about 4.0 (e.g., 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0), which, when combined with plasma, results in pretreated plasma having a pH of about 6.0 to about 6.6 (e.g., 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6), and previously spray-dried plasma, when reconstituted, results in reconstituted plasma having a pH of about 6.5 to about 7.8 (e.g., 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.8). The total concentration of one or more amino acids in the reconstituted plasma is present in an amount of about 1 mM to about 150 mM. Examples of amino acids that can be combined with SDSAS for the pretreatment solution include glycine, alanine, asparagine, glutamine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, glycine is the amino acid added to the SDSAS composition. Examples of SDSAS include ascorbic acid, citric acid, lactic acid, gluconic acid, oxalic acid, halogenated acetic acid, arenesulfonic acid, molybdic acid, phosphotungstic acid, tungstic acid, chromic acid, sulfamic acid, hydrogen chloride (HCl), glycine hydrochloride (glycine HCl), monosodium citrate, and any combination thereof.

[0013] Thus, treatment of the spray-dried formulation, i.e., the feed plasma prior to or simultaneously with spray-drying, preserves and enables the recovery or functionality of active coagulation factors in the rehydrated plasma subjected to the spray-drying process, as well as long-term stability during storage after drying. As discussed further below, these improvements to certain embodiments of spray-drying of plasma, including formulation with SDSAS and / or amino acids, also improve the ease and reduce the cost of rehydration of the plasma product by enabling the spray-dried plasma to be rehydrated with sterile water (e.g., water for injection: WFI or sterile water for injection: SWFI). The spray-dried plasma of the present invention can be reconstituted with sterile water for injection without the need for a buffered rehydration solution or treatment or storage with CO2, or other processes to control the pH of the reconstituted plasma.

[0014] In one embodiment, the spray-dried plasma of the present invention has improved functionality or recovery of active plasma proteins, long-term stability of plasma proteins, and reduced anaphylatoxins. In one embodiment, a method for obtaining dried plasma of the present invention includes combining donor plasma with a pretreatment solution containing SDSAS and an amino acid, and a spray-drying system. The present invention further contemplates adjusting the pH of the donor plasma with SDSAS by adjusting the concentration of SDSAS to about 1 mM to about 50 mM, thereby lowering the pH of the plasma to about 5.0 to about 6.5, to produce formulated plasma. In another embodiment, the present invention further contemplates adjusting the pH of plasma to be spray-dried together with a pretreatment solution containing SDSAS and an amino acid by adjusting the concentration of SDSAS to about 1 mM to about 50 mM and the concentration of an amino acid compound to about 1 mM and about 150 mM in the formulated plasma, thereby lowering the pH of the plasma to about 6.0 to about 6.6, to produce formulated plasma.

[0015] In one embodiment, to obtain the dried plasma of the present invention, the method includes producing spray-dried plasma by combining plasma with a pretreatment solution containing an amino acid (e.g., glycine) in an amount ranging from about 10 μmol / mL plasma to about 110 μmol / mL rehydrated plasma (e.g., about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110 μmol / mL plasma) and SDSAS (e.g., hydrochloric acid (HCl)) in an amount ranging from about 10 μmol / mL plasma to about 30 μmol / mL rehydrated plasma (e.g., about 10, 15, 20, 25, and 30 μmol / mL plasma), thereby obtaining formulated plasma. The method also includes drying the formulated plasma in a spray-drying system as described herein to produce spray-dried formulated plasma. In one embodiment, the pretreatment solution has glycine in an amount of about 84 μmol / mL plasma and HCl in an amount of about 20 μmol / mL plasma.

[0016] In one embodiment, the pretreatment solution comprises glycine in an amount ranging from about 15 mmol to about 30 mmol (e.g., about 15, 20, 25, and 30 mmol) or from about 43 μmol / mL to about 473 μmol / mL, and HCl in an amount ranging from about 3 mmol to about 7 mmol (e.g., about 3, 4, 5, 6, and 7 mmol) or from about 43 μmol / mL to 129 μmol / mL, thereby obtaining formulated plasma, and drying the formulated plasma in a spray-drying system to produce spray-dried formulated plasma. In a specific embodiment, the pretreatment solution comprises glycine in an amount of about 22 mmol and HCl in an amount of about 5.3 mmol.

[0017] In another embodiment, the pretreatment solution has an amount of glycine and an amount of HCl that form a ratio that allows for the presence of free glycine in the pretreatment solution; in some aspects, the ratio of glycine to HCl is about 1.5 to about 8.0 (e.g., 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.5, 7.0, 7.5, 8.0). In certain embodiments, the ratio of glycine to HCl is 4.15. In yet another embodiment, the ratio of glycine to HCl results in the pH of the pretreatment solution being about 2.0 to about 4.0, or in the formulated plasma of step a) having a pH of about 6.0 to about 6.6. When reconstituted with sterile water, formulated plasma having the above-listed ratio of glycine to HCl results in a pH of about 6.7 to about 7.8.

[0018] The present invention further includes a method of producing spray-dried plasma by combining plasma with a pretreatment solution, the pretreatment solution having glycine in an amount ranging from about 15 mmol to about 30 mmol (e.g., about 15, 20, 25, and 30 mmol) and HCl in an amount ranging from about 3 mmol to about 7 mmol (e.g., about 3, 4, 5, 6, and 7 mmol), thereby obtaining formulated plasma, and drying the formulated plasma in a spray-drying system to produce spray-dried formulated plasma. In a specific embodiment, the pretreatment solution has glycine in an amount of about 22 mmol and HCl in an amount of about 5.3 mmol.

[0019] The present invention further contemplates drying formulated plasma in a spray-drying system to produce spray-dried formulated plasma, wherein the spray-dried formulated plasma has a recovery of active von Willebrand factor (vWF) that is at least 10 to at least 100 percentage points higher than the recovery of active von Willebrand factor obtained from otherwise identical spray-dried plasma that has not been subjected to acid formulation using the pretreatment solution of the present invention. In another embodiment, the spray-dried formulated plasma has a recovery of active von Willebrand factor (vWF) that is similar to or within about 20% (e.g., about 15%, 10%, 5%) of that of unfrozen plasma or FDA-approved plasma products relative to fresh frozen plasma. While any SDSAS known in the art can be selected, glycine HCl, citric acid, and lactic acid are preferred materials for use in the present invention. When an amino acid is added to SDSAS to form a pretreatment solution, in one embodiment, glycine is a preferred material of the present invention (e.g., a combination of glycine HCl / glycine or citric acid / glycine). A physiologically compatible pretreatment solution is added to the plasma prior to spray drying, preferably immediately prior to or simultaneously with spray drying. Additionally, the pH of the plasma can be determined prior to adding SDSAS and amino acids to the plasma to determine the appropriate amount of acid to add. In one embodiment, about 7.4 mM citric acid is added to CPD plasma or WB plasma. In one embodiment, the pH of the formulated plasma is about 5.5 to about 6.5 or about 7.2. The present invention further contemplates that the recovery of vWF may be about 10 to about 20 percentage points to about 40 percentage points (e.g., about 10, 15, 20, 25, 30, 35, and 40 percentage points) greater than the recovery of active von Willebrand factor obtained from otherwise identical spray-dried plasma that has not been pretreated with SDSAS and amino acids, or may be about 25 to about 35 percentage points greater than the recovery of active von Willebrand factor obtained from otherwise identical spray-dried plasma that has not been pretreated with SDSAS and amino acids.

[0020] In one embodiment, the present invention involves mixing the pretreatment solution with the plasma to be spray-dried using a technique called rapid mixing. The rapid mixing step is optional. One of the discoveries of the present invention involves rapid or immediate mixing of the pretreatment composition with the plasma. It has been discovered that slowly mixing the pretreatment solution with the plasma allows localized contact or pockets of unmixed acid to come into contact with plasma proteins, which can harm these proteins and specifically increase C5a. In contrast, when the pretreatment solution is rapidly mixed and / or stirred with the plasma, in one embodiment, the amount of C5a is similar to that of fresh frozen plasma or other similar FDA-approved products sold on the market. Rapid mixing and / or stirring allows for immediate, complete, and rapid mixing of the pretreatment solution (e.g., having SDSAS and one or more amino acids) with the plasma. See Examples 17 and 18. Rapid mixing is defined as adding a large volume of plasma to a relatively small volume of pretreatment solution before spray-drying the plasma. Generally, when a large volume is added to a much smaller volume (e.g., about 10 to about 30% (approximately 10, 15, 20, 25, 30%) of the larger volume), mixing of the two volumes results in rapid and thorough mixing of the two volumes. In a preferred embodiment, 260 mL of plasma is added to 50 mL of pretreatment solution. In one embodiment, once rapid / instantaneous mixing occurs, the operator can gently invert the bag containing both the pretreatment solution and the plasma several times (e.g., 1 to 5 times) to further mix the two. In contrast, when mixing a pretreatment solution with plasma, if a small volume of pretreatment solution is injected into a large volume of plasma and then spray-dried, it takes longer for the small volume to fully mix with the large volume, and pockets of small volume may form within the large volume. During this time, localized contact or pockets of unmixed acid formed within the mixture have been found to cause an increase in the amount of C5a in the resulting reconstituted plasma. Agitation is defined as constant shaking or movement of the components of the pretreatment solution (e.g., SDSAS, amino acids, and plasma). Rapid mixing or agitation results in a uniformly mixed plasma preparation with little or no localized contact or pockets of unmixed acid.

[0021] It has been discovered that desirable C5a levels result from pretreatment solutions having added SDSAS and amino acids, rapid mixing / agitation of the pretreatment components, or a combination of both. In particular, the C5a level of reconstituted plasma resulting from the pretreatment solution of the present invention can be about 4.7 ng / mL to about 74 ng / mL, particularly 8 ng / mL to 12 ng / mL (e.g., about 10 ng / mL). The C5a level is reduced compared to plasma not subjected to a pretreatment solution having at least one SDSAS and at least one amino acid. In one embodiment, the C5a level is reduced by about 20% or less (e.g., 20%, 15%, 10%, 5%, or 1%) compared to plasma not subjected to a pretreatment solution of the present invention. In another embodiment, referring to FIG. 28, rapid mixing and certain pretreatment formulations result in C5a levels that are approximately the same as levels in never-frozen plasma, or about 20% or less (e.g., 20%, 15%, 10%, 5%, 1%) of the C5a in never-frozen plasma or previously approved FDA apheresis plasma products.

[0022] The present invention contemplates reconstituting the spray-dried formulated plasma of the present invention. The spray-dried formulated plasma of the present invention can be reconstituted with any physiologically compatible solution. Furthermore, the spray-dried formulated plasma of the present invention can be reconstituted with sterile water (e.g., sterile water for injection (SWFI) or similar) or clean, non-sterile water, which can be filtered after reconstitution, if necessary. Under normal circumstances, the clinician / healthcare provider / end user will rehydrate the unit with the supplied system SWFI unit. In a preferred embodiment, sterile water for injection is used for the reconstitution solution. The reconstituted spray-dried formulated plasma of the present invention is contemplated to have a pH of about 6.5 to about 7.8, or about 6.9 to about 7.5 (e.g., 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.8). The amount of pretreatment SDSAS components can be adjusted to achieve the design pH of the reconstituted spray-dried formulated plasma. Although not necessary as the pH is in a range suitable for infusion into a recipient, the pH of the reconstituted spray-dried formulated plasma can be further adjusted, if desired, using a biocompatible acid (e.g., citric acid) and / or base (e.g., sodium carbonate or sodium bicarbonate).

[0023] In one embodiment, a subject in need of plasma is selected and the reconstituted plasma of the present invention is administered or transfused to the subject in need of plasma. The administration / infusion may be intravenous.

[0024] In one embodiment, it is contemplated that the spray-dried formulated plasma is substantially more stable than spray-dried plasma produced from unformulated liquid plasma when stored under refrigeration for two weeks at ambient or higher temperatures, e.g., 37° C., prior to reconstitution. It is further contemplated that the stability of the spray-dried plasma is determined by measuring the activity of von Willebrand factor and / or other plasma proteins or anaphylatoxins.

[0025] The present invention contemplates a reconstituted spray-dried plasma product for human infusion (administration), wherein the reconstituted spray-dried plasma product is reconstituted, for example, with sterile water for injection, and wherein the reconstituted spray-dried plasma product has a pH of about 6.7 to about 7.8 (see Example 16) or about 6.9 to 7.5 (see Example 15). The reconstituted plasma of the present invention has an active von Willebrand factor of greater than 5 percentage points compared to the recovery of active von Willebrand factor obtained from an otherwise identical spray-dried plasma that has not been formulated with SDSAS and amino acids, or is about 5 percentage points to about 40 percentage points (e.g., about 25 percentage points to about 35 percentage points) higher than the recovery of active von Willebrand factor obtained from an otherwise identical spray-dried plasma that has not been pretreated with SDSAS and amino acids. Furthermore, the present invention relates to reconstituted spray-dried plasma having a C5a level of about 0.1 ng / mL to about 74 ng / mL, particularly 20 ng / mL to 40 ng / mL (e.g., about 30 ng / mL). In one embodiment, the present invention relates to reconstituted spray-dried plasma pretreated with SDSAS, wherein the amino acid has a C5a level that is reduced, for example, by about 20% or less (e.g., 20%, 15%, 10%, 5%, or 1%) compared to plasma subjected to a pretreatment solution containing SDSAS. In another embodiment, the C5a level of the reconstituted plasma of the present invention is the level of an FDA-approved plasma product.

[0026] The present invention includes pretreating plasma as described herein, and then drying the formulated plasma using a spray-drying system and a disposable spray-drying device having a spray-drying head and a drying chamber, the spray-drying system having a drying gas source that provides a drying gas in use and that is in communication with the drying chamber, a plasma source that provides the plasma, and a pressurized aerosol gas source that provides a pressurized aerosol gas. As described herein, the disposable spray-drying device has a spray-drying head with a spray-drying nozzle assembly that, in use, is in fluid communication with the plasma source from the spray-drying system and the pressurized aerosol gas source from the spray-drying system, and, in use, the pressurized aerosol gas flows in a vortex pattern to atomize the plasma entering the drying chamber to obtain atomized plasma droplets. The spray-drying head also includes a drying chamber, and, in use, the atomized plasma droplets evaporate in the presence of drying gas emitted from the drying gas source, thereby obtaining dried plasma particles and moist air, and the dried plasma particles are captured and the moist air is passed through. In one embodiment, a pretreatment step combined with gentle spray drying using the spray drying system described herein allows for increased recovery of functional von Willebrand factor (vWf) recovered in reconstituted plasma.

[0027] The foregoing and other objects, features, and advantages of the present invention will become apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawings, in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention. [Brief explanation of the drawings]

[0028] [Figure 1] 1 is a black and white photograph showing phase contrast microscopy at 100x and 400x magnification of cholesterol crystals in freeze-dried plasma known as LYOPLAS™ plasma. [Figure 2] 1 is a black and white photograph showing phase contrast microscopy at 100x and 400x magnification of cholesterol crystals in freeze-dried plasma known as FLYP™ plasma. [Figure 3] 1 is a panel of black and white photographs showing phase contrast microscopy at 100x magnification of cholesterol crystals in freeze-dried plasma using LYOPLAS™ plasma (left) and FLYP™ plasma (right). [Figure 4] 1 is a panel of black and white photographs showing phase contrast microscopy of spray-dried plasma without visible cholesterol crystals observed as follows: donor plasma at 100x magnification before spray drying (top left panel), spray-dried plasma at 100x magnification (top right panel), donor plasma at 400x magnification before spray drying (bottom left panel), and spray-dried plasma at 400x magnification (bottom right panel). [Figure 5] 1 is a composite bar / line graph showing the microparticle concentration (microparticles / mL) and microparticle size (logarithmic scale (μm)) of single unit dried plasma at initial rehydration and after 7.5 months of room temperature storage 4 hours after rehydration compared to paired thawed frozen control plasmas as follows: Control plasma (CP) at time 0 (T=0), spray-dried plasma of the present invention (ODP) at time 0 (T=0), control plasma (CP) at time 4 hours (T=4), spray-dried plasma of the present invention (ODP) at time 4 (T=4). [Figure 6] 1 is a composite bar / line graph showing particle concentration (particles / mL) and particle size (logarithmic scale (μm)) of single unit dried plasma at initial rehydration and after 12 months of refrigerated storage 4 hours after rehydration compared to its paired thawed frozen control plasma: Control plasma (CP) at time 0 (T=0), spray-dried plasma of the present invention (ODP) at time 0 (T=0), control plasma (CP) at time 4 hours (T=4), spray-dried plasma of the present invention (ODP) at time 4 (T=4). [Figure 7] 10A-10C are panels of black and white scanning electron microscope (SEM) photographs of spray-dried plasma particles from Run #3, with the top left panel at 2000x, the top right panel at 5000x, the bottom left panel at 5000x, the middle right panel at 1000x, and the bottom left panel at 5000x, with measurements overlaid and showing sizes ranging from 0.99 μm to 7.87 μm, and the bottom right panel at 2000x. These photographs demonstrate the small size and amorphous characteristics of the present invention. [Figure 8A]10 shows panels of black and white scanning electron microscope (SEM) photographs of spray-dried plasma particles from run #7, with the top left panel at 2000x magnification, the top right panel at 1000x magnification, the bottom left panel at 5000x magnification, the middle right panel at 5000x magnification, the bottom left panel at 1000x magnification, and the bottom right panel at 2000x magnification. [Figure 8B] Panel of black and white scanning electron microscope (SEM) photographs of spray-dried plasma particles from run #7 at 5000x magnification with measurements overlaid on top, showing sizes ranging from 1.46 μm to 6.53 μm. [Figure 9A] 1 is a bar graph showing the results of clotting time (R) in minutes from a thromboelastography TEG study with reconstituted WB and mock resuscitation (abbreviations: WB:FFP = whole blood (WB) reconstituted with fresh frozen plasma (FFP); WB:ODP - whole blood reconstituted with spray-dried plasma (ODP) of the present invention; WB+10%FFP = whole blood resuscitated with 2 units of FFP; WB+10%ODP = whole blood resuscitated with 2 units of ODP). Reference ranges are indicated by dotted lines. [Figure 9B] 1 is a bar graph showing the results of clotting rate (angle) from a thromboelastography TEG study with reconstituted WB and mock resuscitation (abbreviations: WB:FFP = whole blood (WB) reconstituted with fresh frozen plasma (FFP); WB:ODP - whole blood reconstituted with spray-dried plasma (ODP) of the present invention; WB+10%FFP = whole blood resuscitated with 2 units of FFP; WB+10%ODP = whole blood resuscitated with 2 units of ODP). Reference ranges are indicated by dotted lines. [Figure 9C] 1 is a bar graph showing results of clot strength (MA) in maximum amplitude (mm) from a thromboelastography TEG study with reconstituted WB and mock resuscitation (abbreviations: WB:FFP = whole blood (WB) reconstituted with fresh frozen plasma (FFP); WB:ODP - whole blood reconstituted with spray-dried plasma (ODP) of the present invention; WB+10%FFP = whole blood resuscitated with 2 units of FFP; WB+10%ODP = whole blood resuscitated with 2 units of ODP). Reference ranges are indicated by dotted lines. [Figure 9D]1 is a bar graph showing the results of the lysis index (30 min) in LY30 as a percentage (%) from a thromboelastography TEG study with reconstituted WB and mock resuscitation (abbreviations: WB:FFP = whole blood (WB) reconstituted with fresh frozen plasma (FFP); WB:ODP - whole blood reconstituted with spray-dried plasma (ODP) of the present invention; WB+10%FFP = whole blood resuscitated with 2 units of FFP; WB+10%ODP = whole blood resuscitated with 2 units of ODP). Reference ranges are indicated by dotted lines. [Figure 9E] 1 is a bar graph showing the results of the lysis index (60 min) of LY60 in percentage (%) from a thromboelastography TEG study with reconstituted WB and mock resuscitation (abbreviations: WB:FFP = whole blood (WB) reconstituted with fresh frozen plasma (FFP); WB:ODP - whole blood reconstituted with spray-dried plasma (ODP) of the present invention; WB+10%FFP = whole blood resuscitated with 2 units of FFP; WB+10%ODP = whole blood resuscitated with 2 units of ODP). Reference ranges are indicated by dotted lines. [Figure 10A] 1 is a bar graph showing the results of clotting time (R) in minutes from a thromboelastography TEG study using plasma only (abbreviations: FFP = fresh frozen plasma (FFP); ODP - spray-dried plasma (ODP) of the present invention; WB + 10% FFP = whole blood resuscitated with 2 units of FFP; WB + 10% ODP = whole blood resuscitated with 2 units of ODP). Reference ranges are indicated by dotted lines. [Figure 10B] 1 is a bar graph showing the results of clotting rate (angle) from a thromboelastography TEG study using plasma only (abbreviations: FFP = fresh frozen plasma (FFP); ODP - spray-dried plasma (ODP) of the present invention; WB + 10% FFP = whole blood resuscitated with 2 units of FFP; WB + 10% ODP = whole blood resuscitated with 2 units of ODP). Reference ranges are indicated by dotted lines. [Figure 10C] 1 is a bar graph showing the results of clot strength in maximum amplitude (MA) (mm) from a thromboelastography TEG study using plasma only (abbreviations: FFP = fresh frozen plasma (FFP); ODP - spray-dried plasma (ODP) of the present invention; WB + 10% FFP = whole blood resuscitated with 2 units of FFP; WB + 10% ODP = whole blood resuscitated with 2 units of ODP). Reference ranges are indicated by dotted lines. [Figure 11] 1 is a bar graph showing the results of vWF (von Willebrand Factor):Ristocetin (Rist) cofactor activity (percent (5)) from a ristocetin cofactor assay. (Abbreviations: WB:FFP = whole blood (WB) reconstituted with fresh frozen plasma (FFP); WB:ODP = whole blood reconstituted with spray-dried plasma (ODP) of the present invention; WB+10%FFP = whole blood resuscitated with 2 units of FFP; WB+10%ODP = whole blood resuscitated with 2 units of ODP). Reference ranges are indicated by dotted lines. [Figure 12] 1 is a bar graph showing the results of ADAMTS-13 (von Willebrand factor-cleaving protease) activity by the ADAMTS-13 assay. (Abbreviations: FFP = fresh frozen plasma (FFP); ODP - spray-dried plasma (ODP) of the present invention.) [Figure 13A] 1A-1C are two bar graphs showing the results of a platelet adhesion Bioflux study, showing the percentage (%) of arterial shear at intensity NS(10min) 900 s-1 in fluorescence intensity units (FIU) and area NS(10min) coverage. (Abbreviations: NS = normal shear conditions; WB:FFP = whole blood (WB) reconstituted with fresh frozen plasma (FFP); WB:ODP - whole blood reconstituted with spray-dried plasma (ODP) of the present invention; WB + 10% FFP = whole blood resuscitated with 2 units of FFP; WB + 10% ODP = whole blood resuscitated with 2 units of ODP.) Reference ranges are indicated by dotted lines. [Figure 13B] Included are two bar graphs showing the results of a platelet adhesion Bioflux study, showing the percentage (%) of pathological shear at 4000 s of intensity HS(10 min) in fluorescence intensity units (FIU) and area HS(10 min) coverage. (Abbreviations: HS = high shear conditions; WB:FFP = whole blood (WB) reconstituted with fresh frozen plasma (FFP); WB:ODP - whole blood reconstituted with spray-dried plasma (ODP) of the present invention; WB + 10% FFP = whole blood resuscitated with 2 units of FFP; WB + 10% ODP = whole blood resuscitated with 2 units of ODP). Reference ranges are indicated by dotted lines. [Figure 14A]Included are two bar graphs showing the results of a CAT (calibrated automated thrombogram) thrombin generation assay, showing the lag time in minutes and the endogenous thrombin potential (ETP) (nM, min). (Abbreviations: WB:FFP = whole blood (WB) reconstituted with fresh frozen plasma (FFP); WB:ODP - whole blood reconstituted with spray-dried plasma (ODP) of the present invention; WB + 10% FFP = whole blood resuscitated with 2 units of FFP; WB + 10% ODP = whole blood resuscitated with 2 units of ODP). Reference ranges are indicated by dotted lines. ETP reflects coagulation status and is a measure of whether someone is prone to bleeding (low ETP) or clotting (high ETP). [Figure 14B] 1 includes two bar graphs showing the results of a CAT (calibrated automated thrombogram) thrombin generation assay, showing peak thrombin (nM) and time to peak (min). (Abbreviations: WB:FFP = whole blood (WB) reconstituted with fresh frozen plasma (FFP); WB:ODP - whole blood reconstituted with spray-dried plasma (ODP) of the present invention; WB+10%FFP = whole blood resuscitated with 2 units of FFP; WB+10%ODP = whole blood resuscitated with 2 units of ODP). Reference ranges are indicated by dotted lines. [Figure 15A] 1 includes three bar graphs showing the flow cytometry results of the remaining cellular material in total events, total labeled events, and CD41A (platelets) events. (Abbreviations: FFP = fresh frozen plasma (FFP); ODP - spray-dried plasma (ODP) of the present invention. [Figure 15B] Contains three bar graphs showing the results of flow cytometry of residual cellular material for CD45 (WBC) and CD235 (RBC). (Abbreviations: FFP = fresh frozen plasma (FFP); ODP - spray-dried plasma (ODP) of the present invention; WBC - white blood cells; RBC - red blood cells). [Figure 16]Panels A-C are schematic diagrams showing the unfolding / refolding model of the vWF A2 domain and proton cleavage by ADAMTS13. (A) Illustration of the vWF A2 domain in its native folded state. (B) The first step of unfolding occurs from the C-terminus of the vWF A2 domain and is influenced by the presence of a proximal disulfide bond (cysteine ​​indicated by C). Initial unfolding occurs up to and including the central b4 sheet, which contains the scissile bond (YM). This intermediate step of unfolding exposes the high-affinity ADAMTS13 spacer-binding site. (C) Once the stabilizing effect of the calcium-binding site (CBS) is overcome, this leads to the complete unfolding of the vWF A2 domain and positions the ADAMTS13 active site for nucleophilic attack of the Y1605-M1606 scissile bond. [Figure 17] This is a bar graph showing that formulations of citrate-containing plasma stabilize during spray drying approximately 50% of von Willebrand factor:ristocetin cofactor (vWF:RCo) activity without any effect on other coagulation factors (prothrombin (PT), activated partial thromboplastin time (aPTT), fibrinogen (FGN), factor V (FV), factor VII (FVII), factor VIII (FVIII), factor IX (FIX), vWF antigen (vWF-Ag), % von Willebrand factor:ristocetin cofactor (vWF:RCo)). This is normalized to control plasma (fresh frozen plasma (FFP)) at time 0, the completion of spray drying. CP indicates control plasma; SpDP indicates spray-dried plasma; PreT indicates plasma formulation by SDSAS. [Figure 18]This is a bar graph showing that formulation of plasma with citrate confers stability to vWF and all other coagulation factors (prothrombin (PT), activated partial thromboplastin time (aPTT), fibrinogen (FGN), factor V (FV), factor VII (FVII), factor VIII (FVIII), factor IX (FIX), vWF antigen (vWF-Ag), and % von Willebrand factor:ristocetin cofactor (vWF:RCo)) during 6 weeks of storage at 4°C. SpDP indicates spray-dried plasma. PreT indicates plasma preparation by SDSAS. CP indicates control plasma, and FFP is fresh frozen plasma. [Figure 19] This is a bar graph showing that pre-treatment of plasma with citrate confers stability to vWF and all other coagulation factors (prothrombin (PT), activated partial thromboplastin time (aPTT), fibrinogen (FGN), factor V (FV), factor VII (FVII), factor VIII (FVIII), factor IX (FIX), vWF antigen (vWF-Ag), and % von Willebrand factor:ristocetin cofactor (vWF:RCo)) after 2 weeks of storage at 25°C. SpDP indicates spray-dried plasma. PreT indicates plasma preparation by SDSAS. CP indicates control plasma, and FFP is fresh frozen plasma. [Figure 20] 1 is a bar graph showing that formulation of plasma with citrate confers stability to coagulation factors (prothrombin (PT), activated partial thromboplastin time (aPTT), fibrinogen (FGN), factor V (FV), factor VII (FVII), factor VIII (FVIII), factor IX (FIX), and vWF antigen (vWF-Ag)) during 2 weeks of storage at 37°C. SpDP indicates spray-dried plasma. PreT indicates plasma preparation by SDSAS. CP indicates control plasma, and FFP is fresh frozen plasma. [Figure 21] 1 is a photographic image showing that formulation of plasma with citrate stabilizes vWF during SpD (spray drying). CP indicates control plasma; SpDP indicates spray-dried plasma; PreT indicates plasma formulation with SDSAS; FFP indicates fresh frozen plasma. [Figure 22A] This is a line graph showing the CP / FFP and pH of delivered plasma under a constant plasma delivery rate of 10 mL / min but variable aerosol gas flow rates (0, 5, 10, 15, and 20 L / min). CP indicates control plasma; FFP indicates fresh frozen plasma; vWF indicates von Willebrand factor. [Figure 22B] 1 is a line graph showing the resulting activity (%, IU / dL) of vWF:RCo activity of CP / FFP and fed plasma under a constant plasma feed rate of 10 mL / min but variable aerosol gas flow rates (0, 5, 10, 15, 20 L / min). CP denotes control plasma; FFP denotes fresh frozen plasma. [Figure 23A] A line graph showing the pH of CP / FFP and supplied plasma at an aerosol gas flow rate of 10 L / min; fluid = 2 mL / min, 10 L / min; fluid = 4 mL / min, 10 L / min; fluid = 6 mL / min, 10 L / min; fluid = 8 mL / min, 10 L / min; and fluid = 10 mL / min. CP indicates control plasma; FFP indicates fresh frozen plasma; vWF indicates von Willebrand factor. vWF:RCo (vWF activity measured by vWF ristocetin assay). [Figure 23B] 1 is a line graph showing the resulting vWF:RCo activity (%, IU / dl) of donated plasma at CP / FFP and aerosol gas flow rates of 10 L / min; fluid = 2 mL / min, 10 L / min; fluid = 4 mL / min, 10 L / min; fluid = 6 mL / min, 10 L / min; fluid = 8 mL / min, 10 L / min; fluid = 10 mL / min. CP indicates control plasma; FFP indicates fresh frozen plasma. [Figure 24] 1 is a bar graph showing the effect of different SDSAS formulations on vWF:RCo recovery and pH during nebulization. pH levels before and after nebulization are indicated above the bar graph. CP indicates control plasma; FFP indicates fresh frozen plasma; vWF indicates von Willebrand factor. [Figure 25A]Bar graphs showing the effect of different SDSAS formulations on vWF:RCo recovery and pH during spray drying. (A) Citric acid. pH levels before and after spraying are indicated at the top of the bar graph. vWF stands for von Willebrand factor. vWF:RCo (vWF activity measured by vWF ristocetin assay). [Figure 25B] (B) Bar graphs showing the effect of different SDSAS formulations on vWF:RCo recovery and pH during spray drying. (C) Lactic acid. pH levels before and after spraying are indicated at the top of the bar graph. vWF stands for von Willebrand factor. vWF:RCo (vWF activity measured by vWF ristocetin assay). [Figure 25C] (C) Bar graphs showing the effect of different SDSAS formulations on vWF:RCo recovery and pH during spray drying. (D) pH. pH levels before and after spraying are indicated at the top of the bar graph. vWF stands for von Willebrand factor. vWF:RCo (vWF activity measured by vWF ristocetin assay). [Figure 26] 1 is a color line graph showing the amount of C3 ang / mL and pH for batches 1543, 1542, 1541 and their respective control plasmas (CP) for the experiments performed in Example 16. [Figure 27] 1 is a line graph showing the amount of C5 ang / mL and pH for batches 1543, 1542, 1541 and their respective control plasmas (CP) for the experiments conducted in Example 16. [Figure 28] 1 is a bar graph showing C5a analysis of control plasma (CP) / tube with 400 mM glycine HCl, 400 mM glycine HCl + 1 M glycine, 148 mM citric acid, 148 mM citric acid + 1 M glycine (n=7) and non-frozen plasma (NFP) pretreated rapidly and slowly with control plasma / non-frozen plasma (CP / NFP). [Figure 29]1 is a bar graph showing C3a measurements in ng / mL of CP / FFP (control plasma / fresh frozen plasma), CP / FFP / PreT (control plasma / fresh frozen plasma / pre-treated), and ODP / NFP / PreT (on-demand plasma (applicant's inventive spray-dried plasma), not frozen, pre-treated) mean of n=20±1 SD. [Figure 30] 1 is a bar graph showing mean C5a measurements in ng / mL for CP / FFP, CP / FFP / PreT, and ODP / NFP / PreT, n=20±1 SD. [Figure 31] 1 is a bar graph showing antigen measurements normalized to ODP / NFP / PreT activity and CP / FFP. [Figure 32] 1 is a bar graph showing aPTT (activated partial thromboplastin time), PT (prothrombin time), and TT (thrombin time) of ODP / NFP / PreT normalized by CP / FFP. [Figure 33] 1 is a bar graph showing vWF antigen (von Willebrand factor), vWF:RCo (vWF activity measured by vWF ristocetin assay), and vWF activity of ODP / NFP / PreT (on-demand plasma (applicant's inventive spray-dried plasma), not frozen, pre-processed) normalized to CP / FFP (control plasma / fresh frozen plasma). [Figure 34] 1 is a bar graph showing activation marks D-Dimer, TAT and F1+2 of ODP / NFP / PreT (on-demand plasma (applicant's inventive spray-dried plasma) not frozen, pre-processed) normalized with CP / FFP (control plasma / fresh frozen plasma). [Figure 35] 1 is a bar graph showing chemistry analyzer results of ODP / NFP / PreT (on-demand plasma (applicant's inventive spray-dried plasma), not frozen and pre-processed) for IgG, IgM, IgA, total protein, albumin, triglycerides, cholesterol, LDL cholesterol, HDL cholesterol and calcium normalized to CP / FFP (control plasma / fresh frozen plasma). [Figure 36]1 is a bar graph showing thromboelastography hemostasis system (TEG) results for R reaction time (min), K (min), α (angle), and MA (maximum amplitude (mm)) of ODP / NFP normalized to CP / FFP (control plasma / fresh frozen plasma). [Figure 37A] 1 is a bar graph showing clotting profile results and ELISA assay results for various clotting factors and complement activation for unfrozen plasma pretreated with 400 mM glycine HCl and spray-dried at exhaust gas temperatures of 49, 50, 51, and 52° C. [Figure 37B] 1 is a bar graph showing coagulation activation and complement activation marks (D-dimer, TAT, PF1.2, C3a, and C5a) of fresh frozen plasma normalized to control plasma pretreated with 400 mM glycine HCl and spray-dried at exhaust gas temperatures of 49, 50, 51, and 52° C. [Figure 38A] 1 is a bar graph showing C5a levels in ng / mL at 10 minutes, 1 hour, 2 hours, and 21 hours for rehydrated plasma pretreated with 400 mM, 280 mM, and 140 mM glycine HCl (GlyHCl) and 148 mM, 100 mM, and 50 mM citric acid (CA). [Figure 38B] 1 is a bar graph showing the pH of plasma pretreated with 400 mM, 280 mM, 140 mM glycine HCl (GlyHCl) and 148 mM, 100 mM, and 50 mM citric acid (CA). [Figure 39] 1 is a line graph plotting the pH level of the pretreatment solution and pretreatment plasma sample versus the glycine concentration (mM). [Figure 40] 1 is a bar graph showing C5a levels (ng / mL) for 400 mM glycine HCl supplemented with increasing concentrations of glycine (0, 400, 600, 800, 1000, 1200, 1400, and 1600 mM) at 10 and 60 minutes using rapid mixing (e.g., when a larger volume of plasma is quickly added to a relatively small volume of pretreatment solution). [Figure 41A]1 is a line graph showing the pH of plasma (batches 1949 and 1950) pretreated with pretreatment solution and 400 mM lactate and supplemented with increasing concentrations of glycine (0, 400, 600, 800, 1000, 1200, 1400, and 1600 mM). [Figure 41B] 1 is a bar graph showing C5a levels in ng / mL in plasma (batches 1949 and 1950) pretreated with 400 mM lactate and supplemented with increasing concentrations of glycine, where the pretreated plasma had concentrations of 0, 20, 30, 40, 50, 60, 70, and 80 mM glycine. [Figure 42A] Schematic diagram showing a perspective view of a spray drying disposable device including a liquid plasma bag, a spray drying head, and a spray drying chamber, the disposable having alignment elements that allow it to be aligned with the spray drying equipment and finishing equipment. [Figure 42B] 1 is a model representation of the three-dimensional flow geometry of the disposable flow model in operation, which is used to create the computer flow models described herein. [Figure 43A] FIG. 42B is a schematic diagram showing a perspective view of the spray drying head of the spray drying disposable device shown in FIG. 42A. [Figure 43B] 42B is a schematic diagram showing an exploded view of the spray drying nozzle assembly and spray drying head of the spray drying disposable device shown in FIG. 42A. [Figure 43C] FIG. 1 is a schematic diagram showing a perspective view of a spray drying nozzle assembly from the spray drying head of a spray drying disposable device. [Figure 43D] 43D is a schematic diagram showing a perspective view of the spray drying nozzle assembly of FIG. 43C, but with the aerosol reservoir housing transparent to show the internal structure of the assembly. [Figure 43E] FIG. 43D is a schematic diagram showing a perspective view of the spray drying nozzle assembly of FIG. 43C with the aerosol reservoir housing and the nozzle cap and nozzle cap insert removed to show the manifold and cannula. [Figure 43F]FIG. 1 is a schematic diagram showing a front view of one embodiment of a beveled edge cannula that is part of a spray drying nozzle assembly. [Figure 43G] FIG. 10 is a schematic diagram showing a perspective top view of the cannula and the nozzle cap insert that guides the aerosolized air. [Figure 43H] FIG. 10 is a schematic diagram showing a perspective bottom view of the nozzle cap insert with the cannula inserted. [Figure 43I] FIG. 2 is a schematic diagram showing a top view of the nozzle cap. [Figure 43Ia] FIG. 43I is a schematic diagram showing a bottom view of the nozzle cap of FIG. 43I, with the annular member residing within the cap opening. [Figure 43Ib] 43I is a schematic diagram showing three possible vortex generator flow patterns that can be used with the nozzle cap insert of FIG. 43I. [Figure 43Ic] FIG. 43I is a schematic diagram showing a cross-sectional view of the nozzle cap insert of FIG. 43H residing within the nozzle cap of FIG. 43I. [Figure 43J] FIG. 1 is a schematic diagram showing a perspective bottom view of the plenum of the spray drying head. [Figure 43K] FIG. 1 is a schematic diagram illustrating a partial front view of a spray dryer showing a portion of a drying gas deflector. [Figure 43Ka] FIG. 1 is a diagram showing modeled dry gas flow in a plenum chamber using a 15 m / s constant velocity amplitude surface. [Figure 43L] FIG. 2 is a schematic diagram showing a top perspective view of a baffle plate of a spray drying head. [Figure 43La] FIG. 43La is a schematic diagram showing a cut-out portion of the baffle plate rib design shown in FIG. 43L and a cut-out portion of another variation of the baffle plate rib design, and also shows a cross section of one of the ribs. [Figure 43M] FIG. 2 is a schematic diagram showing a perspective bottom view of a baffle plate of a spray drying head. [Figure 43Ma] Model representation showing uniform jet penetration and drying gas distribution at a constant velocity of 25 m / s, thus introducing uniform drying gas circumferentially around the spray plume. [Figure 43N] FIG. 1 is a schematic diagram illustrating droplet plume formation, aerosol gas flow, and drying gas flow to promote rapid mixing in a disposable device of the present invention. [Figure 43Na] FIG. 10 is a model diagram showing gas velocity magnitude contours within the disposable center plane, illustrating the drying jet penetration into the drying chamber and the effect of the baffle plate flow paths and their interaction with the high velocity spray plume, which acts to draw the drying gas jet radially inward to aid in the desired rapid mixing of the droplets with the gas flow. [Figure 43O] FIG. 1 is a model diagram showing the gas pressure flow (psig) (top) and tangential velocity flow (m / s) (bottom) of the vortex generated within the nozzle insert and cap assembly. [Figure 43P] 1 is a model diagram showing gas velocity amplitude flow (m / s) in the components of a vortex generator. [Figure 43Q] FIG. 1 is a schematic diagram showing the transformation of droplets into dry particles using a disposable of the present invention. [Figure 43R] 1 is a line graph showing droplet wet bulb temperature (° C.) and drying gas temperature (° C.) for droplets dried to particles with 0% relative humidity (RH), 10% RH, and 20% RH. This particular graph illustrates the concept but is not specific to plasma. [Figure 43S] 1 is a line graph showing the evaporative mass transfer of droplet temperature over time for all mean droplet trajectories averaged over three simulated drying gas inlet temperatures in the model: 80° C., 100° C., and 114° C. Note that the evaporation process cools the droplets to keep the delicate liquid protein below 30° C. [Figure 43Sa] Line graph of temperature in °C vs. time (seconds) of plasma droplets as they become particles in the model. Once evaporation is complete, the proteins encased in solid particles are more resistant to high temperatures because they equilibrate with the dryer outlet temperature. In this case, evaporation occurs in less than a fraction of a second (e.g., 0.01-0.05 seconds). [Figure 43T]FIG. 1 is a model diagram showing the paths of droplets having sizes of 5 microns, 15 microns, and 25 microns during evaporation. The diagram shows that smaller droplet size allows for more rapid evaporation mass transfer over a shorter path, allowing for a physically smaller drying chamber. [Figure 44A] FIG. 42B is a schematic diagram showing an exploded view of the drying chamber of the spray drying disposable device shown in FIG. 42A. [Figure 44B] FIG. 1 is a schematic diagram showing a front view of a separator or spacer that can be used in the drying chamber of a spray drying disposable. [Figure 45A] FIG. 2 is a schematic diagram showing a front view of the spray drying apparatus with the door closed. [Figure 45B] FIG. 1 is a partial front view of the spray drying apparatus without the door to reveal the drying chamber housing with alignment elements that allow alignment with the spray drying disposable device. [Figure 45C] FIG. 1 is a schematic diagram showing a front view of the spray drying apparatus with the door handle engaged and the door open. [Figure 46A] 1 shows an alignment element for aligning the spray drying disposable device with the spray drying apparatus. [Figure 46B] FIG. 1 is a schematic diagram showing a partial front view of a spray drying apparatus without the door, with the spray drying disposable device installed, and with the deflector engaged. [Figure 46C] 2 is a schematic diagram showing the structure of dryer 200. Abbreviations included are: AM - air manifold, B - transfer bag, CN - connector, DPT - differential pressure transducer, F - filter, FS - flow sensor, H - heater, MFC - mass flow controller, OS - sensor, P - peristaltic pump, PP - pneumatic piston, PR - pressure regulator, PRV - pressure relief valve / rupture disc, PT - pressure transducer, PV - valve (downward arrow is fail closed, upward arrow is fail open), S - scale, SS - solenoid, TC - thermocouple, TS - thermocouple sensor, and TT - temperature transducer. [Figure 46D]1 is a flow chart showing the steps of a leak detection method using a spray dryer and spray dried disposables. [Figure 46E] 1 is a flowchart showing the steps of a pressure detection method using a spray dryer and spray drying disposables. [Figure 46F] 1 is a flow chart showing the steps of a method for detecting the integrity of a filter and disposable interface using a spray dryer and spray dried disposables. [Figure 46G] 1 is a line graph showing the slope using a method to detect filter integrity and demonstrating that the filter is intact by measuring pressure (psig), elapsed time (min), and rate of pressure change (psi / min). [Figure 46H] 1 is a line graph showing the slope using a method to detect filter integrity and demonstrate that the capture filter failed intact by measuring pressure (psig), elapsed time (minutes), and rate of pressure change (psi / minute). [Figure 46I] 1 is a line graph showing the slope using a method to detect filter integrity and showing that a baffled filter failed intact by measuring pressure (psig), elapsed time (minutes), and rate of pressure change (psi / minute). [Figure 47A] FIG. 1 is a schematic diagram showing a front view of the finishing device in the loading position with no spray drying disposables attached. [Figure 47B] 47B is a schematic diagram showing a front view of the finishing device of FIG. 47A without the front cover with the shuttle in the lowered position. FIG. [Figure 47C] FIG. 47C is a schematic diagram showing a front view of the finishing device of FIG. 47B with the shuttle in the raised position and no disposables attached. [Figure 47D] FIG. 10 is a schematic diagram showing a front view of another embodiment of the finishing device in a raised position and without spray drying disposables attached. [Figure 47E] FIG. 47D is a schematic diagram showing a front view of the finishing device of FIG. 47D without the front cover with the shuttle in the raised position. [Figure 47F]FIG. 47D is a schematic diagram showing a front view of the finishing device of FIG. 47D without the front cover with the shuttle in the lowered position. [Figure 47G] FIG. 47D is a schematic diagram showing a front view of the finishing device of FIG. 47D but without the front cover with the shuttle in the raised and inverted position. [Figure 47H] FIG. 47D is a schematic diagram showing a front view of the finishing device of FIG. 47D without the front cover with the shuttle in a lowered and inverted position. [Figure 47I] FIG. 47D is a schematic diagram showing an enlarged perspective view of a portion of the rail system of the finishing device of FIG. 47D. [Figure 48A] FIG. 1 is a schematic diagram showing a front view of the finishing device with the disposable spray drying head in the aligned and mounted position. [Figure 48B] FIG. 1 is a schematic diagram showing a front view of the finishing device with the disposables in an aligned, raised position. [Figure 48C] A schematic diagram showing a front view of the finishing device in a raised position with a portion of the disposable attached after the first sealing and separation step has been completed and the frame has been rotated into place. [Figure 48D] FIG. 10 is a schematic diagram showing a front view of another embodiment of the finishing device in a raised position with spray drying disposables attached. [Figure 48E] FIG. 48E is a schematic diagram showing a front view of the finishing device shown in FIG. 48D in the lowered position with spray dryer disposables attached. [Figure 48F] FIG. 48D is a schematic diagram showing a front view of the finishing device shown in FIG. 48D in the raised and inverted positions with spray dryer disposables attached. [Figure 48G] FIG. 48E is a schematic diagram showing an enlarged top view of the receiver of the finishing device shown in FIG. 48D. [Figure 48H] FIG. 48E is a schematic diagram showing an enlarged perspective view of the receiver of the finishing device shown in FIG. 48D. [Figure 48I] FIG. 48E is a schematic diagram showing an enlarged perspective view of the tensioner of the finishing device shown in FIG. 48D. [Figure 48J]FIG. 48E is a schematic diagram showing an enlarged perspective view of a separator having a roller that engages with a tensioner of the finishing device shown in FIG. 48D. [Figure 48K] FIG. 48E is a schematic diagram showing an enlarged perspective view of the impactor, separator, and sealer of the finishing device shown in FIG. 48D. [Figure 48L] FIG. 48E is a schematic diagram showing a side view of the impactor, separator, and sealer of the finishing device shown in FIG. 48D. [Figure 49A] FIG. 1 is a schematic diagram showing a front view of a spray-dried plasma unit obtained from a spray-drying disposable device after processing by a finishing apparatus. [Figure 49B] 4 is a schematic diagram showing the structure of a finisher 400'. Abbreviations included are: AM - air manifold, CN - connector, CV - check valve, EM - electric motor, FS - flow sensor, FR - flow restrictor, PP - pneumatic piston, PR - pressure regulator, PT - pressure transducer, PV - valve arrow (downward arrow is fail closed, upward arrow is fail open), SC - speed controller, SR - sensor, and VG - vacuum generator. [Figure 50] 1 is a bar graph comparing the vWF% ratio of reconstituted plasma (vs. undried control aliquots) dried using disposable devices with composite nozzle assemblies without a bevel, with a bevel and a reference stainless steel nozzle. [Figure 51A] 1 is a flowchart illustrating steps of a pre-processing methodology. [Figure 51B] 1 is a flow chart showing steps of a spray drying method using a spray dryer and spray drying disposables. [Figure 51C] 1 is a flow chart showing the steps of a finishing method using a finisher and spray-dried disposables to create dried plasma units. [Figure 51D] 1 is a flow chart showing steps of a storage method after the spray drying unit has been prepared. [Figure 52]Schematic diagram showing cannula geometry to demonstrate shear on vWF protein as it exits the cannula. The curved arrow indicates the aerosol gas vortex direction within the annulus. To demonstrate the amount of shear impact on the liquid plasma at the cannula exit region, the diagram shows cannula edges at 15, 90, 45 degrees (with chamfers and sharp edges), and 60 degrees, showing how the angled edges reduce the shear contact of the cannula. DETAILED DESCRIPTION OF THE INVENTION

[0029] Embodiments of the present disclosure relate to methods and compositions for spray-drying liquid samples. In certain embodiments, the liquid sample is plasma obtained from a blood donor. In preferred embodiments, the blood donor is a human. However, it can be understood that the disclosed embodiments can be used to spray-dry any biological mixture of solid particles and / or molecules in a continuous liquid medium, including, but not limited to, colloids, suspensions, and sols (colloidal suspensions of very small particles).

[0030] The control of reconstituted dried plasma pH according to the present invention using spray drying as described herein is an improvement over reported pH control of reconstituted plasma produced by freeze-drying or lyophilization. Excessively high or low plasma pH is associated with increased morbidity or mortality, including a pH above 7.8 ("alkalosis"). In this respect, the present invention is superior to prior art freeze-dried products and processes. The drying process results in the loss of CO2, which increases the pH of the dried product unless controlled in some way. The present invention allows for reconstitution with sterile water alone, without additional processing steps, and has been approved for clinical trials by the United States Food and Drug Administration. Reconstitution with sterile water alone is highly desirable in dried plasma products. In the event of loss or damage of the pre-measured, pre-packaged sterile water for reconstitution provided as part of an emergency kit, ER, OR, or other emergency use of any dried plasma, a readily available measured amount of sterile water can be used for reconstitution.

[0031] "Human freeze-dried plasma is alkaline, with a pH near 8..." Zaza M, Kalkwarf KJ, Holcomb JB. Dried Plasma. Damage Control Resuscitation. 2019;145-162. Published 2019 May 6. doi:10.1007 / 978-3-030-20820-2_8, page 8, second full paragraph. Zaza et al. defend this by stating, however, that "[freeze-dried plasma] is clinically well tolerated in humans," citing only a 2013 paper by Saillol, et al., "The evolving role of lyophilized plasma in remote damage control resuscitation in the French Armed Forces Health Service." Transfusion. 2013;53:65S-71S. Saillol's paper concerns freeze-dried plasma from the French military, known as French Lyophilized Plasma (FLYP). Saillol et al. acknowledge that "the pH upon reconstitution [of FLYP] approaches 8." Ibid. at 67S. Saillol et al.'s report is limited to combat situations of severe hemorrhage, where the protocol involves FLYP containing tranexamic acid, red blood cells in a 1:1 ratio, and other actions to control the patient's blood pH. Ibid. at 66S. Saillol et al. acknowledge that "further research is needed to determine the specific indications for FLYP in the therapeutic management of civilian patients with severe hemorrhage." Ibid. in the last sentence of the Abstract (see page 65S). In contrast, the lower, well-controlled pH of the present invention is expected to be suitable for use in all situations where plasma infusion is indicated in any amount under any circumstances.

[0032] The pH of reconstituted dried plasma produced by the Terumo-BCT freeze-drying process has been reported to be high, ranging from 7.66 to 7.94. 7.94 is very close to 8.0. The so-called French Lyophilized Plasma (FLYP) plasma product produced by the French Army has also been reported to have a reconstituted pH "close to 8.0." Flaumenhaft, et al., "Retention of Coagulation Factors and Storage of Freeze-Dried Plasma," Military Med., Vol. 6, January / February Supplement, pp. 400-407, 403 (2021). See "TFDP [Terumo Freeze-Dried Plasma] units exhibited a significant elevation in pH after freeze-drying, as expected based on other lyophilized plasma products…" "Sheffield WP, ​​et al.," Retention of hemostatic and immunological properties of frozen plasma and COVID-19 convalescent apheresis in fresh-frozen plasma produced and freeze-dried in Canada," Transfusion. 2021 Dec 14. doi:10.1111 / trf.16772. Epub ahead of print. PMID:34907536.) No Terumo freeze-dried plasma products have been approved for clinical trials in the United States or elsewhere. FLYP plasma was not the subject of clinical trials in the United States. The Flaumenhaft authors concluded that the high pH of Terumo-BCT reconstituted freeze-dried plasma material, with a FLYP plasma pH close to 8.0, "is within the Terumo-BCT required range of 7.0 to 8.0" and "aligns" with the FLYP plasma pH. In contrast, the pH of the spray-dried plasma products of the present invention does not exceed 7.8 and generally has a pH range closer to physiological pH.

[0033] The reported pH of reconstituted dried plasma produced by Teleflex's freeze-drying process is not reported. However, because it is significantly higher than physiological pH (more alkaline) at the end of the freeze-drying process, Teleflex, in its investigator agreement with the United States Food and Drug Administration, has stated that its REPLAS TM Freeze-dried plasma has been described as requiring additional processing and equipment to lower the pH of the Teleflex product upon reconstitution. Specifically, an acidic reconstitution fluid must be used to restore the pH of the reconstituted [freeze-dried plasma] to physiological pH before infusion. Van, et al., J Trauma Injury, Infection and Critical Car Vol 71 No 1, p22 (July 2011). Indeed, according to Van, preliminary studies in our laboratory revealed that LP reconstituted without acid had a pH of approximately 9, and its infusion resulted in rapid death. Ibid. at 20. REPLAS TM The freeze-drying process is described as including the following steps: "Breaking the vacuum chamber with medical-grade carbon dioxide (CO2) gas to compensate for the loss of dissolved CO2 from the starting plasma material during the freeze-drying process" and "In addition, REPLAS TM"The product is packaged in an outer foil pouch that is flushed with a fixed amount of CO2 gas and reconstituted...to bring the product to a near-neutral pH." Jose A. Cancelas, Investigator's Agreement A Phase 1, Single-Center, Partial Double-Blind, Randomized, Controlled (Versus Fresh Frozen Plasma [Ffp] In Cohort 3 Only) Clinical Study of the Safety of Ascending Doses of Autologous Freeze-Dried Plasma (Fdp) In Healthy Volunteers, April 19, 2018; pp. 24-25. Download date: December 6, 2021. https: / / clinicaltrials.gov / ProvidedDocs / 26 / NCT02930226 / Prot_000.pdf. The spray-dried plasma system of the present invention does not require the sophisticated and expensive use of CO gassing or CO storage of dried plasma to control pH in the reconstituted plasma product, or the equipment required to perform these additional pH correction processes.

[0034] plasma Plasma is the fluid remaining after (for example) blood has been centrifuged to remove cellular material such as red blood cells, white blood cells, and platelets. Plasma is generally yellow in color and clear to opaque. It contains proteins (6-8%; e.g., serum albumin, globulins, fibrinogen, etc.), glucose, clotting factors (clotting proteins), electrolytes (Na + , Ca 2+ , Mg 2+It contains dissolved components of blood, such as soluble components (e.g., HCO3-, Cl), and hormones. Whole blood (WB) plasma is plasma isolated from whole blood without the addition of any drugs other than anticoagulants. Citrate phosphate dextrose (CPD) plasma, as its name suggests, contains citrate, added as an anticoagulant, sodium phosphate, and a sugar, usually dextrose. The citrate level in CPD plasma derived from whole blood is approximately 20-30 mM. Therefore, the final citrate concentration in whole blood-derived CPD plasma formulated with 7.4 mM citric acid is approximately 27.4-37.4 mM.

[0035] The plasma of the present invention may be dried in pools or units. Pooling multiple plasma units has several advantages. For example, adding volume from the pool to the finished product can compensate for deficiencies in factor recovery on an equal volume basis. There are also negative aspects. Creating volume from the pool to improve factor recovery is expensive. Importantly, pooled plasma must be constantly tested for pathogens, since any pathogen entering the pool from, for example, a single donor, risks harming hundreds or thousands of patients if undetected. Even if detected, pathogen contamination of pooled plasma renders the entire pool worthless. Testing can be avoided by inactivating pathogens in the plasma chemically, such as by irradiation or solvent detergent treatment, but each such treatment adds cost and complexity to pooled plasma processing. In any case, pooled plasma processing is generally not suitable for blood centers and is generally only practically suited to industrial, high-volume production environments.

[0036] Conversely, unit-by-unit (unit) collection and processing is well suited to a blood center environment, eliminating the risk of pooled plasma pathogen contamination by allowing for pretreatment testing for pathogens and tracking of units to ensure each unit is free of blood center site pathogens. The inventors have discovered that efficient and effective preservation and recovery of functional clotting factors is a criterion by which successful unit plasma processing should be measured. Such efficiency is also highly useful in a pooled plasma environment.

[0037] clotting factors There are many plasma factors involved in coagulation. The methods and compositions of the present invention involve recovering amounts of functional fibrinogen, Factor V, Factor VII, Factor IX, and vWF from rehydrated plasma that has undergone a spray-drying process. Such plasma factors are important intrapatient treatments, particularly after traumatic injury, to promote wound clotting. Therefore, rapid administration of plasma is an important factor contributing to a good clinical outcome. The spray-dried plasma of the present invention can be easily reconstituted at the site of a traumatic event in minutes, without moving the patient or time delay. Furthermore, the spray-dried plasma of the present invention has high levels of functional proteins that are stable for long periods of time without freezing.

[0038] Functional vWF recovery is generally difficult and serves as a metric for preserving all factors. The present invention encompasses recovering an amount of functional vWF in rehydrated spray-dried plasma that is at least about 5 percentage points higher (e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, or more percentage points) than the amount of functional vWF in rehydrated spray-dried plasma that has not undergone the pretreatment process of the present invention. The present invention encompasses recovering an amount of functional vWF in rehydrated spray-dried plasma that is about 5 to about 40 percentage points higher, or about 10 to about 35 percentage points higher, than the amount of functional vWF in rehydrated spray-dried plasma that has not undergone the pretreatment process of the present invention. vWF activity is typically assayed using an assay known as the von Willebrand factor:ristocetin cofactor (vWF:RCo) assay, as known to those skilled in the art. The vWF:RCo assay measures the ability of a patient's plasma to aggregate platelets in the presence of the antibiotic ristocetin. The rate of ristocetin-induced coagulation is related to the concentration and functional activity of plasma von Willebrand factor. Another assay, the vWF antigen assay, measures the amount of vWF protein present in a sample. Yet another assay to determine whether functional coagulation plasma proteins are present in reconstituted pre-spray-dried plasma is to perform a Bioflux study. See Examples 9 and 10.

[0039] In one embodiment, to determine vWF recovery, one or both of von Willebrand factor antigen (% or IU / dL) and von Willebrand factor ristocetin cofactor (% or IU / dL) are measured before and after spray drying. In one embodiment, an acceptable or clinical range for von Willebrand factor ristocetin cofactor (VWF:RCo) is about 50 to about 200 IU / dL, and von Willebrand factor antigen (VWF:Ag) values ​​are about 50 to 200 IU / dL. In one embodiment, the present invention involves determining the amount of vWF in rehydrated spray-dried plasma using a VWF:RCo assay or a VWF:Ag assay that is at least about 5 percentage points higher (e.g., about 5, 10, 15, 20, 25, or more percentage points) compared to the amount in rehydrated spray-dried plasma that has not undergone the pretreatment process of the present invention.

[0040] A pretreatment solution having one or more spray-dried stable acidic substances (SDSAS) and one or more amino acids. The present invention contemplates the use of a pretreatment solution comprising one or more physiologically compatible spray-drying stable acidic substances (SDSAS) combined with one or more amino acids as a formulation for plasma before it is spray-dried. As used herein, phrases such as "SDSAS and amino acids" refer to a pretreatment solution having at least one SDSAS and / or at least one amino acid. Similarly, the use of "SDSAS" or "amino acids" refers to one or more SDSAS or one or more amino acids, respectively. The phrases "formulated plasma" or "pretreated plasma" or "PreT" refer to a mixture of a pretreatment solution (e.g., at least one SDSAS and / or at least one amino acid) and plasma before spray drying. Dry formulated plasma refers to spray-dried plasma that has been pretreated with a pretreatment solution.

[0041] While the present invention is not limited by theory, the inventors speculate that the SDSAS (e.g., citric acid, lactic acid, hydrochloric acid, etc.) of the present invention exerts its effect by preventing or mitigating the increase in pH of plasma during the spray drying process. The addition of an amino acid to the SDSAS allows the pretreatment solution to still have an acidic pH, but not so low as to damage plasma proteins. Non-limiting examples of suitable SDSAS are hydrochloride (HCl), citric acid, and lactic acid. When SDSAS is combined with an amino acid, for example, glycine HCl is included. SDSAS (e.g., HCl, citric acid, or lactic acid) and an amino acid (e.g., glycine) can be added to plasma in a combined form (e.g., glycine HCl) or as separate compounds (e.g., glycine and HCl). Other non-limiting examples of suitable acids are ascorbic acid and gluconic acid. Since CO2 is lost from plasma during spray drying, bicarbonate and H2O can be converted from CO2 and H2O. + The reaction to produce H + shifts the pH away from the normal range, thereby increasing the pH (i.e., Chatelier's principle). Human blood / plasma contains carbonic acid (H2CO3) and bicarbonate anions (HCO3 - ), which is important for maintaining blood pH between 7.35 and 7.45, as values ​​above 7.8 can be fatal. In this buffer, hydronium (HO) + ) and bicarbonate anion are in equilibrium with carbonic acid (Equation 1). Furthermore, carbonic acid in the first equilibrium can decompose into CO2 gas and water, resulting in a second equilibrium between carbonic acid and water (Equation 2).

[0042] In summary, the blood buffers are as follows: H2CO3 + H2O ⇔ H3O + +HCO3 - (Formula 1)

[0043] The following simultaneous equilibria are used: H2CO3⇔H2O+CO2 (formula 2)

[0044] Spray drying expels CO2 and produces H2CO3 and H3O+ As a result, the pretreatment solution of the present invention serves to safely lower the pH of formulated plasma prior to spray drying, resulting in spray-dried plasma that has a resulting physiologically compatible pH when reconstituted with sterile water for injection.

[0045] The addition of glycine helps offset this change. The addition of an amino acid prevents the pH from becoming too low. Thus, in one embodiment, plasma is formulated with a pretreatment agent having SDSAS and an amino acid. The formulation / pretreatment process results in reduced vWF activity loss and / or increased amounts of native vWF compared to spray-dried plasma not subjected to the formulation process of the present invention. SDSAS is present in the pretreatment solution in an amount of about 1 mM to about 50 mM, and the pH of the formulated plasma is lowered to about 5.5 to about 6.5 or about 7.2 to produce the formulated plasma. When an amino acid such as glycine is also present in the pretreatment solution together with SDSAS in an amount of about 1 mM to about 150 mM, the pH of the formulated plasma is about 6.0 to about 6.6.

[0046] Thus, due to the inclusion of physiologically compatible SDSAS and amino acids in the present invention, the inventors have further determined that the rehydration step can be carried out with water alone (e.g., SWFI). Alternatively, sodium phosphate or other agents can optionally be added to the rehydration solution. Furthermore, any other suitable rehydration solution can be used, as can be determined by one of skill in the art.

[0047] Experiments conducted by the present inventors using spray drying have revealed that the level of von Willebrand factor activity in plasma dried by spray drying is affected, in part, by the shear forces generated during the aerosolization process (see Examples below) and the increase in plasma pH. The present invention demonstrates that utilizing a process in which plasma is formulated with at least one SDSAS and at least one amino acid significantly improves the recovery and stability of active vWF over conditions in which SDSAS and an amino acid are not used as formulation agents.

[0048] SDSAS are substances that do not readily evaporate at room temperature and atmospheric pressure. Typically, the boiling point of an SDSAS is greater than about 150°C at atmospheric pressure. In addition to glycine HCl, non-volatile acids suitable for use as the SDSAS of the present invention include phosphorus-containing acids such as ortho-phosphoric acid, pyrophosphoric acid, meta-phosphoric acid, polyphosphoric acid, alkyl- and aryl-substituted phosphonic and phosphinic acids, phosphorous acid, and mixtures thereof. Other non-volatile acids suitable for use as the SDSAS of the present invention include, but are not limited to, ascorbic acid, citric acid, lactic acid, gluconic acid, oxalic acid, halogenated acetic acids, arenesulfonic acids, molybdic acid, phosphotungstic acid, tungstic acid, chromic acid, sulfamic acid, and the like.

[0049] In one embodiment, the pretreatment solution of the present invention can comprise one or more SDSAS and one or more amino acids. Adding an amino acid to SDSAS allows for the protection of plasma proteins without lowering the pH too much, which could result in protein damage and other adverse effects, such as complement activation. The addition of an amino acid increases the pH of the pretreatment solution, but surprisingly does not affect the pH of the rehydrated spray-dried plasma (ODP). In particular, the pH of the pretreatment solution is within the range of about 2.0 to about 4.0, resulting in formulated plasma (e.g., prior to spray drying) having a pH of about 6.0 to about 6.6, and rehydrated plasma having a pH of about 6.5 to about 7.8. In one embodiment, the pretreatment solution of the present invention comprises SDSAS and at least one (e.g., one or more) amino acids. The total concentration of amino acids present in the pretreatment solution is in an amount of about 1 mM to about 150 mM. Examples of amino acids that can be added to the SDSAS pretreatment solution include alanine, asparagine, glutamine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In a specific embodiment, glycine is added to the SDSAS composition, as shown in the Examples. The addition of an amino acid increases the pH of the pretreatment solution, but surprisingly does not affect the pH of the rehydrated spray-dried plasma (ODP). See Example 17. Even more surprisingly, the addition of an amino acid mitigates the increase in C5a. See Example 16. These amino acids have at least two pKa values, as follows:

[0050] [Table 1]

[0051] The SDSAS useful in the process of the present invention can replace (or compensate for) the volatile acid, i.e., CO, that escapes from plasma during spray drying. As noted above, example or suitable acids include, but are not limited to, glycine HCl, ascorbic acid, citric acid, gluconic acid, and lactic acid.

[0052] Volatile acids, as defined herein, have a pKa of less than about 3 at atmospheric pressure and a boiling point of less than about 150° C. Typically, the pKa of a volatile acid is in the range of about 1 to about 15. Non-limiting examples of volatile acids are hydrogen chloride, hydrogen bromide, hydrogen iodide, hydrogen fluoride, acetic acid, formic acid, hydrogen sulfide, hydrogen selenide, sulfur dioxide, fluorosulfonic acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and the like.

[0053] Volatile strong acids can be immobilized with amino acids, etc., to make them nonvolatile and facilitate their use. For example, volatile hydrogen chloride can be converted to glycine hydrochloride (glycine HCl, glycine hydrochloride). To distinguish this from adding amino acids to the pretreatment solution, this describes how SDSAS is produced. The pretreatment solution involves adding an amino acid that is not bound to an acid already conjugated to a stable SDSAS. Alternatively, glycine and HCl can be added to the pretreatment solution in such amounts to form an SDSAS (e.g., glycine HCl) and free amino acid (e.g., glycine) in solution. Because there is a 1:1 relationship between glycine and HCl, more glycine can be added than HCl to obtain a solution containing free glycine and glycine HCl. In one embodiment of the present invention, HCl and glycine are added to a solvent, such as SWFI, to create a pretreatment solution with a final concentration of about 16.8 mM HCl and about 69.6 mM glycine in the formulated plasma. In other words, in one embodiment of the present invention, 5.2 mM HCl and 21.5 mM glycine are added to 50 mL of a solvent, such as SWFI, to form a pretreatment solution. The present invention includes adding the following to a solvent, such as SWFI, to form a pretreatment solution: about 3.0 to about 7.0 mmol (e.g., 3.0, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, and 7.0 mmol) of HCl and about 15 to about 30 mmol of glycine (e.g., about 15, 17, 20, 22, 25, 27, and 30 mmol) in 50 mL of solvent to obtain 260 mg of formulated plasma. Thus, the pretreatment solution contains about 440 mM glycine and about 106 mM HCl. In one embodiment, about 290 mM to about 570 mM (e.g., about 290, 300, 350, 400, 450, 500, 550, and 570) glycine and about 70 mM to about 140 mM (e.g., 70, 80, 90, 100, 110, 120, 130, 140 mM) HCl are present in the pretreatment solution.

[0054] In this case, 16.8 mM glycine HCl and 86.4 (69.6 to 16.8) glycine are present in the formulated plasma of the present invention, which is within the range of about 1 mM to about 50 mM SDSAS and about 1 mM and about 150 mM amino acids (e.g., 50 mM to about 100 mM). The following table shows how the above calculations were obtained.

[0055] [Table 2]

[0056] In one embodiment, a pretreatment solution of the present invention can have a formulation ratio of 405 mM glycine to 98 mM HCl. This embodiment can be advantageously used to treat approximately 266 mL of plasma to be dried with 53 mL of pretreatment solution consisting of 1.61 g of glycine and 0.52 g of HCl, or the equivalent. This formulation results in approximately 67 mM glycine and approximately 16 mM HCl in approximately 319 mL of formulated plasma before the plasma is spray-dried.

[0057] A study of pooled ABO-matched non-frozen plasma (NFP) derived from whole blood treated with a citrate phosphate dextrose (CPD) anticoagulation regimen and pretreated with the pretreatment solution of the present invention demonstrated that dilutions of the pretreatment solution of the present invention with the dried plasma at +20%, +10%, +5%, -5%, -10%, and -20% did not significantly affect the characteristics of the dried plasma when reconstituted and then assayed using a 25-assay panel. In particular, the effect of the pretreatment dilution range on the sensitive vWFRCo assay demonstrated that the normalized recovery of vWF by the assay was within the error range exhibited by the control plasma. pH was also well controlled, ranging from 7.32 to 6.84, with the pH of the control plasma being 7.11.

[0058] These results demonstrate that the pretreatment solution of the present invention reliably enables the production of spray-dried plasma that, after reconstitution, exhibits assay panel results comparable to those of NFP, FFP, and PF24 and has essentially the same assay characteristics as NFP, FFP, and PF24.

[0059] The pretreatment solution of the present invention can have a weight ratio of glycine to HCl of approximately 5 to 3. The formulated plasma treated with the pretreatment solution of the present invention can have a ratio of glycine to HCl in mmol / ml of approximately 5 to 3.

[0060] In one embodiment, the present invention involves adding a volatile acid and an amino acid as separate compounds (e.g., not as salts) to create a solution. The volatile acid and amino acid should be added in amounts that result in about 1 mM to about 50 mM SDSAS and about 1 mM and about 150 mM amino acids. When there is a 1:1 relationship between the volatile acid and the amino acid, such as in the case of HCl and glycine, they are added in equal amounts ranging from about 1 mM to about 50 mM, respectively, and an additional amount of amino acid is added to achieve a free amino acid concentration of about 1 mM and about 150 mM in the solution. In other embodiments, strong corrosive acids can be converted to acid salts for use in pretreating plasma prior to spray drying. Examples include NaHSO4 and NaH2PO4, i.e., acid salts of sulfuric acid.

[0061] In one embodiment, the pretreatment solution has an amount of glycine ranging from about 10 μmol / mL plasma to about 110 μmol / mL plasma (e.g., about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110 μmol / mL plasma) and an amount of hydrochloric acid (HCl) ranging from about 10 μmol / mL plasma to about 30 μmol / mL plasma (e.g., about 10, 15, 20, 25, and 30 μmol / mL plasma), thereby obtaining formulated plasma. In one embodiment, the pretreatment solution has an amount of glycine of about 84 μmol / mL plasma and an amount of HCl of about 20 μmol / mL plasma.

[0062] In another embodiment, the pretreatment solution has an amount of glycine and an amount of HCl that form a ratio that allows for the presence of free glycine in the pretreatment solution; in some aspects, the ratio of glycine to HCl is about 1.5 to about 8.0 (e.g., 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.5, 7.0, 7.5, 8.0). In certain embodiments, the ratio of glycine to HCl is 4.15. In yet another embodiment, the ratio of glycine to HCl results in the pH of the pretreatment solution being about 2.0 to about 4.0, or in the formulated plasma of step a) having a pH of about 6.0 to about 6.6. When reconstituted with sterile water, formulated plasma having the above-listed ratio of glycine to HCl results in a pH of about 6.7 to about 7.8.

[0063] The present invention further includes a method of producing spray-dried plasma by combining plasma with a pretreatment solution, the pretreatment solution having glycine in an amount ranging from about 15 mmol to about 30 mmol (e.g., about 15, 20, 25, and 30 mmol) and HCl in an amount ranging from about 3 mmol to about 7 mmol (e.g., about 3, 4, 5, 6, and 7 mmol). In certain embodiments, the pretreatment solution has glycine in an amount of about 22 mmol and HCl in an amount of about 5.3 mmol.

[0064] Non-volatile acids and acid salts are collectively defined and included in the present invention as spray-dried stable acidic substances (SDSAS). In one embodiment, the pretreatment solution of the present invention comprises an SDSAS and one or more amino acids.

[0065] In one embodiment, the SDSAS and / or one or more amino acids of the present invention are added to the plasma within about 30 minutes, about 20 minutes, about 15 minutes, about 10 minutes, about 5 minutes, about 1 minute, or time 0 (0 minutes) of spray-drying the plasma. In one embodiment, the SDSAS of the present invention is added simultaneously with the plasma as it is being pumped through the spray-drying apparatus. The term "simultaneously" is defined herein to mean within about 60 seconds, about 50 seconds, about 40 seconds, about 30 seconds, about 20 seconds, about 10 seconds, about 5 seconds, about 1 second, and about 0 seconds. The addition of amino acids to the SDSAS, which increases the pH of the pretreatment solution, may, in one embodiment, allow the plasma product (e.g., the pretreatment solution and the plasma to be spray-dried) to be stored or allowed to stand for up to about 24 hours (e.g., 1, 5, 10, 15, 20, or 24 hours) prior to spray-drying.

[0066] In one embodiment, the present invention involves mixing the pretreatment solution with the plasma to be spray-dried using a technique called rapid mixing. The rapid mixing step is optional. One of the discoveries of the present invention involves rapid or immediate mixing of the pretreatment composition with the plasma. It has been discovered that slowly mixing the pretreatment solution with the plasma allows localized contact or pockets of unmixed acid to come into contact with plasma proteins, which can harm these proteins and specifically increase C5a. In contrast, when the pretreatment solution is rapidly mixed and / or stirred with the plasma, in one embodiment, the amount of C5a is similar to that of fresh frozen plasma or other similar FDA-approved products sold on the market. Rapid mixing and / or stirring allows for immediate, complete, and rapid mixing of the pretreatment solution (e.g., having SDSAS and one or more amino acids) with the plasma. See Examples 17 and 18. Rapid mixing is defined as adding a large volume of plasma to a relatively small volume of pretreatment solution before spray-drying the plasma. Generally, when a large volume is added to a much smaller volume (e.g., about 10 to about 30% (approximately 10, 15, 20, 25, 30%) of the larger volume), mixing of the two volumes results in rapid and thorough mixing of the two volumes. In a preferred embodiment, 260 mL of plasma is added to 50 mL of pretreatment solution. In one embodiment, once rapid / instantaneous mixing occurs, the operator can gently invert the bag containing both the pretreatment solution and the plasma several times (e.g., 1 to 5 times) to further mix the two. In contrast, when mixing a pretreatment solution with plasma, if a small volume of pretreatment solution is injected into a large volume of plasma and then spray-dried, it takes longer for the small volume to fully mix with the large volume, and pockets of small volume may form within the large volume. During this time, localized contact or pockets of unmixed acid formed within the mixture have been found to cause an increase in the amount of C5a in the resulting reconstituted plasma. Agitation is defined as constant shaking or movement of the components of the pretreatment solution (e.g., SDSAS, amino acids, and plasma). Rapid mixing or agitation results in a uniformly mixed plasma preparation with little or no localized contact or pockets of unmixed acid.

[0067] The present invention relates to the addition of SDSAS and at least one amino acid to plasma to be spray-dried for a period of time prior to spray drying that is sufficiently short to obtain a formulation ("plasma formulation") having a desired pH and to prevent denaturation or damage to certain plasma proteins, such as von Willebrand factor, due to prolonged exposure to low pH conditions, or to prevent an increase in C5a. In one embodiment, as described below, by keeping the time delay between formulation of the plasma with SDSAS and spray drying to 30 minutes or less, recovery of plasma proteins, including von Willebrand factor, is improved without undesirable protein damage due to prolonged exposure to low pH conditions prior to spray drying.

[0068] The time between pretreatment formulation and spray drying depends on the pH / acidity of the plasma preparation created by mixing SDSAS, amino acids, and plasma. In one embodiment, the time from contacting SDSAS and amino acids with plasma to spray drying ranges from about 0 seconds (e.g., the time at which aerosolization occurs: time 0) to about 30 minutes. In one embodiment, the time between adding the pretreatment solution to the plasma and spray drying should be kept to a minimum to minimize protein denaturation. The actual maximum time between formulation and spray drying is determined empirically. This close-in-time formulation at time 0 is referred to herein as a "co-formulation."

[0069] There are several ways in which co-formulation can be performed. In some embodiments, a formulation station is provided in conjunction with the spray dryer. In conjunction with the formulation station, the weight or volume of the pre-spray dried plasma is determined, and the SDSAS and amino acid dosage are measured to achieve the desired pH of the plasma formulation. The dosage can be introduced into the plasma by any convenient method, including injection through a port on the plasma bag. In one embodiment, the bag containing the plasma and the bag containing the pretreatment solution are sterilely connected by tubing using a tubing sealer that can sterilely heat seal both ends of the tubing together. In such cases, the transfer of plasma to the pretreatment bag can be performed manually or using a collection monitor or scale. Gravity can be used to assist the transfer by suspending the plasma bag higher than the pretreatment bag. The formulation station can be operated manually, semi-automatically, or automatically. Of course, the timing of administration should be controlled as described above. The timing control can be manual, semi-automatic, or automatic.

[0070] In another embodiment, appropriate doses of SDSAS and one or more amino acids are introduced into the plasma flow path of the spray dryer prior to the spray drying head, and the introduction of the pretreatment solution is controlled manually, semi-automatically, or automatically to yield the desired plasma product.

[0071] In a further embodiment, an appropriate amount of pretreatment solution (e.g., SDSAS and one or more amino acids) is introduced into the spray-drying chamber sufficiently close to the spray-drying nozzle to mix the pretreatment solution with the plasma to form the plasma formulation before spray-drying occurs in the spray-drying chamber connected to the spray-drying head. The introduction of the pretreatment solution (e.g., SDSAS and one or more amino acids) is controlled manually, semi-automatically, or automatically to yield the desired plasma formulation.

[0072] In yet another embodiment, the pretreatment solution is combined with the donor plasma using a sterile connecting device and scale, as further described herein.

[0073] C5a G protein-coupled receptors are widely distributed throughout the human body, constituting approximately 60% of known cell receptor types and mediating signal transduction across cell membranes for a wide variety of endogenous ligands. They are involved in a diverse array of physiological and pathophysiological processes, including, but not limited to, those related to the cardiovascular, central and peripheral nervous systems, reproduction, metabolism, digestion, immunity, inflammation, and growth disorders, as well as other cell regulatory and proliferative disorders. One of the most intensively studied G protein-coupled receptors is the complement (C) system in humans and other mammals, which contains over 20 components involved in a regulated series of reactions that result in complement activation. The blood complement system has a wide range of functions related to a wide range of host defense mechanisms, including antimicrobial and antiviral effects. Products derived from the activation of C components include the nonself-recognition molecules C3b, C4b, and C5b, as well as the anaphylatoxins C3a, C4a, and C5a, which affect various cellular immune responses. These anaphylatoxin molecules are involved in the pro-inflammatory effects of both acute and chronic inflammation and the associated pain and tissue damage.

[0074] This data reveals the surprising result that adding an amount of glycine to the acid pretreatment solution increases the pH of the pretreatment solution, further protecting plasma proteins and mitigating C5a elevation. Addition of appropriate levels of glycine does not affect the final pH of the rehydrated spray-dried plasma (ODP).

[0075] The pretreatment solutions of the present invention desirably result in rehydrated plasma with reduced C5a levels or levels in FDA-approved apheresis plasma products. In particular, the present invention includes pretreatment solutions that result in C5a levels similar to those of fresh frozen or unfrozen plasma or available FDA-approved apheresis plasma products. As shown in Figure 28 and the results of Example 17, when local contact with low-pH acids can be avoided, C5a levels are similar to those of never-frozen plasma. Local contact with low-pH acids can be avoided by raising the pH using an amino acid such as glycine, by utilizing the rapid mixing technique described above, or by a combination thereof. As can be seen from Figure 28, when glycine HCl at pH 1.32 is used without the addition of a more basic amino acid such as glycine, the rapid mixing technique reduces C5a levels from approximately 64 ng / mL to approximately 31 ng / mL. When the pH was lowered by adding glycine to SDSAS (e.g., a glycine HCl / glycine pretreatment solution), the rapid mixing technique resulted in C5a levels of approximately 12 ng / mL, close to the level of Never Frozen Plasma (NFP), which is approximately 10 ng / mL. Using citric acid, which has a pH of 2.28 by itself without added amino acids, and the rapid mixing technique resulted in C5a levels similar to those of NFP (12.66 ng / mL). The pH of citric acid is higher than that of glycine HCl. When a citric acid pretreatment solution is combined with an amino acid (glycine), the solution has a pH of 3.4, and rapid mixing does not actually affect C5a levels, e.g., approximately 10 ng / mL, because both are close to those of NFP. It has been discovered that desirable C5a levels result from pretreatment solutions with SDSAS and amino acid addition, rapid mixing / agitation of the pretreatment components, or a combination of both. In particular, the C5a level of the reconstituted plasma resulting from the pretreatment solution of the present invention can be about 4.7 ng / mL to about 74 ng / mL, particularly 8 ng / mL to 12 ng / mL (e.g., about 10 ng / mL). The C5a level is reduced compared to plasma not subjected to the pretreatment solution having at least one SDSAS and at least one amino acid.In one embodiment, C5a levels are reduced by about 20% or less (e.g., 20%, 15%, 10%, 5%, 1%) compared to plasma not subjected to the pretreatment solution of the present invention. In another embodiment, referring to FIG. 28, rapid mixing and certain pretreatment formulations result in C5a levels that are approximately the same as levels in never-frozen plasma, or about 20% or less (e.g., 20%, 15%, 10%, 5%, 1%) of the C5a in never-frozen plasma or previously approved FDA apheresis plasma products.

[0076] Similarly, in one embodiment, rapid mixing and / or stirring is not required for pretreatment solutions having a pH of about 3 to about 6 (e.g., 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0). A key discovery is that while the pH of the pretreatment solution varies, e.g., ranges from about 1 to about 4, the pH of the plasma remains approximately the same, e.g., about 6.2.

[0077] Protein stability of pretreated plasma Proteins can undergo physical degradation (e.g., unfolding, aggregation, insoluble particulate formation) through several mechanisms. Many proteins are structurally unstable in solution and prone to conformational changes due to various stresses encountered during purification, processing, and storage. These stresses include temperature shifts, pH changes and exposure to extremes, shear stress, surface adsorption / interfacial stress, etc. Proteins in solution can be converted to a solid format (i.e., converted to a powder or other dry format by significantly reducing or removing water and other volatile components of the protein solution) to improve storage using several methods.

[0078] Freeze-drying (also known as lyophilization) is the most common processing method for removing water from biologics, enhancing their stability, temperature tolerance, and shelf life. It involves freezing a suspension, colloid, or solid and then "drying" it under vacuum via sublimation (phase transition). During this process, proteins can be subject to cold denaturation, interfacial stress (adsorption at the water / ice interface), exposure to increasing alkaline pH (CO2 loss), and dehydration stress. Freeze-drying is well established within the industry; however, it requires expensive equipment that takes up a lot of space within manufacturing facilities. Freeze-drying can also take several days to complete, and manufacturers requiring powdered products must incorporate a granulation step into the process. In environments with tighter budgets, limited time, and limited facility space, freeze-drying can be a challenging option for some companies. Due to the space required, drying plasma using lyophilization technology is limited to plasma manufacturers and cannot be performed in blood centers.

[0079] Due to the difficulties inherent in freeze-drying plasma in terms of time, space and cost, the present invention relates to an improved spray-drying process for plasma that overcomes the known difficulties associated with spray-drying plasma.

[0080] In the spray-drying process, a viscous liquid is pumped through a supply line to a nozzle, and the exiting fluid stream is atomized into a large number of droplets under the influence of an aerosol gas. The droplets are mixed with a drying gas to form dry particles. The freeze-drying process is a much shorter and cheaper process than lyophilization, and can be carried out in laboratories and blood centers. However, prior to the present invention, this process could cause plasma proteins to suffer from extensive shear stress, interfacial stress, thermal stress, dehydration stress, and extreme pH.

[0081] Aerosolization exposes liquid samples to shear stress, resulting in extremely rapid and significant expansion of the air-liquid interface. The combined effect of shear stress and air-liquid interfacial stress can cause serious detrimental effects on labile compounds such as proteins. Complex biomolecules are difficult to spray-dry because they are highly sensitive to high shear stress. While some control over the amount of shear stress encountered can be obtained, for example, by selecting the type of sprayer used and the aerosolization pressure used, applying spray-drying techniques to human plasma is extremely challenging because it contains so many diverse proteins. Diverse proteins may be susceptible to different stresses, which can make it difficult to determine processing conditions suitable for all types of proteins found in plasma. In particular, vWF, which is naturally designed to be shear-sensitive due to its biological function, is the most shear-sensitive human plasma protein. Most other plasma proteins, with the exception of vWF, remain largely intact after spray-drying. As shown in the Examples section, spray-drying reduced vWF activity to below detection levels (see Example 27, Figure 17).

[0082] Ionizable amino acid residues have been shown to play important roles in protein binding to other molecules and enzyme mechanisms. They also have a significant impact on protein structure, stability, and solubility. The types of interactions these side chains have with their environment depend on their protonation state. For this reason, their pKa values ​​and the factors that influence them are of intense biochemical interest. Strongly altered pKa values ​​are often found in the active sites of enzymes, enhancing the ability of ionizable residues to act as nucleophiles, electrophiles, or general bases and acids. As a result of changes in the protonation of these residues, protein stability is pH-dependent. Therefore, inhibiting plasma alkalinization during spray drying could potentially improve the processing and storage stability of many plasma proteins.

[0083] As mentioned above, the spray-drying process subjects plasma proteins to forces different from those found in the freeze-drying process. First, spray-drying exposes plasma proteins to high stresses during the aerosolization process as the plasma is forced through a narrow orifice exposed to the high-velocity airflow necessary to create droplets of appropriate size for drying. Second, the spray-drying process exposes plasma proteins to the high temperatures necessary to force water out of the aerosolized droplets. Third, the spray-drying process dramatically and rapidly increases the pH of plasma proteins as a result of the rapid release of CO2 during drying. Because freeze-drying does not subject plasma proteins to these forces, especially this unique combination of forces, those skilled in the art would find no suggestion or motivation in freeze-drying technology for improving the spray-drying process for plasma.

[0084] Despite the difficulties associated with spray drying plasma, the spray drying process of the present invention results in high recovery and stability of functional plasma proteins, particularly but not limited to, vWF, with the recovery of vWF being at least about 5 percentage points or more (e.g., about 5, 10, 20, 30, 40, 50, 60, 70, 80 percentage points or more) in the rehydrated spray-dried plasma compared to the amount of active / native vWF in rehydrated spray-dried plasma that has not been subjected to the pretreatment step of the present invention.

[0085] The compositions and processes of the present invention relate to the effect of formulating liquid plasma with an SDSAS, such as glycine HCl, alone or in combination with an amino acid, on the recovery rate from the spray-drying process and the stability of functional vWF and other coagulation factors (during storage of the dried and rehydrated plasma after spray-drying). This can be accomplished by adding an SDSAS, such as glycine HCl, citric acid, or lactic acid, alone or in combination with an amino acid, such as glycine, to the liquid plasma before spray-drying begins or simultaneously with the spray-drying process. During the spray-drying process, CO2 loss occurs, which causes the pH of the plasma composition to become more alkaline (e.g., increase), and the SDSAS and amino acid are added to maintain the plasma pH in a range that prevents significant denaturation of coagulation factors, particularly vWF. Therefore, pretreatment of plasma with citric acid, glycine HCl, or other SDSAS, or in combination with amino acids, serves at least three main purposes: 1) increasing the in-process recovery of plasma proteins; 2) increasing the stability of plasma proteins during storage; and 3) rehydrating spray-dried plasma with water (e.g., sterile water, WFI), eliminating the need for a specific rehydration solution.

[0086] When liquid plasma is formulated with SDSAS and amino acids before drying, the acids are present in the dried plasma product at levels consistent with improved shelf life and reduced degradation of coagulation factors during storage. "Consistent levels for improved shelf life" also refers herein to levels that result in a physiological pH upon reconstitution of the spray-dried plasma. The use of SDSAS and amino acids also allows for simple rehydration with low-cost, readily available sterile water for injection, or, in emergencies, purified water at physiological pH. The convenience, low cost, and improved safety associated with direct rehydration with water are clear. Advantages include savings from being able to ship dried plasma products without the weight and bulk of rehydration fluid, cost savings from not having to specially formulate rehydration fluid, and reduction or elimination of refrigeration or freezing during storage.

[0087] Thus, the present inventors have discovered that plasma formulation with SDSAS and amino acids results in high recovery or functionality of plasma proteins, particularly vWF, highly improved storage properties of the dried plasma, and spray-dried plasma with a near-neutral pH when rehydrated with water without a buffered rehydration solution. Thus, the present invention makes it possible to produce spray-dried plasma without the added expense and complexity of pretreatment with additional stabilizers, such as polyols and others known in the art. However, the use of stabilizers is not contraindicated and may be beneficial in some cases.

[0088] In a further embodiment, new compositions for plasma spray drying are made by administering, by any means, pre-spray dried plasma supplemented with citrate (i.e., citric acid) or other suitable SDSAS and an appropriate concentration of amino acids, as disclosed herein.

[0089] In further embodiments, the freshly administered citrate formulated plasma prior to spray drying has a citrate concentration of about 27.5 mM and about 40.4 mM, or about 31.6 mM and 34.2 mM.

[0090] In a further embodiment, new spray-dried plasma products are made by spray-drying formulated plasma with appropriate levels of a suitable SDSAS (e.g., citric acid) and a suitable amino acid prior to or simultaneously with drying, and then drying the plasma to the desired level of moisture, which is generally less than 2%.

[0091] In various embodiments, citric acid or other SDSAS and amino acids are added to plasma as a formulation. Experiments regarding the effects of SDSAS and amino acids on protecting the activity of proteins found in plasma are further described in the Exemplification section of this specification. For example, citric acid is used at concentrations of about 1 to about 15 mM or about 5 to about 10 mM (e.g., 7.4 mM). Therefore, adding the indicated concentrations of citric acid before or simultaneously with spray drying can better preserve plasma proteins. The activity of vWF is provided in the examples because this factor is particularly susceptible to denaturation and damage due to spray drying (see Figures 17 and 18) and is therefore a good indicator protein for demonstrating the beneficial effects of SDSAS and amino acids on the recovery and stability of spray-dried plasma proteins.

[0092] Examples of other physiologically compatible SDSAS and amino acids are known to those of skill in the art and are described herein.

[0093] In one embodiment, single-donor plasma expressed from collected whole blood or by apheresis that has never been frozen and is less than 24 hours old is desirably utilized in this process. Plasma is collected from the blood by standard techniques known to those skilled in the art, as described herein. Plasma is collected by a process called plasma analysis. Plasmapheresis refers to the procedure of separating plasma from blood by either centrifugation or membrane filtration. The system process can also be used when pooled plasma is desired, and with starting plasma material produced with any currently available anticoagulation system, such as those known as CPD, CP2D, ACD-A, and ACD-B. A sterile, non-pyrogenic, single-use container containing SDSAS, e.g., a 50 ml solution of glycine and hydrochloric acid packaged in a 500 ml container in an overwrapped pouch, is used. In one embodiment, the process of the present invention involves converting a single-donor unit of plasma collected by standard procedures into a single unit of spray-dried plasma.

[0094] The dried plasma of the present invention can be from a third-party donor or from the potential recipient themselves. The latter is known as autologous plasma. Autologous plasma is highly desirable because it overcomes compatibility issues, e.g., it does not need to be ABO / Rh typed prior to use, and the plasma is less likely to carry foreign substances, such as pathogens or immunogens, to a given recipient.

[0095] In vitro characterization data demonstrate that system manufacturing effects are comparable between units manufactured with different starting materials. Units manufactured from apheresized plasma (ACD-A anticoagulated) showed similar percent changes due to manufacturing effects on the starting material compared to units manufactured from whole blood-derived plasma (CPD anticoagulated). Statistical analysis (ANOVA) was performed on the percent changes before and after manufacturing between the two starting materials across 20 assays, including clotting time, coagulation function, and activation markers. Of the 20 assays, total protein concentration, PT, TT, and factor VIII and factor XIII activity were determined to be statistically significantly different, but the mean percent changes were similar, and all mean values ​​were within the clinical reference range. In summary, the in vitro test results support the conclusion that manufacturing effects on both apheresized and whole plasma are comparable, with coagulation profiles within ±20% of their paired controls or within the normal reference range.

[0096] Spray Dryer and Spray Drying Process Generally, a spray drying system (spray drying device) is provided for spray drying a liquid sample such as plasma.

[0097] The pretreated plasma is dried using components and a system for using a disposable spray-drying device. The spray-drying system includes a spray-drying apparatus (hereinafter referred to as a "drying apparatus," "machine," "spray dryer," or "dryer"), a spray-drying finishing apparatus (hereinafter referred to as a "finishing apparatus," "seal and separator," or "finisher"), and a disposable spray-drying device (hereinafter referred to as a "disposable device" or "disposable"). The present invention includes a system that enables a disposable spray-drying device with a liquid spray nozzle and drying chamber to efficiently dry liquids, including liquid human or animal plasma, while protecting active components such as plasma proteins. The disposable spray-drying device is installed in a spray dryer that controls the plasma flow, pressurized aerosol gas flow, drying gas flow, temperature, pressure, etc., within the disposable. Upon completion of the spray-drying process, the disposable containing the dried plasma powder is aligned and processed by the spray-drying finishing apparatus, where portions of the disposable are sealed and separated to form a dried plasma unit. Furthermore, the present invention advantageously provides an apparatus for performing the functions of spray-drying and finishing products containing dried human plasma.

[0098] The disposable spray dryer of the present invention has a compact drying chamber that produces dry powder (<2% residual moisture) at a high powder production rate. The disposable is small, easy to handle, and provides a high-performance, easy-to-use drying chamber. The drying system of the present invention is a significant improvement, providing a removable, disposable drying chamber for spray drying that is suitable for processing small batch sizes such as individual blood units.

[0099] Certain of Applicant's older disposable drying chambers were very long, measuring 58 inches to 66 inches or more in length, allowing sufficient time (flight path) to dry plasma to acceptable residual moisture levels. See Applicant's Patent Nos. 8,533,971, 8,595,950, 8,434,242, 8,601,712, 8,533,972, and 10,843,100. However, their lengths made these prior art disposables unacceptable for practical use because they were difficult and inefficient to handle during installation in spray dryer equipment. As further described herein, the shorter disposables of the present invention are easier to handle than these prior art disposables, which required user reach and bending distances of more than 6' and less than 5', respectively. The shorter disposables make spray drying of human plasma practical for real-world applications by real-world people. Additionally, the disposable drying chamber of the present invention is a removable, disposable drying chamber that maintains the quality and integrity of the plasma while improving processing time and product quality at a low cost.

[0100] Several challenges have been overcome by shortening the drying chamber of the present invention. For example, drying any product to a predetermined degree of dryness involves exposing the material being dried to sufficient heat energy to achieve the desired level of dryness while maintaining the functionality of the substance being dried. However, shortening the drying chamber also shortens the drying path.

[0101] The disposable drying chamber of the present invention is improved by: more efficiently produced plasma; Fairly short; Easy to use for people of a wide range of status; Drying materials in less time; Decrease in inlet air temperature; A nozzle assembly and dry environment are achieved to obtain rapid mixing of the atomized droplets with the drying gas and rapid evaporation; Achieve a lower level of residual dryness, e.g., less than 2.5% residual moisture; and As further described herein, a specially designed, cost-effective composite spray drying nozzle is utilized.

[0102] Overview of spray-dried disposables In particular, the disposable 100 has two general regions: a spray drying head 2 and a plasma drying chamber 28 .

[0103] Overview of the spray drying head The disposable 100 spray-drying head 2 includes a guide 4 offset so as to be positioned above a plenum 6 and a baffle plate 8 having a raised portion 9 (FIGS. 42A and 43A). The plenum 6 includes the guide 4 at the top of the spray-drying head 2. Within the guide 4 is a spray-drying nozzle assembly 20 having a plasma inlet 18 connected to liquid plasma via a plasma line 16 and a pressurized aerosol gas inlet 14 connected to pressurized gas via an aerosol line 10 and an aerosol filter 12. Also shown is a drying gas inlet port 22, which communicates with a drying gas source (not shown), which may be air, nitrogen, or another drying gas source. Optionally, the drying gas inlet port 22 may be covered by a removable cover, such as a self-adhesive paper label. This cover should be removed immediately before installing the disposable 100 in the spray dryer 200. The drying case source may optionally be in communication with a moisture-reducing drying system. In some embodiments, the drying gas source is an Atlas-Copco SF 22+ compressor (Atlas Copco, Nacka, Sweden) in conjunction with an Atlas-Copco CD45 desiccant drying system, which supplies clean dry air (CDA) to the spray dryer and heats the air to the appropriate temperature for spray drying. In one embodiment, the drying gas flows through a filter from the CDA, such as a Millipore Series 3000 0.2 micron filter CTGB71TP3 manufactured by Millipore Sigma, Danvers, MA, USA. The CDA source, in one embodiment, is used to supply the drying gas and pressurized gas. In certain embodiments, the spray drying nozzle assembly 20 includes a "manifold" that regulates the plasma and aerosol lines. When the plasma source, pressurized gas source, and drying gas source are combined, liquid plasma droplets are formed and dried into dried plasma (e.g., fine amorphous plasma powder). The plenum 6 has a notch, which is a locator, referred to herein as a locator 26 or a second locator, as further described herein.

[0104] Briefly, guide 4 fits into receiver 204 of spray dryer 200, which also properly aligns disposable 100 with dryer 200 (FIGS. 45B and 45C). Guide 4 also aligns spray dryer head 2 in a specific orientation relative to spray dryer 200 so that drying gas inlet port 22 receives a drying gas source (not shown). Ridge 9 fits into ridge receiver 207 of spray dryer 200 to provide support. Guide 4, together with ridge 9, allows disposable 100 and spray dryer 200 to be aligned laterally (e.g., in a plane defined by the top and bottom surfaces of the spray dryer), which keeps the disposable secured so that it does not move up and down within the dryer's spray drying chamber housing. Additionally, ridges 9 on disposable 100 mate with receivers 404 on finisher 400 to secure disposable 100 to finisher 400 while finisher 400 transfers the plasma and seals and separates the disposable into dried plasma units 60. See Figures 46A-C. This alignment arrangement also provides for easy and versatile attachment of the disposable to both the dryer and finisher.

[0105] A first locator 206 (FIGS. 45B, 45C, 46A) is positioned on the spray-drying apparatus 200, and a second locator 26 (FIGS. 42A and 43A) is positioned on the spray-drying disposable 100, such that the first and second locators engage during installation of the disposable 100 onto the spray-drying apparatus 200, enabling alignment of the disposable with the spray-drying apparatus. The same locator 26 (second locator) on the disposable is also used to align the disposable with a third locator 452 (see FIGS. 47A-C) on the spray-drying finishing apparatus 400, which directs the dried plasma to specific compartments of the disposable, seals the dried plasma, and separates the dried plasma into plasma units with the dried plasma. This positioning arrangement aligns the disposable axially to the spray-drying apparatus, for example, around an axis defined by the center of the receiver of the guide 4 (see axis A in FIG. 43A). This positioning arrangement allows the disposable to be easily and generally attached to both the drying and finishing equipment.

[0106] The spray-drying head 2 includes a nozzle assembly 20 as part of the disposable. This nozzle assembly allows for spray drying of plasma within the disposable. The overall system design is modified to include a spray dryer and a nozzle as part of the disposable instead of the spray dryer, so that spray drying occurs entirely within the disposable. This design helps keep the plasma disposable throughout the drying and finishing process and away from parts of the dryer or finisher that require decontamination between uses. This design also minimizes contamination of external pathogens by keeping the plasma disposable throughout the process. The nozzle assembly coordinates the plasma flow and the pressurized / aerosolized gas flow so that both are released at the appropriate velocity and airflow to atomize the liquid plasma at the tip of the nozzle, ready for rapid mixing with the drying gas. The disposable 100 spray-drying head 2 further includes a plenum 6 and a baffle plate 8, which directs the drying air for rapid mixing with the aerosolized plasma and creates an air curtain to minimize the accumulation of dried plasma on the drying chamber walls.

[0107] Overview of the plasma drying chamber The drying chamber 28 is a disposable area where the plasma dries. The drying chamber is designed to capture the dried plasma while allowing humid air to escape. The design of the drying chamber also allows it to be sealed and separated to form commercially available dried plasma units.

[0108] Drying chamber 28 has three general regions: an upper portion defined by dimension X (see FIGS. 44 and 46A ); a middle portion defined by dimension U, which is the region between positions 44A and 44B; and a lower portion defined by dimension V, with the portion below position 44B including filter 36 and separator 38. The upper portion is the space where the atomized liquid plasma encounters the drying gas, evaporating the liquid within the droplets and drying them. In particular, the atomized plasma rapidly mixes with the drying gas and dries, as further described herein. As the plasma rapidly mixes and dries, it circulates and moves downward toward the filter. While the majority of evaporation occurs at the top (dimension X) of drying chamber 28, the plasma continues to dry as it falls into the middle (dimension U) and bottom (dimension V) of drying chamber 28.

[0109] Drying chamber 28 also includes a central section 46 defined by dimension U, which has "seal and separate" locations 44A and 44B, label 40, spike ports 42A and 42B, and hanging slot 34. Central section 46 also includes locator pin opening 32C. The central section is then processed by a spray dryer finishing device, which moves the dried plasma to specific locations in the plasma drying chamber and seals and separates it at or near cut locations 44A and 44B. The section between locations 44A and 44B becomes dried plasma unit 60, which is ultimately rehydrated and transfused to the patient.

[0110] The disposable 100 further includes a positioning arrangement for reversibly attaching the outer wall of the disposable 100 to the finisher 400. The outer edges of the walls of the spray drying disposable device 100 are provided with positioning openings 32A, 32B, and 32C (FIGS. 42A and 48A). The positioning pins 432A, 432B, and 432C are positioned on the finisher 400 such that when the positioning openings 32A, 32B, and 32C are positioned around the positioning pins 432A, 432B, and 432C of the finisher 400, the drying chamber 28 of the disposable 100 is aligned on the finisher. See FIGS. 47C, 48B, and 48C.

[0111] The lower section of the drying chamber 28 includes a lower filter 36 (also referred to herein as a "trap filter"), a lower filter separator 38, a drying gas outlet 30, and locator pin openings 32A and 32B. Optionally, the gas outlet 30 may be covered by a removable cover, such as a self-adhesive paper label. In one embodiment, this cover should be removed immediately before installing the drying chamber in the spray dryer 200. Briefly, the lower filter separates the dried plasma from the moist air, and the separator acts as a spacer between the drying chamber wall and the filter, allowing air to pass more easily and preventing pressure buildup. Moist air refers to the air moving through the drying chamber and includes a combination of the drying gas, aerosolized gas, and moisture removed from the plasma droplets. During plasma drying, the moist air passes through the lower filter 36 and lower filter separator 38, passes through the air flow path, and exits through the gas outlet 30, leaving the dried plasma behind in the lower filter 36.

[0112] The disposable 100 further includes another alignment arrangement for the gas outlet 30 of the disposable 100 and the gas exhaust port 208 of the dryer 200. The spray dryer has a gas exhaust port 208 for venting drying gas, and the bottom of the disposable 100 has a gas outlet 30 that mates with the exhaust port 208 of the dryer 200 (FIGS. 45B and 46A). Additionally, the spray dryer finisher 400 has a receiver 414 for the drying gas outlet 30 to secure the bottom of the disposable 100 to the finisher 400 (FIGS. 48B, 48C). Again, this drying gas arrangement allows the disposable to be universally attached to both the dryer and the finisher.

[0113] Additionally, the overall length of the disposable (measured from the top of the spray-drying head to the bottom of the drying chamber) is limited to about 40 inches or less (e.g., about 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, or 24 inches or less), preferably about 34.8 inches. Disposables having a length of about 40 inches or less have been difficult to achieve because drying of the plasma occurs in a smaller space and volume, but gently without degrading plasma proteins. The length of the disposable, measured from the bottom of the spray-drying head 2 or the bottom of the baffle plate 8 to the bottom of the filter 36, shown as dimension Y in FIG. 46A, is about 31 inches or less (e.g., about 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, or 19 inches or less), and in one embodiment, is preferably about 25.9 inches. In another aspect, the area of ​​the disposable 100 encompassed by dimension Z, which is the length from the bottom of the spray-drying head 2 and the top of the filter 36, is about 22 inches or less (e.g., about 22, 21, 20, 19, 18, 17, 16, 15, or 14 inches), preferably about 19.11 inches. In yet another example, the length of dimension X, which is the length between the bottom of the spray-drying head 2 and the top section 46, is less than about 16 inches (e.g., about 16, 15, 14, 13, 12, 11, 10, 9, or 8 inches), preferably about 12.14 inches. In one embodiment, the length of a disposable can be varied or shortened. For example, the length of a disposable of the present invention can be further shortened by about 1 inch to about 8 inches (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 inches) along dimension X, thereby shortening the overall length by the same amount. In other embodiments, the disposable can also be shortened by the same amount everywhere along dimensions Y and Z.

[0114] Computational model In some figures, computational models were used to show flow paths, particle evaporation, etc. Figure 42B shows the three-dimensional flow geometry of the disposable in operation that was used in the model.

[0115] The three-dimensional model shown in Figure 42B was based on the disposable shown in Figure 42A and the dryer shown in Figures 45A-C. These computer simulations demonstrate that the flow and mixing process was modeled by first constructing a three-dimensional flow field geometry. See Figure 42B. This geometry was extracted from a computer-aided design (CAD) model of the system hardware to create a high-fidelity representation of the flow field within the ODP system. 0.0195 m 3 The volumetric flow domain was discretized into 3.3M spatial cells, and a computational mesh was generated using the commercially available Ansys-Gambit meshing software. The flow model was calculated using the commercially available computer code, Ansys-Fluent version 2019-R1, running on an HPZ840 multiprocessor workstation.

[0116] The simulations utilized ideal gas properties, the KE turbulence model, and a steady-state segregation solver that assumed: Drying gas inlet temperature = 114C Drying chamber exhaust temperature = 65C System heat loss = 0.18kW Drying gas flow rate = 750 slpm Atomizer aerosol gas flow rate = 40 slpm Feed rate = 13.5 mL / min, varies depending on exhaust temperature Liquid water droplets with a non-volatile mass of 8.5% and a diameter of 5 microns (monodisperse size) Exhaust port pressure = 2.76 kPa (0.4 psig)

[0117] The inlet and product capture filters are modeled using a "porous zone" function with flow resistance values ​​set to match the measured operating pressures in the drying gas manifold of 71.7 kPa (10.4 psig) and 27.6 kPa (4 psig) in the drying chamber at the start of the batch.

[0118] To calculate the average droplet diameter and temperature during constant-rate evaporation for a given set of process conditions, two customized C programs, "prsc_udf_multi_2017.c" and "processdata_multi_2017.c," were developed in PARSEC to obtain the average droplet drying path from the converged Fluent-coupled DPM solution. The program "prsc_udf_multi_2017.c" is used to incrementally export the droplet tracking data for information of interest. The program "prsc_udf_multi_2017.c" reads the exported data file generated from the first program and then obtains the averaged path from all tracked particles. The output file can be loaded into an Excel file.

[0119] The data shown in Figure 42B, 43Ka, 43Ma, 43Na, 43O, 43P, 43S, 43Sa, and 43T were generated using this model.

[0120] Overview of spray dryers The spray dryer 200 of the present invention provides a donor plasma liquid flow (e.g., pretreated), a drying air flow, a pressurized aerosol gas flow, a disposable compressed air line, a disposable exhaust line, a housing exhaust line, and a leak detection line.

[0121] Along with these flow lines, the spray dryer 200 of the present invention further includes a leak detection method 1000 that utilizes a series of pressure transducers, flow sensors and valves to assess whether the disposable 100 has a leak during spray drying.

[0122] The spray dryer 200 further includes a pressure detection method 1200 that enables a pressure transducer present on the outside of the wall of the disposable 100 to measure the pressure inside the disposable 100. This process involves heating the wall of the disposable, allowing it to soften. During use, the wall of the disposable exerts a force on force sensors PT08 224A and PT09 224B, which measure such force. The amount of force is used to calculate the amount of pressure within the disposable. If the pressure within the disposable 100 exceeds a set amount (e.g., greater than 7.02 psi), the computer system causes the dryer 200 to enter fail-safe mode. If the pressure is within a set acceptable amount (e.g., between about 6.7 psi and less than about 7.02 psi), the computer system determines whether enough plasma has been dried by determining the amount of donor plasma remaining in the donor plasma bag. If a sufficient amount of plasma has been dried, the computer system communicates that the drying run was successful and the finishing process can begin. If an insufficient amount is dried, the drying run fails and the disposable 100 is discarded.

[0123] Additionally, the dryer 200 includes a method 1400 for determining the integrity of the bottom filter 36, the baffle filter 94, and / or the plenum interface. This methodology utilizes pressure transducers in the inlet and housing to determine the pressure gradient during spray drying. The gradient is compared to a model, and if the gradient deviates from the model, the computer system determines that the disposable 100 has failed.

[0124] Finishing machine overview Once spray drying is completed on dryer 200, a finisher 400 or 400' of the present invention moves the plasma to the desired compartment, then seals the disposable walls and cuts the disposable walls to form the dried plasma units. The finisher 400 or 400' provides an impactor, sealer, separator, and air extraction.

[0125] Workflow Overview A summary of the process using the disposables, spray dryer, and finisher described herein is as follows: The spray-drying plasma methodology of the present invention includes pre-treating a provided liquid plasma unit or a thawed previously frozen liquid plasma unit, drying the liquid plasma using a spray-drying apparatus equipped with a spray-drying disposable device to obtain a disposable with dried plasma, and finishing the disposable using a finishing apparatus designed to seal and separate the disposable, converting it into a dried plasma unit. The unit can be used or stored. Once ready for use, the plasma unit is rehydrated and ready for transfusion to a recipient.

[0126] Regarding pretreatment, the pretreatment process involves adding a biocompatible component (e.g., a spray-drying stable acidic substance) to liquid plasma (or thawed fresh frozen plasma) that protects plasma proteins during the spray-drying process, which involves high temperature and pressure.

[0127] In one embodiment, creating the pretreatment solution involves adding to a solvent such as SWFI about 3.0 to about 7.0 (e.g., 3.0, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, and 7.0) mmol of HCl and about 15 to about 30 mmol of glycine (e.g., about 15, 17, 20, 22, 25, 27, and 30 mmol of glycine) in 50 mL of solvent to obtain 260 mL of formulated plasma, i.e., about 440 mM glycine and about 106 mM HCl are present in the pretreatment solution. In one embodiment, about 290 mM to about 570 mM (e.g., about 290, 300, 350, 400, 450, 500, 550, and 570) glycine and about 70 mM to about 140 mM (e.g., 70, 80, 90, 100, 110, 120, 130, 140 mM) HCl are present in the pretreatment solution. Pretreatment vessels are commercially available and can be formulated, filled, and finished, for example, by Berkshire Sterile Manufacturing (Lee, Massachusetts, USA). In one embodiment, the pretreatment solution has about 440 mM / 50 ml glycine and 106 mM / 50 ml hydrochloric acid. (United States Pharmacopeial Convention ("USP") Monographs (12601 Twinbrook Parkway, Rockville, MD 20852-1790, USA). The pretreatment solution, when combined with liquid plasma to form formulated plasma, protects plasma proteins during the drying process. The formulated plasma has a pH in the range of about 5.5 to about 7.2, which offsets the effects of spray drying on pH, and is generally closer to normal physiological pH, about 6.5 to 7.8 (e.g., about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4). The resulting rehydration product is in the pH range of 7.5, 7.6, 7.7, and 7.8 (7.5, 7.6, 7.7, and 7.8), although in some cases, a pH lower than 6.5 or higher than 7.8 may be harmful to the recipient. The dried plasma product obtained from this invention retains its von Willebrand factor and other blood proteins, and is plasma with low cholesterol crystals, low particulates, low pathogens, and well-controlled pH due to the pretreatment steps described above. Furthermore, the resulting dried plasma has certain properties that are distinct from and superior to freeze-dried plasma.

[0128] As known in the art, a sterile connection device (SCD) is used to connect the plasma unit to the pretreatment container and the liquid plasma; in one embodiment, a volume of plasma is transferred using, for example, a blood collection monitor / mixer. After the liquid plasma is transferred to the pretreatment container, in one embodiment, it is gently mixed in the pretreatment container by inversion. Other mixing methods, such as rocking, shaking, and stirring, can be used. Additionally, mixing can be performed by an operator or by devices known in the art. The bag containing the liquid plasma is tubing sealed, separated, and discarded. The pretreatment container 64 with the pretreatment solution and liquid plasma (i.e., formulated plasma 66) is then connected to the disposable device with the plasma tubing 16 using the SCD, resulting in the improved spray-drying disposable device shown in FIG. 42A.

[0129] The spray dryer disposable device 100 is a sterile, non-pyrogenic, single-user container (e.g., approximately 35 inches long) that utilizes a pathogen-retaining filter to filter the air before it enters the drying chamber and as it exits the drying chamber. See FIG. 42A. The spray dryer disposable apparatus is sterilely connected to liquid plasma with plasma tubing, tubing 16.

[0130] Briefly, the drying process is as follows. See Figures 45A-4C, 46A-5B. In one embodiment, pre-treated plasma is aseptically spray-dried in a disposable spray dryer device 100. See Figures 45A-4C. During the process, in one embodiment, a positive air flow is maintained. The pre-treated plasma is atomized using a nozzle contained within the single-use disposable spray dryer device to generate fine plasma droplets. These droplets are then exposed to heated air. The resulting dried plasma particles are captured in filter 36 of drying chamber 28. The disposable spray dryer device is then undocked from the spray dryer and transported to a finishing device.

[0131] The finishing process is outlined below. See Figures 47A-47C, 48A-48C, and 34. Once undocked from the spray-drying apparatus 200, the disposable device 100 with dried plasma is transferred to the finishing apparatus 400. The finishing apparatus 400 mechanically, acoustically, or otherwise impacts or agitates the spray-drying disposable device containing dried plasma to consolidate the dried plasma powder into what will eventually become the spray-dried plasma unit of the spray-drying disposable device. The finishing apparatus utilizes an impactor to assist the dried plasma in moving first to the bottom of the disposable and then to the compartment that will become the spray-dried plasma unit 60 in the second example. The spray-dried plasma unit 60 is sealed and separated from the rest of the disposable device using an impulse seal. This is the final closure step to produce the plasma unit 60. In one embodiment, the seal is visually inspected, the excess portion of the disposable device is discarded, and the dried plasma unit 60 is produced (see Figure 49).

[0132] For an overview of the dried plasma storage process, dried plasma units 60 are removed from the finishing equipment and stored in resealable, moisture-barrier foil pouches containing desiccant. See Patent No. 9,561,184. In one embodiment, the dried plasma units are quarantined and stored refrigerated until all required blood screening tests are completed. Once final release criteria are met, the pouches are opened and the dried plasma units are relabeled for release. The dried plasma units are then placed in resealable or other pouches, sealed, and stored according to the storage protocol.

[0133] In one embodiment, the dried plasma unit is compatible with commercially available fluids or other transfer sets for rehydration with sterile water for injection (SWFI). Once rehydrated, the dried plasma unit 60 is also compatible with blood administration sets for transfusion. In certain embodiments, the spray-dried plasma unit 60 is rehydrated in its existing container using an appropriate amount of sterile water for injection (e.g., 200 mL, 208 mL) prior to transfusion.

[0134] Detailed explanation of spray dried disposables Detailed description of the spray drying head 42A, there is shown a perspective view of a spray drying disposable device 100. As mentioned above, the disposable generally has two parts: a spray drying head 2 and a drying chamber 28. The spray drying head includes a plenum 6, a guide 4, a baffle plate 8, a baffle filter 94, a nozzle 20, and a locator notch 26 (also referred to herein as a "second locator").

[0135] In one embodiment, the purpose of the spray drying head 2 is, in part, to A) help secure the disposable 100 to the dryer 200, B) regulate the flow of drying air, aerosolized pressurized gas, and plasma flow, C) house the nozzle assembly, and D) house the baffle filter.

[0136] With regard to securing the disposable 100 to the dryer 200, the system of the present invention includes an integrated universal alignment system. In one embodiment, the locator notch 26 of the plenum 6 is shown in FIG. 43A. FIG. 43A also better illustrates the plenum 6, guide 4, baffle plate 8, and ridge 9. The locator notch 26, also referred to as the second locator, aligns with the locator protrusion 206, also referred to as the first locator, on the spray drying apparatus 200 (shown in FIGS. 43K, 45B, 45C, and 46A). This positioning arrangement allows the spray drying head 2 of the disposable 100 to be axially aligned with the spray drying apparatus 200. The positioning arrangement can include any arrangement in which a locator on the disposable attaches to, mates with, complements, or otherwise communicates with a locator on the dryer. Examples of positioning arrangements include recess / protrusion arrangements, complementary shape arrangements, hook / receiver arrangements, channel and groove arrangements, latch and catch arrangements, magnetic arrangements, etc. In FIG. 46A , a male locator is on the spray dryer and a complementary female locator is on the disposable, but the arrangements can be reversed. The complementary nature of the arrangements allows for easy adjustment and alignment by the operator and can prevent the door from closing unless the disposable is aligned within the spray dryer. In one embodiment, the positioning arrangement can include any arrangement that allows for alignment between the locator on the disposable and the locator on the dryer, and also allows for alignment between the disposable and the finisher. In another embodiment, the dryer and finisher have the same locators that mate with the disposable to create universal alignment. Having a universal arrangement reduces the training required and increases muscle memory, as operators insert disposables into the spray dryer and finisher in a similar manner.

[0137] Once the first locator on the spray dryer and the second locator on the disposable are aligned, in one embodiment, the system of the present invention provides positive feedback to the operator. In one embodiment, the spray dryer 200 has a spring clip 232 attached to the top of the drying chamber housing that engages with guide 4 when the disposable is aligned and secured within the spray dryer. See FIG. 46A. The spring clip 232 is optional. In this case, the positive feedback to the operator is an audible "click." Such feedback can include an audible indicator (e.g., an audible click) or a visual indicator (e.g., a sensor that provides communication to a display indicating alignment). The retaining clip 232 is also an alignment element because it aligns with ridge 9, described further below.

[0138] FIG. 43A also shows the guide 4 offset from the center of the baffle plate 8. The offset design of the guide on the plenum 6 allows the disposable 100 to be attached to the receiver 204 (shown in FIGS. 45B and 46A) of the spray dryer 200 in a specific orientation. Before inserting the disposable device into the dryer, the operator removes and discards the adhesive cover, if present, from the top, exposing the drying gas inlet port 22 and exposing the gas outlet 30. The use of such a cover is optional. In a preferred embodiment, the operator removes and discards the adhesive cover from only the drying gas inlet port 22 and inserts the spray dryer head 2 into the spray dryer head receiver 404. The cover for the drying gas outlet 30 at the bottom of the disposable can be removed later just before it is ready to be attached to the gas exhaust port 208. The operator typically aligns the ridge 9 formed by the baffle plate 8 over the spray dryer head 2 of the disposable and inserts it into the groove 207 of the spray dryer 200. See FIG. 46A. Once engaged, the operator can manually push the spray drying head 2 further inward, and it will self-align with the groove receiver 207 as long as the notch locator 26 on the spray drying head 2 is within about 30 degrees (e.g., within about 30, 25, 20, 15, 10, or 5 degrees) of alignment with the projected locator 206 on the dryer 200. Insertion and alignment of the spray drying head can be accomplished quickly, for example, within 10 seconds (2-5 seconds). The receiver 204 on the guide 4 also functions as the drying gas inlet for the spray dryer and provides a drying gas source (not shown). The ridge 9 on the spray drying head 2 also provides support and complementarily fits into the groove 207 on the receiver 210. This also allows the spray drying head 2 of the disposable 100 to be laterally aligned with the dryer 200.

[0139] In one embodiment, the receiver 210 has a groove 207, as shown in Figure 45B. The arrangement of ridges and grooves between the spray drying head and the dryer can be any arrangement that allows the spray drying head to fit within the drying chamber housing 202, such that the arrangement provides support and lateral alignment. In addition to the groove 207, the receiver may be a shelf, ledge, arm, stop, base, or other structure that engages with a baffle plate and allows the spray drying head to remain stable throughout the spray drying process.

[0140] The operator then inserts the disposable by placing the guide 4 into the receiver 204 of the spray drying apparatus 200. Once inserted and aligned, the spray drying disposable can no longer move up or down. When using this guide and positioning arrangement described above, they align the disposable so that it cannot move up or down, and cannot move axially about the axis defined by the center of the guide 4. As shown in Figures 45B and 46A, the guide fits into the receiver 204 such that the fit is snug or tight. In this embodiment, once the spray drying end is aligned and in the engaged position, the operator can remove the bottom adhesive cover at the drying chamber gas outlet 30 and attach it to the gas exhaust port 208, as described further herein.

[0141] Once the positioning arrangement (locators 26 and 206) are aligned, guide 4 is inserted into receiver 204, ridge 9 is inserted into groove receiver 207, and retaining clip 232 is engaged, in one embodiment, the spray drying head is inserted, secured, and aligned. Specifically, in one embodiment, retaining clip 232 engages with ridge 9 to hold spray drying head 2 in place. Retaining clip 232 provides an audible indicator that the spray drying head is properly aligned and inserted. In the embodiment shown in FIGS. 45B, 45C, and 31A, the retaining clip is a spring clip. The retaining clip engages with ridge 9 and can be any type of retainer, including, for example, a fastener, pin, catch, slide, etc. The retainer can be made of metal, plastic, rubber, etc. The retainer that engages with the spray drying head is optional.

[0142] As shown in Figures 45B, 45C, and 46A, a spring clip is used as an audible indicator to allow the operator to know that the spray drying head 2 of the disposable 100 is properly inserted and aligned with the dryer 200, although any type of indicator can be provided. The indicator can be audible, visual, or tactile. In one embodiment, an audio indicator provides audible feedback that the loading of the spray drying head 2 of the disposable 100 has been completed correctly, mechanically or otherwise. The audible indicator can be mechanical, such as the sound of a spring clip locking into place, or it can be generated by a sensor (mechanical or pressure / contact sensor) in communication with an actuator or processor that receives a signal of correct positioning of the spray drying head 2 within the dryer 200 and provides a visual indicator to the operator, for example, on the display 212 or indicator light 234. In an alternative embodiment, the sensor can send feedback to the processor, which can activate an audio indicator on a speaker to notify the operator of proper placement. In yet another embodiment, the feedback may be in the form of a tactile response, for example, a vibration to alert the operator to incorrect or correct placement. The feedback may include an audible indicator (e.g., an audible click) or a visual indicator (e.g., the sensor may provide a communication to a display indicating alignment).

[0143] 43B is an exploded view of the spray drying head 2, showing a portion of the spray drying nozzle assembly 20, along with the plenum 6, outer filter sealing ring 90, inner filter sealing ring 92, plenum filter 94, and baffle plate 8 having ridges 9. From top to bottom in FIG. 43B, the nozzle assembly 20 includes a strain relief valve 75, a plasma and pressurized aerosol gas manifold 72, an aerosol reservoir 74, a cannula 78 having an opening 79, a liquid nozzle cap insert 80, and a nozzle cap 76. The nozzle cap 76 has an inner wall with a diameter D o (See FIG. 43Ia) also shows an opening 110 having a diameter D c1 shows a cannula 78 having an outer wall (outer diameter) defined by a diameter D o is slightly larger than the diameter Dc, and the difference is the distance D d The resulting difference in diameter is the distance D d creates an annulus 81 that allows pressurized air received from aerosol reservoir housing 74 to form a vortex, facilitating the formation of small droplets of fluid that flow into drying chamber 28 and are dried. See Example 27.

[0144] Thus, the length of the cannula ranges from about 2 to about 5 inches, and in one embodiment is 3.500 inches + / - .005 inches.

[0145] More specifically, with reference to Figures 43A and 43B, the spray-drying nozzle assembly 20 has a plasma inlet 18 connected to pre-treated liquid plasma 66 (shown in Figure 42A) via plasma tubing 16, and a pressurized aerosol gas inlet 14 connected to a pressurized gas source (not shown) via aerosol tubing 10 and aerosol filter 12. Additionally, a drying gas inlet port 22 is shown in Figures 42A and 43A, which communicates with a drying gas source (not shown). When the plasma source, pressurized gas source, and drying gas source are combined, liquid plasma particles are formed under the pressurized (aerosolized) gas and dried into finely divided dry plasma (e.g., plasma powder).

[0146] Figures 43C and 43D show detailed perspective views of the spray drying nozzle assembly 20. In particular, Figures 43B and 43J show where and how the spray drying nozzle assembly fits within the assembly opening 96 of the plenum 6 of the spray drying head 2. A plasma and pressurized aerosol gas manifold 72 accommodates the plasma source via inlet 18 and directs the pressurized aerosol gas source via inlet 14. A strain relief 75 mates with and communicates with the manifold 72, supports the tubing 10 and 16, and prevents the tubing from collapsing under pressure during packaging, shipping, and spray drying. The strain relief 75 also prevents the tubing from collapsing in packaging and during shipping. The spray drying nozzle assembly 20 includes an aerosol gas reservoir housing 74 in which pressurized aerosol gas is held and builds up before being released through the liquid nozzle cap insert 80 and nozzle cap opening 110 (shown in Figures 43G, 43H, 43I, 43Ia, and 43Ic). The nozzle assembly 20 is housed by the aerosol gas reservoir housing 74 and secured by the nozzle cap 76. The liquid nozzle cap insert 80 leads the cannula 78 and holds it in place during use. The annulus 81 is positioned between the outer surface of the cannula 78 and the inner surface of the opening 110. As described further herein, the design of the liquid nozzle cap insert 80 and the nozzle cap 76 allows the pressurized aerosol gas to flow through the annulus 81 in a swirl pattern, maximizing aerosolization and promoting rapid mixing of the aerosolized plasma droplets with the drying gas. The entire nozzle assembly 20 is secured to an opening 96 in a plenum 6, which includes a baffle plate 8 having ridges 9, between which a filter 94 is located and sealed by an inner filter sealing ring 92 and an outer filter sealing ring 90. See FIG. 43B.

[0147] Figure 43D shows the aerosol gas reservoir housing 74 as transparent so that the cannula 78 and its attachment to the liquid nozzle cap insert 80 and nozzle cap 76 can be seen, while Figure 43E shows the manifold 72 and cannula 78 with the aerosol gas reservoir housing 74, liquid nozzle cap insert 80, and nozzle cap 76 removed. Figure 43F shows the bottom tip, the end opposite the manifold, of the cannula 78, which has an outer wall surface 84, an inner wall surface 86, a flat edge 88, and a sloped or angled edge 82 (e.g., a chamfer) on the bottom surface of the cannula.

[0148] It has been discovered that when used in spray drying to produce atomized plasma particles, cannulas having angled edges (e.g., chamfers) on the inner diameter assist or enable more of the proteins in the plasma to remain intact, functional, or both. Thus, the beveled edge cannulas of the present invention reduce the amount of protein degradation during spray drying because they reduce shear on the liquid plasma film passing through the angled edge cannula.

[0149] In a specific embodiment, the blood protein vWF was measured. vWF is considered a more fragile and easily degradable protein, as further described herein. In one embodiment, using a spray-drying nozzle with an angled cannula of the present invention maintains vFW recovery compared to a nozzle with a non-angled cannula. Indeed, based on the data described in Example 28, using a composite nozzle with a beveled cannula increased vFW recovery compared to both a composite nozzle with a non-angled cannula and a benchmark stainless steel nozzle (Buchi Model No. 4244, Buchi Corporation, New Castle, Delaware, United States). In one embodiment, using a nozzle with an angled cannula resulted in an increase in functional vFW recovery in an amount ranging from at least about 1% to 25% (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25%) compared to a nozzle with a non-angled cannula. In particular, as described in Example 28, the data show that spray drying using a beveled cannula having a 45 degree angle and a length of 0.005 inches increased vWF RCO assay results by approximately 9% to 22% compared to the same system operated with a composite nozzle having a cannula without the beveled edge, and surprisingly, an improvement of 3.7% compared to the benchmark control Buchi nozzle.

[0150] Plasma proteins preserved through the spray-drying process using a beveled edge cannula include von Willebrand factor (vWF). vWF is involved in coagulation, repair of vascular injury, and platelet adhesion. In particular, vWF is a large adhesive glycoprotein with established functions in hemostasis. It acts as a vascular injury sensor by acting as a carrier for factor VIII and attracting platelets to sites of vascular injury. Regulation of vWF multimer size and platelet tethering function is mediated by ADAMTS13, a constitutively active plasma metalloprotease. It is secreted into the blood and degrades large vWF multimers, reducing their activity. Unusually, the protease activity of ADAMTS13 is controlled not by a natural inhibitor but by a conformational change in its substrate induced when vWF is subjected to elevated rheological shear forces. This results in the conversion of vWF from a globular to an elongated protein. This conformational transformation unfolds the vWF A2 domain, revealing cryptic exosites and cleavage bonds. To enable vWF proteolysis, ADAMTS13 performs multiple interactions that position the protease as a substrate and engage the cleavage site when exposed by shear forces. ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13), also known as von Willebrand factor-cleaving protease (vWFCP), is a zinc-containing metalloprotease enzyme.

[0151] Without being limited to a theory of operation, it is believed that during spray drying, plasma proteins are subjected to significant shear forces due to the spraying mechanism as the solution is fluidized from the end of a fine nozzle and comes into contact with drying air to form droplets. The process of unfolding multimeric vWF is expected to be caused by the hydrodynamic forces of high shear stress during spray drying, combined with air-liquid interfacial stress. Shear-induced structural changes in vWF, when combined with other physical factors associated with spray drying, such as high temperature and / or unfavorable pH and air-liquid interfacial stress, can lead to protein denaturation (when unfolded vWF cannot properly refold after spray drying) and proteolysis (when unfolded vWF exposes proteolytic sites of ADMATS13), potentially compromising vWF activity and other proteins in spray-dried plasma.

[0152] The spray drying system of the present invention can be optimized to reduce protein damage caused by shear forces and temperature, and the specially designed cannula of the present invention helps minimize shear and damage to proteins (including vWF).

[0153] In one embodiment, the cannula of the present invention has a bottom edge, at least a portion of which is angled, and is referred to herein as a beveled edge cannula. In one example, the entire bottom edge can be angled, or a portion of the bottom edge can be a flat edge (e.g., at an angle of about 90° from the outer or inner wall surface). In another embodiment, as shown in FIG. 43F, a portion of the cannula's lower edge is a flat edge, such as flat edge 88 (e.g., at an angle of about 90° from the outer or inner wall surface), and a portion of the cannula's lower edge is beveled, such as angled edge 82 (e.g., at an angle of 45° from the outer wall surface or an angle of 135° from the inner wall surface). This embodiment, shown in FIG. 43F, has a flat edge (90° from the outer wall) that forms a 45° angle, and is referred to as a "chamfer" or "beveled edge."

[0154] When the cannula has a bottom edge and the entire bottom edge is angled from the outer wall to the inner wall, the angle measured from the outer wall surface ranges from about 30° to about 60° (e.g., about 30°, 35°, 40°, 45°, 50°, 55°, 60° angles), and the angle measured from the inner wall surface ranges from about 120° to about 150° (e.g., about 120°, 125°, 130°, 135°, 140°, 145°, 150° angles). The length of the angled bottom edge ranges from 0.001 inch to about 0.010 inch (e.g., about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.007, 0.008, 0.009, 0.010 inch).

[0155] When the cannula has a bottom edge with a flat edge and an angled edge, the flat edge is angled at about a 90° angle (e.g., about 85% to about 95%) from the outer wall surface. The angled edge has an angle ranging from about a 30° angle to about a 60° angle measured from the outer wall surface (e.g., about a 30°, 35°, 40°, 45°, 50°, 55°, or 60° angle), and in one embodiment, 45° + / - 5°, and an angle ranging from about a 120° angle to about a 150° angle measured from the inner wall surface (e.g., about a 120°, 125°, 130°, 135°, 140°, 145°, or 150° angle), and in one embodiment, 135° + / - 5°. See FIG. 52 for examples of 45° and 30° angled edges. The length of the flat edge portion ranges from about .001 inch to about .009 inch (e.g., about .001, .002, .003, .004, .005, .006, .007, .007, .008, .009 inches), and the length of the angled edge portion ranges from about .001 inch to .009 inch (e.g., about .001, .002, .003, .004, .005, .006, .007, .007, .008, .009 inches), and in one embodiment, is .005 + / - .003. The ratio of the length of the flat edge to the length of the angled edge ranges from about 5 to about 500 percent. In one embodiment, the flat edge is adjacent the outer wall surface and the angled edge is adjacent the inner wall surface.

[0156] Beveled edge cannulas, with or without flat edges, exert less stress / shear on the plasma droplets exiting the cannula compared to non-angled cannulas with a 90° angle. Without being bound by any particular theory, it is believed that when a plasma droplet exits a non-angled 90° cannula edge, the plasma droplet or a portion of the plasma film is subjected to a shearing effect, degrading a high percentage of the plasma proteins therein. In this case, a non-angled 90° cannula exerts shear forces on the droplets, thereby degrading the proteins in the plasma. When a plasma droplet exits a cannula with an angled edge, as in the present invention, less shear force is exerted on the plasma droplet. As the plasma is drawn by the airflow of the beveled edge cannula, it accelerates based on the plasma feed rate, pulling the plasma around the cannula edge. Unlike a cannula with a non-angled 90° edge, the plasma is not rotated 90 degrees. Angling the edges of the cannula softens the turn the plasma makes as it exits the cannula, thereby subjecting the liquid film to less shear as it is withdrawn. The liquid plasma film exiting an angled cannula is thicker and accelerates more slowly, thereby reducing the shear exerted on the liquid.

[0157] The inner diameter of the cannula ranges from about 0.010 inches to about 0.040 inches, and in one embodiment, 0.030 inches + / - 0.002 inches, and the outer diameter ranges from about 0.030 inches to about 0.060 inches, and in one embodiment, 0.050 inches + / - 0.0005 inches. The angled edge of the cannula affects the size of the atomized droplets. Upon exiting the angled cannula, droplet sizes range from about 5 microns to about 35 microns, and in one embodiment, the droplet size is about 10 microns. The small droplet size, defined in part by the angled edge of the cannula, promotes rapid mixing, faster evaporation, and reduced drying time. See Figure 43T, which shows that larger droplet sizes take longer for droplets to evaporate at higher drying gas temperatures. The droplet shape is dictated by its surface tension, creating a sphere after exiting the cannula. Droplet size is also primarily affected by the liquid feed rate (ALR) and the relative pressurized gas velocity to the nozzle design.

[0158] The cannula of the present invention can be made from stainless steel materials suitable for medical devices. Examples of usable stainless steel grades include grades 304 and 316. Stainless steel for use in the cannula of the present invention is commercially available, for example, from Bergsen Metals (Santa Fe Springs, California, USA) or Fort Wayne Metals (Fort Wayne, Indiana, USA). The nozzle assembly (excluding the cannula), nozzle insert, nozzle cap, plenum and baffle plate, outer filtering, inner filtering, etc. can be made from plastics used in medical devices, such as polycarbonate, polypropylene, polysulfone, or combinations thereof. Each of the aforementioned components can be made from the same material, different materials, or combinations thereof. Such plastics are commercially available and can be purchased from, for example, Covestro AG (Kaiser-Wilhelm-Allee 6051373 Leverkusen, Germany), Teknor Apex (Pawtucket, Rhode Island USA), Colorite Plastics of NJ Inc. (101 Railroad Ave, Ridgefield, New Jersey USA), American RENOLIT Corporation (301 Berkeley Drive, Suite B, Swedesboro, New Jersey USA), and Exxon Mobile (Technology Centers, Baytown, TX USA 77520, United States), or can be molded from, for example, Egli Machine (Sidney, NY USA) Co. and Southwest Mold, Inc. (Tempe, AZ USA). Other now known or later developed materials can be used for the cannula and / or nozzle, as long as, when combined, they result in maintaining or increasing the recovery of vWF in plasma after spray drying.

[0159] Stainless steel nozzles, such as the Buchi Model No. 4244 (Buchi Corporation, New Castle, Delaware, United States), are often used in spray drying but are expensive to manufacture or purchase, especially for disposable devices that are discarded after each spray drying run. For example, a typical Buchi stainless steel nozzle body, part number 4244, costs between $1,000 and $2,000. The nozzle assembly of the present invention is a composite nozzle for use in spray drying, and particularly for spray drying, of delicate materials such as human plasma, at a cost of less than $30.00, orders of magnitude less than a stainless steel nozzle such as the Buchi Model No. 4244. The described Buchi nozzle serves as a useful benchmark for composite nozzles, as it has been used by the present applicant to produce dried human plasma that regularly retains plasma proteins to acceptable levels.

[0160] As shown, except for the cannula, which is made of stainless steel, most of the nozzle assembly is made of cheaper plastic material, as mentioned above. Therefore, the nozzle assembly is also called a "composite nozzle" or "composite nozzle assembly," which refers to two or more different types of materials used to make the nozzle assembly (e.g., stainless steel cannula and polycarbonate nozzle insert and nozzle cap). Example 28 shows that the beveled cannula of the composite nozzle assembly provides improved vWF recovery compared to those with non-beveled cannula and vWF recovery as good as that of the expensive stainless steel nozzle.

[0161] As the plasma exits the tip of the cannula, it is exposed to pressurized aerosol gas at the nozzle cap 76. More specifically, the pressurized aerosol gas exits in a vortex pattern through the annulus 81 and impinges on the liquid plasma droplets flowing from the beveled / angled edge 82 of the cannula 78, atomizing the plasma and forming a plume. As the atomized plasma exits the spray-drying nozzle assembly, it is exposed to drying gas and dries into plasma powder in the drying chamber. In one embodiment, the tip of the cannula 78 is flush with the distal end of the opening 110.

[0162] The liquid nozzle cap insert 80 secures the bottom of the cannula 78 and directs the pressurized aerosolized gas flow. FIG. 43G shows a perspective top view of the liquid nozzle cap insert 80. As can be seen, the cap insert 80 has an insert wall 116 and a cannula anchor 120 with an opening (not shown) through which the cannula 78 extends. The top of the insert wall 116 forms a ridge, and the sides of the insert wall 116 define a series of recesses 118 and protrusions 119. The cannula anchor 120 supports the tip of the cannula 78 in the plasma flow. The angled edge 82 of the cannula 78, where the plasma exits, and the annular portion 81, through which the pressurized aerosol gas is released, create the actual nozzle. The cannula anchor 120 is a hollow, cylindrical base, but can be any shape as long as it supports the cannula and maintains its position during spray drying. A recess in the wall, recess 118, allows pressurized air to pass from the reservoir (defined by reservoir housing 74) to the region between nozzle cap insert 80 and nozzle cap 76 before exiting central opening 110 in nozzle cap 76. As the pressurized air exits central cap opening 110, it exits through annular portion 81 defined by the outer wall of cannula 78 and the inner wall of opening 110. More specifically, when cap insert 80 is secured to cap 76 and cannula 78 is within opening 110, the pressurized air exits through annular portion 81. See FIG. 43Ia. Thus, the diameter of opening 110 is larger than the outer diameter of cannula 78. Notably, opening 110 in nozzle cap 76 has a diameter D o(See FIG. 43Ia) also shows a diameter D c 1 shows a cannula 78 having an outer wall defined by a diameter D o is the diameter D c The difference is the distance D d The resulting difference in diameter is the distance D d creates an annulus 81 that allows pressurized air received from the aerosol reservoir housing 74 to form a vortex, facilitating the formation of small droplets of fluid that flow into the drying chamber 28 and are dried. c The distance D is about 0.030 to about 0.070 inches (e.g., 0.030, 0.040, 0.050, 0.060, 0.070), and the diameter of the opening 110 is 0.075 to 0.100. d " is also referred to as "the radial distance of the annular portion 81." In one embodiment, the diameter D c is .050+ / -.0005 inches, diameter D o The radial distance D between the outer surface of the cannula 78 and the inner surface of the opening 110 is 0.082 + / - .001 inches. d is a space where a rotating vortex of pressurized aerosol gas flows, helping to create small droplets of plasma for mixing with the hot drying gas during spray drying. d has a range of 0.005 inches to 0.030 inches (e.g., 0.015 and 0.021 inches).

[0163] Along these lines, the data from Example 27 shows that the radial distance D d It has been shown that the amount of dry matter affects both the yield of the dried product from the drying process and the preservation of vWF. The yield is the ratio of the starting solids in the liquid material being dried by weight to the dry material recovered by the drying process by weight.

[0164] Prior to the present invention, one source of yield loss occurred when dried spray material that was not completely dried and retained more than about 2.5% residual moisture could not be recovered and would come into contact with and adhere to the internal structure of the dryer disposable during drying.

[0165] Example 27 illustrates the reduction in the amount of material visibly adhering to the underside of the baffle plate 8 after the drying cycle is complete. The data presented in Example 27 demonstrates the reduction in the amount of material visibly adhering to the underside of the baffle plate 8 after the drying cycle is complete. d The graph shows that the overall weight yield increased by changing the radial distance of the annulus from 0.021 inches to 0.015 inches. At the 0.021 inch annulus size, the yield was acceptable. However, by decreasing the annulus width / diameter to 0.015 inches, the yield improved by over 2.2%. Other features of the disposable 100 increase yield and include, in part, the drying jets 142 that form an air wall within the plasma drying chamber 28, as further described herein.

[0166] Example 27 also describes an increase in vWF recovery as measured by Ristocetan (RCO) assay by changing the radial distance of the annular 81 from 0.021 inches to 0.015 inches. The vWF recovery was acceptable with an annular dimension of 0.091 inches. However, vWF recovery increased by more than 2.0% by decreasing the annular width to 0.082 inches. Other features of the disposable 100 also increase vWF recovery, including, in part, the beveled edge cannula 78, as described herein.

[0167] The space between the nozzle cap insert 80 and the nozzle cap 76 prior to exiting the central opening 110 of the nozzle cap 76 is generally referred to herein as a "vortex generator" and includes a series of channels and curved pads, as further described below. Pressurized air passes through recesses 118, which function as openings in the nozzle assembly 20, allowing the air to enter the channels and travel down the channels and between the curved pads. See Figures 43G, 43H, 43I, and 43Ic.

[0168] Referring to FIG. 43H, the bottom surface of the cap insert 80, unoccupied by the pads 122 beneath the protrusions 119 / recesses 118, serves as the walls of the vortex generator channels. The pads 122 form a kidney-like shape that aids in locating the recesses 118 for the vortex airflow pattern. The nozzle cap shown in FIG. 43I, cap 76, has a complementary receiver 112 for receiving the pads from the cap insert 80. The complementary fit between the nozzle insert 80 and nozzle cap 76 is shown (in cross section) in FIG. 43Ic. The nozzle cap 76 also has a nozzle cap channel 106 extending from the bulbous head 108 and terminating in an opening 110. The bottom surface of the cap insert 80 not occupied by the pads 122 and further complemented by the channel 106 in cap 76 is the space through which pressurized air flows. The vortex generator includes the recess 118 and the surface of the bottom of the cap insert 80 not occupied by the pad 122, the bulbous head 108, and the channel 106 of the cap 76, the shapes and positions of which cause the pressurized air to form a vortex airflow pattern. The bulbous head 108 receives the pressurized airflow through the recess 118, and the curved, sloped surface of the channel 106 provides a curved boundary for the air to flow through. In other words, the recess 118 is the inlet port, providing the airflow, and the channel 106 provides the vortex. The channel 106 is arched, further enhancing the curved airflow and directing the tangential airflow toward the opening 110 where the cannula 78 resides. These channels, the channel 106, guide the air in a circular motion from the bulbous head 108 to the nozzle cap opening 110, all working together to expel the pressurized air as a vortex through the opening 110. The design provides tangential momentum to provide efficient generation of the vortex. The channels 106 are in the form of an arc or curve, with a radius of curvature ranging from about 0.10 inches to about 0.25 inches, and in one embodiment, a radius of about 0.140 + / - 0.010 inches. The generated vortex includes four channels, but can have about 2 to 12 channels (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 channels). Other types of molded channels can be used. Figure 43I shows the design molded into the nozzle cap 76.Designs A and B both exhibit straighter channels, but Design A does not correspond to a bulbous head, while Design B exhibits a bell-shaped head. Design C is similar to the design shown in FIG. 43I, but has leaves rather than bulbous ends. The present invention includes nozzle caps with Designs A and B, but it has been found that Design C appears to be a more efficient vortex generator. The various designs demonstrate that any combination of channels, heads, and shapes can be used to generate vortices in the annulus. Other types of channels include conical shaped channels, including diverging or diverging conical shapes, etc.

[0169] Once the vortex is generated, the pressure and velocity flow patterns are shown in Figures 43O and 43P. Figure 43O shows the contours of static gas pressure in psig at the top and tangential velocity of the pressurized aerosol gas flow in m / s at the bottom. As can be seen, there is an inverse relationship between pressure and velocity. In regions where pressure increases, velocity decreases, and vice versa. In particular, at the bulbous head 108 where the pressurized gas enters the vortex generator, there is a higher relative static gas pressure (e.g., about 2.54 x 10 1 psig) and a relatively low velocity flow rate (e.g., about 2.00 x 10 1 Conversely, in annulus 81, there is a relatively low or negative gas pressure (e.g., about -2.24 psig) and a higher velocity (e.g., about -1.58 x 10 2 ~Approx.-3.75×10 2 m / s). As the pressurized aerosol gas moves along the curved nozzle cap channel 106, the pressure and velocity are the velocity between them. Therefore, the vortex generator of the present invention generates a vortex of approximately 2.54×10 1 psig to approximately -2.24 psig gas pressure and approximately 2.00 x 10 1 m / s~approx.-3.75×10 2 m / s. In one embodiment, any vortex generator can be used with the present invention as long as it generates gas pressures and velocities in these ranges. Similarly, FIG. 43P shows a more detailed view of the velocity pattern that occurs in annulus 81. Pressurized gas travels between the outlets of channel 106 as it becomes incorporated into vortices. As the pressurized gas enters annulus 81, it accelerates and becomes a vortex.

[0170] The vortex generator in this embodiment includes a curved pad / ramp, a bulbous head that receives the pressurized airflow, and a curved channel that extends to the exit opening. The present invention can include other vortex generators, such as wings, edges, wedges, vanes, etc. Other shaped channels can also be used to create vortex generators. Those skilled in the art can utilize other vortex generators present in the inserts and caps of the nozzle assemblies of the present invention, so long as the pressurized air exits between the inner surface of the opening 110 and the outer surface of the cannula 78 in a vortex.

[0171] Pressurized air circulates between the exterior surface of cannula 78 and the interior surface of opening 110. Specifically, the pressurized gas exits through annulus 81. Plasma is pumped through cannula 78 by peristaltic pump 214 at approximately room temperature. The plasma travels down the interior of stainless steel cannula 78 and is drawn out of cannula 78 by the pressurized aerosol air stream exiting annulus 81. The high-velocity aerosolizing air stream atomizes the droplets. In one embodiment, the steady-state plasma delivery rate is about 6 to about 23 mL / min (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23). In a preferred embodiment, 13.5 mL / min is the steady-state delivery rate after the system has warmed to thermal equilibrium.

[0172] In one embodiment, the plasma feed rate is related to or dependent on the outlet temperature. This is done in a closed loop. As the outlet temperature decreases, the system adjusts to decrease the plasma feed rate. Conversely, as the outlet temperature increases, the system increases the plasma feed rate. The outlet temperature may be lower, for example, when the spray dryer is warming up or as time passes during a spray drying run. Specifically, in one embodiment, the plasma feed rate can be adjusted as follows:

[0173] [Table 3]

[0174] Chart values ​​calculated based on thermodynamic principles, assuming constant system heat loss, complete droplet evaporation, and dryer outlet relative humidity less than 11.8%.

[0175] Thus, at lower outlet temperatures, the plasma feed rate is reduced to maintain the target drying chamber outlet temperature required to dry the plasma to less than 2% residual moisture. At higher outlet temperatures within this range, the plasma feed rate can also be increased, and a plasma residual moisture content of less than 2% can still be maintained only if the total gas flow rate can be increased and / or the drying chamber outlet temperature can be increased to maintain the target system relative humidity.

[0176] In one embodiment, the closed loop comprises an exhaust temperature in the range of about 62° C. to about 68° C. and a plasma feed rate in the range of about 6 to about 23 mL / min.

[0177] There is negative pressure directly below the cannula, and the pressurized gas flow is at a high velocity. Generally, velocity increases along a path of decreasing static pressure. The pressurized aerosol gas travels through a series of channels 106, atomizing the plasma droplets and creating vortex flows that guide the initial droplet trajectories. The aerosol flow rate is about 20 slpm to about 60 slpm (e.g., about 20, 25, 30, 35, 40, 45, 50, 55, 60 slpm), and in one embodiment, about 40 slpm. This occurs at a pressure of about 180 kPa to about 260 kPa (e.g., about 180, 190, 200, 210, 220, 230, 240, 250, 260 kPa), and in one embodiment, about 227.5 kPa (33 psig). The aerosol flow acts to draw the liquid supply from the cannula, where it forms a film across the end. The expansion of the aerosol gas as it exits the orifice locally cools the gas field near the nozzle, which also acts to cool the droplets and slightly slow evaporation. Also, in one embodiment, the pressure just below the end of the cannula is lower than the pressure inside the cannula, and the pressurized gas velocity accelerates as it travels along the outer surface of the cannula. Upon exiting, the spherical plasma droplets collide with the pressurized gas and aerosolize, forming a spray plume surrounded by a ring of drying gas jets, as described further below. See Figure 43N. Mixing of the aerosol and drying gas sets the initial conditions for the evaporation process.

[0178] Figure 43Q is a schematic diagram showing liquid plasma droplets undergoing a drying process. The plasma droplets are atomized and approximately spherical as they exit the nozzle assembly cannula into the drying chamber. Dried plasma particles are formed by heat and mass transfer. Drying occurs in two stages: evaporative drying (constant rate) drying, which occurs during initial drying (e.g., less than 1 second), and drop velocity drying (diffusion limited), which occurs after the evaporative drying stage and continues as long as the dried particles are subjected to an ambient relative humidity lower than their internal relative humidity.

[0179] Factors involved in the evaporative drying phase of plasma droplets include the temperature of the plasma and drying gas, the surface area of ​​the droplets, the humidity in the drying gas, and the air circulation within the plasma drying chamber. As shown in Figure 43Sa, when the drying gas initially exits the nozzle assembly, its temperature is approximately 90°C to approximately 130°C (e.g., approximately 100°C to approximately 114°C), and the temperature of the plasma droplets within the plume is approximately 20°C to approximately 65°C. Heat flows from points of higher temperature to points of lower temperature, in this case, drying gas heat, which flows to the plasma droplets. Regarding surface area, the droplets are spherical, thereby maximizing their surface area, and the droplet size is very small, so mass and heat transfer can occur rapidly. Because the relative humidity in the drying gas is very dry (e.g., approximately 0.1% RH), the low humidity of the surrounding drying gas facilitates evaporation of plasma particles. Finally, as described in more detail below, drying gas is emitted into the plasma drying chamber at a downward angle into the plume of atomized droplets using several drying gas jets, initiating rapid mixing of the drying air with the atomized droplets and increasing the evaporation rate of the droplets. The drying rate is constant; as the liquid droplets evaporate and lose moisture, moisture is transferred from the liquid plasma droplets to the drying gas, and heat from the drying gas is transferred to the plasma droplets, resulting in dry particles. The plasma droplets enter the drying chamber at essentially room temperature, and the temperature remains constant for most of the evaporation period. See Figure 43S. As most of the moisture leaves the particles, their temperature increases and equilibrates with the dryer chamber exit temperature of 65°C. During evaporation, the droplets are maintained at a lower temperature, thereby protecting heat-sensitive proteins such as vWF. See Figure 43S. During the evaporation process, the temperature of the droplets and the proteins therein experience a lower temperature, i.e., the thermodynamic wet-bulb temperature, compared to the inlet drying gas temperature, thereby protecting the proteins. See Figure 43R. Evaporation reduces the protein temperature to near the thermodynamic wet bulb value, and evaporation slows the increase in particle temperature. See Figure 43Sa.

[0180] The starting droplet size generated by the nozzle assembly influences the residence time in the drying chamber required to complete evaporation. Larger droplets have a smaller ratio of evaporation surface area to droplet mass, resulting in a slower mass transfer rate from the droplet. This slower rate requires a greater distance between the nozzle assembly 20 and the lower filter 36 to prevent excessively wet particles from depositing on the filter membrane of the lower filter 36. Excessively wet particles can cause "clogging or plugging" of the porous filter membrane, preventing the process from completing due to excessive chamber pressure buildup, preventing powder production. See Figure 43T.

[0181] Furthermore, Figure 43T shows that in all cases, the majority of evaporation occurs in the upper portion 148 of the disposable. This is particularly evident when using small droplet sizes, e.g., less than 15 microns. As can be seen from Figure 43T, the drying chamber can be shortened to a chamber where the majority of evaporation occurs, yet the dried particles can achieve less than 2.5% residual moisture before being deposited on the lower filter 36. In other words, in one embodiment, when the droplet size is less than about 15 microns and less than about 2.5% residual moisture is achieved, the drying chamber 28 can be shortened by an amount of about 8 inches to 1 inch.

[0182] Turning to the plenum, its functions include 1) allowing the introduction and flow of drying gas to the disposable, 2) housing the nozzle assembly, and 3) supporting the drying chamber during the spray drying process. The underside of plenum 6 is shown in Figure 43J. Plenum 6 has two openings: opening 96 for receiving nozzle assembly 20 and drying gas inlet port 22 for receiving drying gas.

[0183] The nozzle assembly receiver opening 96 is complementary in shape to the top of the nozzle reservoir housing 74 and manifold 72. The top of the nozzle assembly 20 is secured within the opening 96. The length of the nozzle assembly matches the height of the plenum 6 so that the bottom of the nozzle assembly 20 extends beyond the baffle plate 8. See Figures 46A and 46B. In certain embodiments, the cannula is flush with the nozzle assembly and baffle plate. The nozzle assembly 20 can be secured with adhesive, fasteners, or an interlocking assembly (e.g., spring latch, threaded fit, etc.).

[0184] The other opening in plenum 6 is drying gas inlet port 22, which accepts drying gas. A drying gas source (not shown) enters the plenum through drying gas inlet deflector 242, shown in Figure 43K. The disposables are secured and aligned, the door to the spray dryer is closed, and spray drying begins. Drying gas inlet deflector 242 descends through drying gas inlet port 22 and provides drying gas to plenum 6. Drying gas inlet deflector 242 has an elbow shape, as shown in Figure 43Ka, so that the drying gas flows toward the far inner sidewall of the plenum, creating a tangential mixture. The right angle of deflector 242 distributes the drying gas throughout plenum 6, creating a low-velocity, highly uniform pressure reservoir. Uniformity is desirable to create a low-velocity, uniform pressure of the drying gas as it exits each of the drying jets 142. If the drying gas is not deflected away from the side of the plenum 6 but instead deflected downward, the air pressure may be asymmetric, with drying jets closer to the drying gas inlet experiencing higher pressures compared to those further from the inlet. Therefore, the present invention includes drying gas inlets that are deflected toward the side of the plenum with a 90-degree elbow, as in the case of deflector 242. Other shapes for deflector 242 can be used to create uniform air pressure within the plenum 6. For example, the deflector can be angled at an angle less than 90 degrees, measured from the top of the plenum. For example, the deflector can have an angle ranging from about 60 to about 110 degrees relative to the top of the plenum 6, such that the drying gas pressure across the width of the plenum 6 is substantially uniform. Alternatively, two or more drying gas inlets from opposite sides can be used to create substantially uniform drying gas pressure across the width of the plenum 6.

[0185] As shown in FIG. 43J, the plenum 6 has concentric ribs 98 and radial ribs 102. These ridges provide structural support to the plenum 6. The additional support provided by the concentric radial ribs allows the plenum to withstand the pressure and heat of the spray drying process. Because the drying gas is a low-velocity, uniform-pressure air container, the concentric ribs 98 and radial ribs 102 do not contribute to or affect the airflow of the drying gas. Similarly, the protrusions 104 on the inner sidewall of the plenum are used in the injection molding process when manufacturing the plenum and do not play a role in the flow of the drying gas.

[0186] As shown in Figures 43L, 43La, and 43M, the baffle plate has several functions: A) it acts as a support for securing the disposable 100 when the disposable is aligned and inserted into the spray dryer 200; B) it creates a drying gas air flow path and releases drying air into the plasma drying chamber 28 of the disposable 100; and C) it supports the baffle filter 94.

[0187] FIG. 43L shows a top inside view of the baffle plate 8. The inner surface of the baffle plate 8 has a baffle plate nozzle opening 140 through which a portion of the nozzle assembly 20 resides. The baffle plate 8 also includes a raised outer ring 124 having a base 126 and a raised inner ring 128 having a base 130. The outer sealing ring 90 is disposed around the outer ring 124, and the inner sealing ring 92 is disposed around the inner ring 128. The sealing rings prevent dry gas from escaping the edge of the filter 94; instead, the dry gas flows through it. The inside of the baffle plate 8 further includes a locator 132 for inserting the locator notch 26 of the plenum 6. The plenum and the baffle plate have locators for aligning them with one another. The baffle plate 8 has a baffle locator 132 that receives a plenum locator 152 on the plenum 6.

[0188] The baffle plate ribs 134, 136, and 138 support the baffle plate filter 94 (shown in FIG. 43L) during use, while keeping the majority of the filter's surface elevated from the baffle plate. The baffle plate ribs also act as guides for the dry gas flow. It has been determined that if the baffle plate filter 94 were to lie flat against the inside of the baffle plate 8 without the ribs, the dry gas flow would slow down and not flow freely through the multiple dry jets 142. Specifically, to avoid this phenomenon, the baffle plate 8 has radial ribs 134 connecting the inner ring base 130 to the outer ring base 126. Each radial rib 134 has a consistent contour throughout its length, allowing the filter to sit in an elevated position compared to when it rests directly on the inside surface of the baffle plate. The radial ribs 134 also form pie-shaped air channels 139 that lead to the dry jets 142. The radial ribs 134 are the sidewalls of the pie-shaped air channels 139. The baffle plate 8 has two types of ribs that extend from the outer ring base 126 but do not connect to or reach the inner ring base 130. These ribs include short radial ribs 136 and intermediate radial ribs 138. Both the short radial ribs 136 and the intermediate radial ribs 138 have a consistent height profile as they extend inward from the outer ring base 126 and then rapidly taper to a tapered end 137. The tapered end 137 helps support the filter without creating corners through which the filter can penetrate. Specifically, the baffle filter 94 rests on the ribs 134, 136, and 138 and is pressed against them by air pressure, e.g., about 11.5 psig, during spray dryer operation. The tapered ends of the ribs 136 and 138 reduce stress on the baffle filter, preventing damage to the filter and reducing loss of filtration efficiency. See Figure 43La. The ribs inhibit the baffle filter 94 from adhering to the inner baffle plate surface. The connecting and non-connecting ribs are interspersed on the inner baffle plate surface and, in the embodiment shown in FIG. 43L, form a pattern in the pie-shaped air channels 139 (e.g., with a connecting rib, a short non-connecting rib, two middle non-connecting ribs, a short non-connecting rib, a connecting rib, etc.). Each pie-shaped air passage 139 is defined by two connecting ribs on either side.The connecting and non-connecting ribs can be in any pattern so long as they support the baffle filter 94 while allowing drying gas to flow through and under the filter 94 and through air channels 139 to the drying jets 142. For example, Figure 43La shows another arrangement of ribs 136 and 138.

[0189] In one embodiment, the pressure drops as the drying gas passes through the baffle filter 94. The input drying air pressure in the plenum 6 before passing through the filter and into the pie-shaped air flow passage 139 is about 8 to about 15 psig during operation, approximately 10.4 psig in one embodiment. As the drying gas passes through the baffle filter 94, the pressure drops by about 40 to 60%, or approximately 6 psig in one embodiment. The pressure drop across the baffle filter 94 is utilized to aid in the even distribution of the drying gas injected into the drying chamber, as shown in FIG. 43Ma. This feature helps minimize asymmetric drying within the chamber and shorten the overall length. The resulting pressure within the drying chamber 28 in the area defined by dimension Z ranges from about 4 psig to about 7 psig, approximately 5.5 psig in one embodiment. As discussed further herein, the lower filter 36 of the disposable 100 causes a pressure drop of approximately 40-80%, or in one embodiment, approximately 3.0-5.5 psig, which increases as dried plasma accumulates on the filter, resulting in an outlet air pressure of approximately 1-2.5 psig. In one embodiment, the gas exhaust port 208 of the spray diaper 200 is slightly constricted so that the exhaust gas venting to the outside is approximately 1.5 to approximately 3 psig. Any valves, sensors, or tubing lengths beyond the exhaust outlet will add a small pressure increase.

[0190] In one embodiment, the flow of dry gas through the baffle plate 8 is not restricted. In one aspect, the height and arrangement of the ribs 134, 136, 138 of the baffle plate 8 are such that the baffle plate filter 96 distorts somewhat under the pressure of the dry air, but does not materially affect the pressure drop. Note that, as noted above, the baffle plate filter 96 creates a pressure drop as the dry gas passes through it, but the baffle plate 8 itself does not. The cross-sectional area of ​​the pie-shaped channel 139 is equal to or greater than the cross-sectional area of ​​the opening of the dry gas inlet deflector 242. Alternatively, the cross-sectional area of ​​the pie-shaped channel 139 is equal to or greater than the sum of the cross-sectional areas of all the openings of the dry gas jets 142.

[0191] The data presented in Example 8 demonstrates that the air flow passages 139 of the baffle plate 8 shown in Figure 43L do not interfere with the bacterial filtration efficiency (BFE) of the baffle filter 94, allow for greater than a log 6 reduction in pathogens when challenged with Staphylococcus aureus (S. aureus) in the BFE under American Society for Testing and Materials (ASTM) F2101-14, and do not damage the baffle filter 94 during operation of the spray dryer 200. See Examples 8 and 9.

[0192] In one embodiment, the baffle filter 94 is a 0.2 micron filter (e.g., a 0.22 micron filter) that prevents pathogens that may be introduced into the drying gas from entering the drying chamber. The filter can be at least a 0.2 micron filter, such as a 0.1 micron filter or smaller, as long as it allows the drying gas to flow through it as described herein. The filter is strong enough to withstand the heat and pressure of the spray drying process, but flexible enough not to tear when pressed against the ribs as air flows through it. The baffle filter is such a filter and can be a 4 micron deep or membrane filter. Filters are commercially available from Gore (231 East Oak Street, Bozeman, Montana, USA), Lydal (Rochester, New Hampshire, USA), Teijin (Chiyoda-ku, Tokyo, Japan), or Sabeu (Northeim, Germany). Any type of commercially available filter can be used as long as it prevents pathogens from being introduced into the drying chamber, but is porous enough to allow the drying gas to pass through at the specified flow rate. The baffle filter and bottom filter may be made, for example, from a polyethylene filter matrix. In one embodiment, the baffle filter 94 is commercially available from Sabeu of Northem, Germany under art. no. 063090.

[0193] Referring to Figure 43M, the underside of the baffle plate can be seen. After passing through the baffle filter 94, the drying gas exits through a plurality of drying gas jets 142. In one embodiment, the drying gas jets 142 are parallel to one another and have centerlines along their lengths that are perpendicular to the baffle plate 8. Despite the mechanical structure described for the jets 142, the drying gas air exiting the jets is angled inward toward the centerline of the drying chamber 28. Figures 43N and 43Na show the flow pattern of the drying gas jets 142.

[0194] The drying gas jet 142 effectively creates a "wall of dry gas" within the plasma drying chamber 28, as shown in FIG. 43Ma, while promoting rapid mixing with the atomized plasma particles. The dry jet airflow is partially directed at the plume of atomized liquid plasma droplets for rapid mixing. The wall of dry gas minimizes the accumulation of dried plasma on the interior walls of the plasma drying chamber 28.

[0195] Within the multiple drying gas jets 142 are multiple recesses 144. The recesses 144 are used to provide additional support to the structure so that the plenum 6 and baffle plate 8 do not buckle and contribute to the airflow during spray drying. The drying gas jets 142 are arranged concentrically with the recesses 144. In the embodiment shown in FIG. 43M, there are 16 drying jets 142. The present invention can have more or fewer drying jets ranging from 2 to 32 jets.

[0196] Additionally, the drying gas jet 142, like the nozzle assembly, is not flush with the baffle plate but extends beyond the plane of the baffle plate. Extending the nozzle assembly 20 and drying gas jet 142 beyond the plane of the baffle plate allows the plasma to dry away from the baffle plate surface, reducing the accumulation of dried plasma on the outer surface of the baffle plate and / or the bottom of the nozzle assembly during the drying process.

[0197] In light of the above structure, the heated drying gas dries the atomized plasma droplets as follows: The heated drying gas is supplied to the top of the plenum through deflector 242 at a flow rate of about 500 slpm to about 1000 slpm (e.g., about 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 slpm), and in one embodiment, about 750 slpm. The heated drying gas enters the plenum at a temperature of about 100°C to about 130°C (e.g., about 100, 105, 110, 115, 120, 125, 130°C), and in one embodiment, about 114°C. Deflector 242 redirects the gas 90 degrees to aid in uniformity of airflow within the plenum. The drying gas is forced through baffle filter 94 (e.g., a 0.2 micron sterilization-rated filter) located on the top surface of the baffle plate. As mentioned above, the baffle plate 8 is designed with channels to create pie-shaped air channels 139, with the filter providing the upper surface of the channels. The pie-shaped ducts 139 direct the drying gas into 16 individual drying gas jets 142. This flow configuration creates jets directed inward toward the atomizer to aid in plume containment. The mixture of heated drying gas, aerosol gas, droplets, and water vapor drives evaporation, converting the plasma into dry powder. The process is completed in less than one second under the spray-drying process conditions of the present invention, with individual particles formed at the top, defined by the dimension X of the drying chamber 28.

[0198] An inner concentric ridge 146 on the exterior of the baffle plate 8 is a base for attaching the walls of the plasma drying chamber 28. The plasma drying chamber 28 can be attached to the baffle plate 8 using a collar or ring, adhesive, fasteners, etc. The plasma drying chamber 28 can also be attached to the baffle plate 8 at the ridge 146 by heat welding the chamber to the baffle plate 8. The attachment points can also be molded as part of the baffle plate. The drying chamber can be attached to the baffle plate by any number of commercially available methods.

[0199] Detailed description of the drying chamber As described herein, the purpose of drying chamber 28 is to A) allow drying of nebulized plasma while preserving proteins and their function, B) capture the dried plasma while allowing gases to escape, and C) subsequently convert it into a commercially available dried plasma unit without a filter. The drying chamber, in one embodiment, is a sterile, non-pyrogenic, disposable, dual-purpose chamber in which plasma is dried, collected, and stored in one portion of the chamber for use.

[0200] 44 and 46A, the drying chamber 28 is shown, which includes an upper section defined by a length X, a middle section defined by a length U, and a lower section defined by a length V.

[0201] The upper portion 148 is attached to the baffle plate 8 via a baffle plate ring 156 at the outer concentric ring 146. The baffle plate 8 protrudes the nozzle assembly 20. As mentioned above, the nozzle assembly 20 and the drying gas jet 142 extend beyond the plane defined by the baffle plate 8. Therefore, convergence of the atomized plasma occurs at the upper portion 148 of the plasma drying chamber 28. While the majority of the drying of the atomized plasma particles occurs at the upper portion 148, the plasma continues to dry as it travels along the length of the drying chamber 28. When the pressurized air is within the nozzle assembly, it forms a vortex configuration. As the plasma film exits the cannula and the pressurized air exits the annulus as a vortex, the droplets aerosolize or atomize, forming a plume, as shown in Figure 43N. The vortex configuration weakens and expands as it travels downward. Meanwhile, the drying gas jet 142 is angled inward toward the plume to contain the plume and direct the gas to rapidly mix with the aerosolized plasma droplets. The combination of the weakened vortex and the flow from the angled drying gas stream dilutes the plasma droplet spray plume, resulting in more drying gas surrounding the plasma droplets and promoting rapid mixing of the drying gas with the droplets. This action promotes efficient evaporation of the plasma droplets, which occurs throughout most of the upper portion of the drying chamber. As with the present invention, rapid mixing occurs, and the droplets evaporate relatively quickly at a lower temperature than the drying gas, preserving the plasma proteins. See Figure 43S. In contrast to freeze-dried plasma, the rapid drying of the plasma of the present invention largely avoids the formation of crystals in the dried plasma, particularly undesirable cholesterol crystals.

[0202] The gas flow from the drying air jets 142 forms an air curtain that prevents the dried plasma particles from depositing on the inner sidewalls of the drying chamber. Additionally, the angled air wall formed from the drying jets 142 also helps direct the dried plasma particles downward toward the lower filter 36.

[0203] While the majority of the plasma evaporates and dries in the upper section 148, drying of the plasma continues in the middle section 46 defined by dimension U. The middle section 46 includes "seal and separate" positions 44A and 44B, the label 40, spike ports 42A and 42B, and the hanging slot 34. The "seal and separate" positions 44A and 44B are where the drying chamber 28 is cut to create the dried plasma unit 60 (shown in FIG. 49 ). As described herein, the finishing device 400 moves the plasma within the disposable, seals and separates at positions 44A and 44B to isolate the middle section 46, and removes the upper and lower sections 148 and 150 of the disposable to create the dried plasma unit. The spike ports 42A and 42B are for use with the dried plasma unit. The spike ports can be used to reconstitute the dried plasma with a reconstitution solution or sterile water for injection (SWFI). The spike port is a plugging and / or connection device and can be configured to "thread off" to expose a connection port for use in a sterile environment. Other commercially available spike port connectors and adapters can be used as long as they are suitable for a sterile environment. The hanging slot 34 is an opening used to attach the plasma bag 64 to an IV (intravenous) pole. The spike ports 42A and 42B and the hanging slot 34 are fabricated and used in the same manner as those for IV medical bags. The central section 46 also includes a locator pin opening 32C. As described further herein, the locator pin opening 32C is used to secure the disposable 100 to the finishing apparatus 400 so that the disposable 100 remains in place during sealing and separation.

[0204] While most of the plasma evaporates and dries in the upper section 148, drying continues in the lower section 150 defined by dimension V. Referring to the exploded view of the disposable in FIG. 44, the lower section of the drying chamber 28 includes the lower filter 36, the lower filter separator 38, the drying gas outlet port 30, and the locator pin openings 32A and 32B. Moist air (e.g., the drying gas, the aerosolized gas, and moisture removed from the aerosolized plasma droplets) flows into the lower section 150 through the lower filter 36, the lower filter separator 38, and the gas outlet 30 secured to the gas exhaust port 208. After passing through a channel or space between the filter 36 and the outer wall of the drying chamber 28, the moist air exits through the gas exhaust port 208, where it is filtered and released to the outside air. When the air is released to the outside air, a filter is used to prevent contamination of the plasma within the spray dryer in the event of a breakage. Such a filter can be a HEPA filter, a UPLA filter, or the like. HEPA filters for filtering the exhausted air can be purchased commercially.

[0205] The lower / trapping filter 36 separates the dried plasma from the moist air. Specifically, the lower filter 36 traps dried plasma particles / powder while allowing moist air to pass through. The dried plasma accumulates on the filter throughout the drying process. The goal of the drying process is to complete the majority of the evaporation of the plasma droplets (i.e., complete the mass transfer process) before the dried particles hit the filter surface. Effective evaporation occurs upon rapid mixing of the dry air with the atomized plasma droplet size distribution, which ranges from about 1 micron to about 35 microns. The rapid mixing described herein is enhanced by the vortex flow of the pressurized air, the droplet size of the atomized plasma droplets, and the drying gas flow. The length of the drying chamber depends on the atomized plasma droplet size. A shorter drying chamber allows for less time for the droplets to complete evaporation / mass transfer, while a longer drying chamber allows for larger droplets to be used. Completion of the evaporation process for a particular droplet size depends in part on the length of the drying chamber. As the initial plasma particles collect on the filter, the subsequent dried plasma particles create a depth of powder through which the airflow penetrates and pressure builds in the system, yet still allows moist air to pass through effectively. If the residual moisture of the dried plasma particles is less than 2%, moist air can pass through the dried plasma on the lower filter 36, pass through the lower filter 36, and exit through the gas outlet 30 / gas exhaust port 208.

[0206] The dried plasma produced by the present invention is a fine, highly amorphous, and very dry (eg, less than 2% residual moisture) powder such that little or no clogging of the lower filter 36 occurs.

[0207] While the initial powder entering the lower filter is exposed to the chamber outlet temperature for the duration of the batch, subsequent powders have a shorter residence time in the filter. The residual moisture content in plasma dried with the disposables and dryers of the present invention is very low, e.g., less than about 2.5%, 2%, 1%, and preferably less than about 1.46% residual moisture, as measured, for example, by a Karl Fischer moisture sensor, Model No. C30S Compact KF Coulometer (Mettler, Toledo Billerica, Massachusetts, USA). This very low moisture level results from effective and efficient evaporation of plasma droplets occurring at the top and process conditions of the drying chamber 28. In this embodiment, the powder moisture level is in equilibrium with the relative humidity of the chamber outlet airflow. Plasma particles with higher moisture levels accumulate on the lower filter 36, forcing moist air to pass through the filter at a slower rate, thereby increasing the pressure within the chamber. Essentially, plasma particles that are too moist to evaporate efficiently clog the filter, preventing or significantly reducing the flow of moist air. However, the present invention has efficient evaporation, thereby allowing moist air to pass through the trapped dried plasma particles. Dried plasma with less water content improves protein stability during storage.

[0208] In one embodiment, the lower filter 36 is a 0.2 micron filter so as to be small enough to prevent plasma particles from passing through while allowing moist air to pass through with minimal pressure rise. The filter can be at least a 0.2 micron filter, for example, a 0.1 micron filter or smaller, so long as it allows moist air to flow as described herein. The lower filter 36 is commercially available from Lydall Inc. of Rochester, New Hampshire, USA, under model number 70L02A.

[0209] The lower filter 36 may be supported by a filter frame built into or attached to the filter 36 and attached to the inner wall of the plasma drying chamber 28. The filter 36 is attached around the entire periphery of the inner wall. In other words, the filter frame or the filter itself is attached around the entire periphery of the inner wall so that there are no openings between the inner wall of the drying chamber 28 and the attachment point of the filter 36. Attaching the filter to the inner wall in this manner forms a barrier against dried plasma particles and moist air, which causes the plasma and moist air to move downward toward the gas outlet 30, with the filter 36 capturing the dried plasma while allowing the moist air to pass through. A filter frame 37 is attached to the inner surface of the drying chamber 28 by heat welding. In another embodiment, the filter frame may be attached to the inner surface of the drying chamber 28 by a combination of adhesive (e.g., UV adhesive) and RF welding, for example, by an insulator unit from UFP, Inc., Chicopee, Massachusetts, USA.

[0210] As shown in Figures 44A and 44B, a lower filter separator 38 is positioned between the filter 36 and the inner wall of the drying chamber 28. The separator 38 acts similarly to the ribs on a baffle plate, lifting the filter away from the inner wall of the drying chamber 28. This prevents the filter from adhering to the inner wall of the drying chamber 28, allowing moist air to pass through more easily and preventing pressure buildup. The lower filter separator 38 can be textured or ribbed to maintain space between the filter 36 and the inner wall of the drying chamber 28. In one embodiment, the filter separator 38 is ribbed with multiple spacers. See Figures 42A and 44A. In another embodiment, the filter separator 38' comprises a porous, coarse, circular woven fabric of filaments. See Figure 44B. In the embodiment shown in Figure 44B, there are two separators. The separator can be made from a single piece or multiple pieces (e.g., 1, 2, 3, 4, 5, or 6 pieces). Any type of spacer or standoff can be used to maintain separation between the filter 36 and the inner wall of the drying chamber 28. Another example of a separator includes a flexible three-dimensional matrix of polymer filaments. In the embodiment shown in FIG. 44, the separator 38 surrounds most of the filter 36. In other embodiments, the separator 38 only needs to surround the filter 36 sufficiently to maintain a space between the filter 36 and the inner wall of the drying chamber 28. The spacer / separator 38 is made from a material that can withstand the heat and pressure of the spray drying process and is compatible with the plasma. In one embodiment, the separator is injection molded and can be made from a thermoplastic elastomer such as olefin or polyester or polypropylene. In another embodiment, the separator can be made from nylon with a thermoplastic polyurethane frame. In the embodiment shown in FIGS. 42A and 44A, the separator 38 is Baltex NPD 88 grade, has a width of 8.750 inches + / - 0.65 inches, a height of 13.000 inches + / - 0.65 inches, and a thickness of approximately 0.197 inches. The material used in this embodiment is a 100% polyester spacer mesh fabric.44B, separator 38' is two pieces, model 02257 (Freudenberg Filtration Technologies, Weinheim, Baden-Wuerttemberg, Germany), and is approximately 8.80 inches + / - 0.6 inches wide, 6.40 inches + / - 0.6 inches high, and approximately 197 inches + / - 0.030 / - 0.010 inches thick. During drying of the plasma, moist air passes through lower filter 36 and lower filter separator 38 or 38' and exits through gas outlet 30, leaving the dried plasma within lower filter 36.

[0211] Another important aspect relates to the length of the disposable 100. In previous versions, the disposable was approximately 66 inches long. Longer disposables allowed for more time, space, and heat to dry the plasma particles. However, longer disposables were more difficult for operators to set up and use, cumbersome, and hard to handle. See Examples 30 and 31. In fact, according to CDC MHANES 2015-2016 data, a 66-inch long disposable is longer than the height of many operators, such as the 79th percentile of U.S. women at 5'6" tall. Men under 5'6" tall still represent a significant number of potential operators of the present invention, comprising the 14th percentile of U.S. men according to the same data.

[0212] Shortening the disposable to that shown in Figure 42A presented several challenges. A shorter disposable meant a shorter drying chamber. A shorter drying chamber meant that the plasma particles had to be evaporated and dried over a shorter distance, in a smaller volume, and in a shorter time, all without damaging the proteins in the plasma. In other words, the plasma had to be dried gently, but quickly, and in less space.

[0213] Despite these obstacles, the present invention includes disposables 100 having a length of about 40 inches or less (e.g., about 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, or 24 inches or less), preferably about 34.8 inches. The 34.8 inch long disposables 100 are easily handled, installed, and removed from dryers and other parts of processing equipment by minimally trained personnel ranging in height from the 5th percentile (4'11") to the 99th percentile (6'6") for men and women, according to U.S. data. See Examples 30-33.

[0214] The length of the disposable, measured from the bottom of the spray dry head 2 or the bottom of the baffle plate 8 to the top of the bottom filter 36, shown as dimension Y in Figure 44, is about 31 inches or less (e.g., about 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19 inches or less), and in one embodiment, is preferably about 25.90 inches. In another aspect, the area of ​​the disposable 100 encompassed by dimension Z, which is the length from the bottom of the spray dry head 2 and the top of the filter 36, is about 22 inches or less (e.g., about 22, 21, 20, 19, 18, 17, 16, 15, 14 inches), and preferably about 19.11 inches. In yet another example, the length of dimension X, which is the length between the bottom and top section 46 of the spray drying head 2, is less than about 16 inches (e.g., about 16, 15, 14, 13, 12, 11, 10, 9, 8 inches), preferably about 12.14 inches.

[0215] In fact, comparing earlier developed versions of disposables, with a disposable length of approximately 66 inches and dimension Z of approximately 48 inches for disposables of the present invention, the difference in overall length is approximately 30 inches, or a 46% reduction, and the difference in dimension Z is approximately 29 inches, or a 60% reduction. A significant difference can be achieved by shortening the overall length of the disposable or along dimensions X, Y, and / or Z. In another embodiment, the length of the present invention can be further shortened by about 1 inch to about 8 inches (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 inches) along dimension X, thereby reducing the overall length by the same amount. In one embodiment, length X ranges from about 30 to about 37 inches. In other embodiments, disposables can also be shortened by the same amount everywhere along dimensions Y and Z.

[0216] This shorter, single-use disposable 100 dries liquid plasma that preserves protein function of even the most fragile proteins, such as von Willebrand factor and other proteins. The spray drying system of the present invention and the spray drying system shown in the figures meets FDA vWF requirements.

[0217] Reducing the length of the disposable 100, including the spray drying head 2 and plasma drying chamber 28 of the present invention, results in a system that is significantly more usable by operators in a variety of situations than those of the prior art. For example, the top loading slot height of a prior art dryer using the described 66-inch disposable was 72.5 inches (over 6'), compared to only 54 inches for the dryer 200 shown in Figures 45 and 46. While the lower (exhaust) stooping load height of a prior art dryer using the 66-inch disposable dryer described herein was only 16 inches above the floor, the load height of the disposable 100 in the dryer 200 described herein is a much more comfortable 27.5 inches. Multiple episodes of human factors testing (see Examples 30-33) demonstrated that the shorter disposables allow for unhindered installation of the disposable 100 into the spray dryer 200 by operators ranging in height from the 5th percentile (4'11") to the 95th percentile (6'6") of U.S. height. A shorter disposable allows for easier reach and bending or flexing required by the operator to install the disposable in the spray dryer and to safely and effectively attach and remove the disposable before and after operation of the spray dryer.

[0218] The plasma drying chamber tubing, baffle plate ring 156, exhaust port, etc. are made from blown or flat polyvinyl chloride (PVC) and heat-sealed to form the drying chamber. The baffle plate ring 156 is heat-sealed for disposable use, and once heat-sealed, it can be attached to the baffle plate with adhesive or the like. In one embodiment, the drying chamber expands during use to take the shape of the enclosure that is the spray-drying chamber housing of the dryer. Other commercially available materials and other vinyl materials can be used to fabricate the plasma drying chamber of the present invention. A sheet of PVC material is formed by injection molding and / or heat welding to form the spray-drying chamber and then sterilized.

[0219] In one embodiment, the plasma drying chamber of the present invention functions as a single-use chamber in which spray drying occurs. Sterilization by gamma or X-ray irradiation provides sterility for the plasma drying chamber. Development and manufacturing of the drying chamber are performed under ISO 13485 design control. Certification of materials in contact with the drying air or donor plasma within the drying chamber assembly provides lot traceability. Certification provides for toxicity testing and certification for human use.

[0220] The overall size of the spray dryer is generally much smaller than other production spray dryers, which are often too large and unsuitable for use in blood centers, military medical units, or similar locations. The spray drying system of the present invention is designed to accommodate and be used in blood component laboratories, whereas other production spray dryers are typically used in large, industrial-scale facilities.

[0221] As discussed above and in co-pending application No. (Attorney Docket No. 0118.0168-000, entitled "Usability Of A Disposable For A Spray Drying Plasma System," filed on the same day, the entire teachings of which are incorporated herein by reference), the spray dryer of the present invention is largely automated and can be used by personnel with limited training. This is in contrast to the extensive training and skill requirements associated with industrial or laboratory spray drying, such as with spray dryers sold by Buchi Corporation, 19 Lukens Drive, Suite 400, New Castle, DE 19720, United States, Model No. 4244.

[0222] The liquid plasma was pretreated before undergoing the spray-drying process, as further described in a co-pending related patent application (Application No. 17945126). The pretreatment solution protects plasma coagulation factors during the spray-drying process. A volume of frozen or unfrozen plasma (e.g., approximately 260 ml) is transferred to a plasma pretreatment container containing a spray-drying stable acidic substance (SDSAS), such as 50 mL of a glycine and hydrochloric acid solution. In one embodiment, single-donor plasma expressed from collected whole blood or by apheresis that has never been frozen and is less than 24 hours old is desirably utilized in this process. Plasma is collected from the blood by standard techniques known to those skilled in the art, as described herein. Plasma is collected by a process called plasma analysis. Plasmapheresis refers to the procedure of separating plasma from blood by either centrifugation or membrane filtration. The system process can also be used when pooled plasma is desired and with starting plasma material made with any currently available anticoagulation system, such as those known as CPD, CP2D, ACD-A, and ACD-B. A sterile, non-pyrogenic, single-use container containing SDSAS, e.g., a 50 ml solution of glycine and hydrochloric acid packaged in a 500 ml container in an overwrapped pouch, is also suitable. In one embodiment, the process of the present invention involves converting a single donor unit of plasma collected by standard procedures into a single unit of spray-dried plasma.

[0223] In vitro characterization data demonstrate that the effects of the system's spray-drying process are comparable between units spray-dried using different starting materials. Units manufactured from apheresized plasma (ACD-A anticoagulated) showed similar percent changes due to manufacturing effects on the starting material compared to units spray-dried from whole blood-derived plasma (CPD anticoagulated). A statistical analysis (ANOVA) was performed on the percent changes before and after manufacturing between the two starting materials across 20 assays, including clotting time, coagulation function, and activation markers. Of the 20 assays, total protein concentration, PT, TT, and factor VIII and factor XIII activity were determined to be statistically significantly different, but the mean percent changes were similar, and all mean values ​​were within the clinical reference range. In summary, the in vitro test results support the conclusion that manufacturing effects on both apheresized and whole plasma are comparable, with coagulation profiles within ±20% of their paired controls or within the normal reference range.

[0224] Detailed description of spray dryer The spray dryer 200 provides pressurized aerosol gas, plasma, and drying gas to the disposable 100 and an exhaust for moist air. The disposable device 100 is placed within the dryer, which provides pressurized gas, plasma, and drying gas so that drying can occur within the disposable.

[0225] Figure 45A is a front view of the spray drying apparatus 200 with the door closed, and Figure 45B shows the spray drying apparatus 200 without the door to allow a view into the dryer. Disposables are placed into the dryer for spray drying. Figure 45B shows the projected locator 206, which is a first locator that receives the notch locator 26 of the disposable device 100. Additionally, a receiver 204 (see Figures 45B and 46A) above the projected locator 206 allows the disposable to be easily received so that it is aligned. Figures 45B and 45C also show the spray drying head receiver 210 for receiving the spray drying head 2, including the baffle 6.

[0226] At the top, spray dryer 200 includes an aerosol line 216 that provides a pressurized atomizing gas source (not shown). The gas source provides clean, dry air with a dew point of minus 40° C., such as an Atlas-Copco SF22 oil-free scroll compressor combined with an Atlas-Copco CD45 desiccant dryer (Atlas Copco Manufacturing company, Nacka, Sweden). The pressurized gas source need not be located near spray dryer 200, but can optionally be located at a distance and in a different space. Such a device is intended to be easily connected to or in communication with a device that receives pressurized air. The spray dryer apparatus 200 heats the air from the source to an appropriate temperature (e.g., about 100 to about 120°C (e.g., about 100, 105, 110, 115, 120°C), in one embodiment at about 114°C. See Figures 45A-45C. In one embodiment, there are redundant in-line filters (e.g., commercially available filters of 0.2 μm or less) in the drying gas line and aerosolization gas line in addition to the filters in the spray dryer disposable device, as further described herein.

[0227] A display 212 provides instructions and information to the operator. An aerosol line 216 is adjacent to the spray dryer head 2 installed in the dryer 200. The aerosol line 216 has a luer lock that attaches to the aerosol filter 12 (which may be a luer lock). In one embodiment, they thread together. The aerosol line 216 is adjacent to the aerosol filter 12 and the aerosol tube 10 when the spray dryer head 100 is installed in the dryer 200. In one embodiment, the aerosol line 216 exits the dryer head 2 between about 4 inches and 10 inches, with about 6 inches being the preferred distance, measured from the top of the spray dryer head 2 to the attachment point of the aerosol filter 12. Furthermore, the aerosol line 216 is directed downward with the luer lock filter at the bottom so that an operator can easily reach and attach the aerosol filter 12 to the aerosol line 216 about 4'6" and 5'6" above the floor, with about 5' being the preferred distance.

[0228] Indicator lights 234 (see FIG. 45A) are located above the display 212 and provide color / visual information (e.g., green = proceed, red = problem, yellow = assistance needed) to the operator. Below the display 212 is a peristaltic pump 214 that pumps liquid plasma through guides 226 into the nozzles of the spray-drying head 2. The peristaltic pump 214 has a plunger latch 214A that is used to secure the plasma tubing 16. The peristaltic pump 214 disposably dispenses plasma at the rates described herein. The dryer 200 also includes a hook 222 for hanging the plasma bag, an emergency shut-off switch 218, and a circuit breaker 220. See FIGS. 45A, 45B, and 45C. The tube guides 226 allow the user to easily position and align the plasma tubing 16 that leads to the pretreated liquid plasma bag 64 and the aerosol tubing 10 that attaches to the aerosol line 216. The aerosol tube 10 is attached to an aerosol line 216 via an aerosol filter 12 with a thread lock (eg, luer lock or luer taper) and provides a source of pressurized gas (not shown).

[0229] FIG. 46B shows the disposable spray dryer 100 installed in the dryer 200. This figure illustrates the position of the aerosol filter 12 in the aerosol line 216 of the disposable 100. A plasma / aerosol guide, guide 226, is provided to protect the path of the plasma tubing 16 and aerosol tube 10. The plasma tubing provides the flow of liquid (to be dried) plasma 66, which travels from the liquid plasma bag 64 through the pump 214 to the disposable 100 during spray drying. The aerosol tube 10 provides a continuous flow of pressurized air from the aerosol line 216 to the disposable 100. A continuous flow of plasma and pressurized air is necessary to ensure continuous spray drying, making this guide an important aspect of the present invention. The plasma / aerosol guide 226 allows the tubing to be properly positioned to ensure it does not kink or buckle during operation. The plasma / aerosol guide 226 is positioned sufficiently between the plasma bag hook 222 and the plasma flow inlet 18 on the installed disposable, and between the aerosol tube 10, the aerosol line 216, and the aerosol inlet 14 on the installed disposable. The placement of the plasma / aerosol guide 226 allows for easy threading of both the plasma tube 16 and the aerosol tube 10. Once the disposable 100 is aligned, the operator threads the tubes 10 and 16 through the plasma / aerosol guide 226. In one embodiment, the plasma / aerosol guide 226 has a retention notch for retaining the plasma tube and / or the aerosol tube within the plasma / aerosol guide during operation of the spray dryer. In one embodiment, the plasma / aerosol guide 226 is readily visible to an operator with a height between the 5th and 95th percentiles when standing in front of the dryer (e.g., approximately 2 feet from the dryer) under load.

[0230] 46B also shows the placement of the aerosol line 216, which provides the source of pressurized gas. Once the operator threads the aerosol tube 10 through the plasma / aerosol guide 266, the operator attaches the aerosol filter 12 to the aerosol line 216 by connecting a luer lock or thread lock. In this embodiment, the connection is easy to make and involves only aligning and rotating the luer lock / thread lock. The proximity of the spray drying head 2, plasma / aerosol guide 226, and aerosol line 216 allows the operator to quickly and easily screw in and attach the aerosol line.

[0231] Similarly, once threaded through the plasma / aerosol guide 226, the plasma tube 16 is threaded through the peristaltic pump 214 and a latch 214A is closed onto the plasma tube to hold the plasma tube 16 in place during spray drying. Again, the proximity of the spray drying head 2, plasma / aerosol guide 226 and peristaltic pump 214 allows for quick and easy screwing and fastening.

[0232] The operator controls (e.g., display 212, pump latch 214A, tube guide 226, aerosol line 216, door handle 230) are positioned to be easily visible and operable by a wide range of stator operators. Operators of shorter stature could not easily see the display 212 in previous versions. This problem has been addressed with the present invention, and the display 212 is now easily visible and accessible to 99% of all people with a variety of conditions. These controls are within approximately 12, 13, 14, 15, 16, 17, 18, 19, or 20 inches of each other, and in one embodiment, they are within approximately 15 inches of each other. In one embodiment, the controls are readily visible to operators with heights between the 5th and 99th percentiles when standing in front of the dryer (e.g., about 2 feet from the dryer) and under load. The controls are positioned not only in close proximity to each other, but also in close proximity to the components on which they are attached or used. Furthermore, the controls are oriented in the direction of attachment of their respective components. Additionally, the layout of the plasma / aerosol guide 226, pump latch 214A, and aerosol line 216 are logically arranged according to the air / plasma flow.

[0233] Dryer 200 has a gasket 203. Gasket 203 resides around the perimeter of housing 202 and / or along the inside of door 228. Gasket 203 has a partial hourglass shape when dryer 200 is viewed from the front. Gasket 203 helps form a seal between door 228 and housing 202 to help retain gas between housing 202 and disposable 100 during spray drying operations. Gasket 203 acts as an insulator to prevent gas from escaping dryer 200. Gasket 203 can be made from rubber or a similar material that can be molded into the slot or recess where it resides.

[0234] Similarly, emergency shutoff 218 is located so that it can be easily located by the operator, specifically, it is located lower and further away from the operator controls mentioned above. The idea is that by locating emergency shutoff 218 away from the main controls, it encourages the operator to make a deliberate decision to use it. Next to emergency shutoff 218 is circuit breaker 220. Emergency shutoff 218 and circuit breaker 220 provide two ways to turn off dryer 200 in the event of an emergency.

[0235] 45A-45C also show the spray drying apparatus 200 including an exhaust port 208 that accepts the gas outlet port 30 of the disposable device 100. The alignment apparatus of the present invention, in one embodiment, includes attaching the gas outlet 30 of the disposable 100 to the gas exhaust port 208 of the spray dryer 200 or to the gas outlet receiver 414 of the finisher 400. (See FIGS. 46A-46C and 47A-47C.) By attaching the gas outlet 30 of the disposable 100 to the gas exhaust port 208 of the spray dryer 200 during spray drying, the bottom of the disposable 200 can be secured to the dryer, thereby holding the disposable in place during the plasma drying process. Similarly, the finisher 400 is designed to accept the gas outlet 30 of the disposable 100 via the gas outlet receiver 414 to keep the disposable in place during the plasma drying process by shaking / impinging the plasma in place, removing air, sealing, and separating the plasma. The gas outlet 30 of the disposable device 100 is a cylindrical outlet with a lip made from a strong, rigid plastic material. The exhaust port 208 of the spray dryer 200 has an O-ring and a gasket that secure the lipped cylindrical gas outlet 30 to form a strong attachment. The gas outlet receiver 414 of the finisher 400 has a receiver with a "U"-shaped slot so that the gas outlet can be securely attached to the finisher and remain attached during the finishing process. The disposable gas outlet, the spray dryer gas exhaust port, and / or the gas outlet receiver can include any configuration for attaching the disposable gas outlet so that it remains intact during use of the device or finisher to which it is attached. The gas exhaust port or gas outlet receiver can be made from stainless steel, plastic, rubber, etc.

[0236] Stated differently, in the embodiment shown in FIG. 46A, to align the spray-drying disposable device 100 within the spray-drying apparatus 200, the operator must insert the offset guide 4 of the disposable 100 into the receiver 204 of the dryer 200, align the positioning features of the disposable and the dryer, thereby engaging the retaining clip, and insert the gas outlet of the disposable into the exhaust gas port of the dryer. Once these alignment elements are engaged, the disposable is aligned and ready to be locked into place. After attaching the plasma source and pressurized gas source, the operator can lock the door of the spray-drying chamber housing and begin the spray-drying process. The operator locks the door 228 by swinging the handle 230 side to side to engage and lock it into place. See FIG. 45C. The operator can lock the door by inserting the key 236 into the keyhole 238. In another embodiment, one or any combination of these alignment arrangements can be engaged to align the disposable with the spray drying equipment.

[0237] If the operator improperly aligns the disposable 100 with the dryer 200 (e.g., inserts the spray-drying head 2 with the locator notch 26 facing outward), the ridge 9 will not fully seat in the groove 207 and the spring clip 232 will not engage the spray-drying head 2. In this case, even if the operator attempts to close the door 228, the door 228 will not close. If the door 228 is not fully closed and the handle 230 cannot lock into place, the dryer will not be able to proceed with drying. Preventing drying when the disposable 100 is not properly aligned and installed ensures safe operation.

[0238] In another embodiment, the operator inserts a disposable 100 having a locator notch 26 within 30 degrees (e.g., within 30, 25, 20, 15, 10, or 5 degrees) of the locator protrusion 206. In other words, the operator can approach, but not fully align, the locator notch device. In this case, when the operator closes the door 228, the spray drying head 2 self-aligns so that the locator protrusion 206 is inserted into the locator notch 26. As the door 228 closes, it applies a force to the spray drying head 2, causing it to slide circularly along the receiver 210 until the locators 26 and 206 are aligned, the ridge 9 is fully seated within the groove 207, and the spring clip 232 engages. Aligning the spray drying head is an easy task that does not require a lot of force and / or training, but if the operator mistakenly inserts the spray drying head 2 within about 30 degrees of the correctly positioned notch alignment, the system will automatically correct the spray drying head installation.

[0239] In one embodiment, dryer 200 automatically monitors and controls at least four processes (e.g., pretreated plasma flow, aerosol air flow, drying air flow, and exhaust air flow) to ensure that the drying process is completed within operating ranges. In one embodiment, dryer 200 includes an array of sensors and actuators that allow for automatic control of the spray drying process.

[0240] In one embodiment, the dryer may be run according to the following parameters:

[0241] [Table 4]

[0242] Dryer Architecture The architecture of dryer 200 is shown in Figure 46C. Dryer 200 regulates and / or drives at least the following flow paths: pretreated or donor plasma flow line (lines C, I), dry air line (lines B, E, G), pressurized aerosol gas air line (lines A, D, H), disposable compression line (line F), disposable exhaust line (line J), ​​enclosure / housing exhaust line (line K), and leak detection line (line L). Such flow lines are examples providing plasma, drying gas, pressurized aerosol gas, and / or exhaust flow. Any number of flow configurations can be arranged as long as the dryer provides donor plasma, drying gas, and pressurized aerosol gas to the exhaust lines for disposable and humid air. Additional or fewer flow lines than shown in the figure can provide these flow lines. For example, in one embodiment, clean dry air is the source of both the drying gas and the pressurized aerosol gas. In this embodiment, lines are shared until the pressurized aerosol line branches off into another line. Similarly, the disposable exhaust line and the housing exhaust line can be combined into a single line before passing through a filter and mixing with outside air.

[0243] Plasma Flow Line The plasma flow line provides donor plasma in liquid form to nozzle 20 of disposable 100 at a rate ranging from about 5 to about 20 mL / min for atomization and drying. In one embodiment, the donor plasma is pretreated as described herein.

[0244] The plasma flow line is labeled Line C in FIG. 46C. Plasma flow begins with plasma bag B01, also referred to herein as plasma bag 66. As mentioned above, plasma bag 66 is attached to hook 222. In this embodiment, hook 222 is a hook scale S01, which provides the weight of plasma bag 66. After and during the spray-drying process, the plasma bag 66 and any amount of donor plasma are weighed, and the weight is transmitted to a computer system having, among other things, memory, storage, and a processor. The weight of the plasma bag with the pretreated plasma can determine the amount of pretreated donor plasma to be dried. In one embodiment, the pretreated plasma weighs 330 to about 385 g, which means the volume of the pretreated plasma is about 335 ml to about 395 ml. This is determined using calculations for the density of the pretreated plasma, which is about 1.02 to 1.025 g / mL. The plasma tubing 16 is 1 / 8 inch, and in one embodiment, the flow rate is set at 13 g / min.

[0245] The pretreated plasma travels through the plasma tubing 16 and the peristaltic pump 214, P01, which regulates the plasma flow rate. A tubing clamp 244 is located between the plasma bag 66 and the peristaltic pump 214 and can be used to manually open and close the plasma tubing 16. The peristaltic pump 214 has a door or latch 214A. A sensor 246, shown as sensor OS10 in FIG. 46C, is located on the peristaltic pump latch 214A and evaluates the latch state, either open or closed. When the sensor detects a closed latch 214A, a signal is communicated to a computer system that communicates with the peristaltic pump 214 to proceed with the pumping of the pretreated plasma. If the peristaltic pump latch 214A is not closed, the computer system displays a message to the user to close the latch 214A. The sensor is generally a device that provides input data to the system, which converts analog data from the sensor (e.g., when the latch is closed) into digital data. The plasma flows through the peristaltic pump 214 at a rate specified by the pump 214 to the nozzle assembly 20, shown as position I in FIG. 46C. The pump 214 is instructed by the computer system as to speed and to proceed or stop once drying is complete or the desired weight of the pre-treated plasma bag is achieved (e.g., between about 66 grams and about 85 grams). At the nozzle assembly, the plasma contacts the pressurized aerosol gas and atomizes, as described herein. Note that FIG. 46C shows the position of the nozzle assembly 20 when the disposable 100 is inserted into the dryer 200. The plasma flow rate at the nozzle is about 5 to about 20 mL / min.

[0246] Dry Gas Flow Lines As further described herein, the dry gas flow line provides clean, heated, dry air to the atomized liquid plasma droplets to dry them during rapid mixing within the disposable 100.

[0247] In the embodiment shown in Figure 46C, the dry air line is the source of the drying gas and the pressurized aerosol gas. In other embodiments, they may be separate systems.

[0248] The dry air line, as shown in FIG. 46C, begins with a compressed dry air (CDA) supply, continues through lines B, E, and ends at G when the dryer is operating. As mentioned above, CDA is commercially available. The CDA system connects to the dryer 200 via connector 248, designated CN01 in FIG. 46C. Upon entering the dryer 200, the clean air travels through pressure transducer PT01 250, ball valve PV01 254, and pressure regulator PR01 256. A pressure transducer is an electromechanical device designed to measure pressure. The pressure transducer senses the applied pressure and provides an output consisting of an electrical signal indicative of the amount of pressure. In one embodiment, the pressure transducer has an electrical output that is directly proportional to the applied air pressure. Pressure transducer PT01 250 measures the pressure of the dry gas in the line and communicates the pressure to the computer system via a digital signal. The pressure of the clean air at pressure transducer PT01 250 ranges from about 80 psig to about 120 psig. The wire, in one embodiment, is a 1-inch wire moving at a speed of 790 sLpm. The drying gas velocity ranges from about 10 to about 1000 sLpm. The solenoid valve is an electrically controlled valve. The solenoid valve in dryer 200 has an electric coil with a movable ferromagnetic core and a plunger at its center. The solenoid valve drives valve PV01 254, which is a pneumatically actuated three-way ball valve whose actuating air pressure is controlled by the solenoid valve. When commanded open, the solenoid valve is energized, thereby allowing actuating air to flow to the pneumatic actuator. This air pressure then rotates the ball valve 90 degrees, allowing the drying gas to flow. Specifically, this valve uses air pressure to rotate a ball 90°, allowing the downstream line to connect to ambient air (when in "closed" or "off") or pressurized CDA air (when in "open" or "on"). The control air pressure itself is enabled / disabled via a solenoid valve, which controls only the air that actuates valve PV01 254.Downstream of the pneumatically actuated ball valve PV01 254 is a tie port, which allows for in-line supply of drying gas but also allows a small amount to be diverted to an air manifold, as described further herein. Similarly, a pressure regulator, such as PR01 256, adjusts the system flow pressure in response to upstream or downstream pressure changes. When the drying gas exits pressure regulator PR01 256, the purified air has a pressure of approximately 70 to 80 psig and flows at a rate of approximately 10 to 790 slpm. The purified air then passes through filter F01 258, a 0.2-micron hydrophobic polytetrafluoroethylene filter suitable for removing pathogens. This filter ensures that pathogens from the CDA supply do not contaminate the drying process. After passing through filter F01 258, excess pressure, if any, is relieved via pressure relief valve PRV04260 by allowing the pressurized air to exit the system through a secondary passageway and vent to the room. Pressure transducer PT02 262 measures the pressure clean air in the line to ensure the pressure is within the desired range before heating. The pressure of the clean air at pressure transducer PT02 262 ranges from about 70 psig to about 80 psig.

[0249] Following line B in FIG. 46C, clean, dry air flows through mass flow controller MFC02264. A mass flow controller is a device used to measure and control the flow of clean, dry air. The mass flow controller used with the dryer of the present invention has an inlet port, an outlet port, a mass flow sensor, and a proportional control valve. Mass flow controller MFC02264 regulates the flow of clean, dry air in a range of about 0 to about 1,000 slpm. The clean, dry air flows through temperature transducer TT03 266, which measures the temperature of the air and converts the temperature into a digital signal that is sent to a computer system. During use, the temperature of temperature transducer TT03 266 measures a range of about 10°C to 35°C. Based on the clean, dry air temperature measured by temperature transducer TT03 266, the computer system calculates the amount of heat required to raise the temperature of the clean, dry air to a range of about 110°C to about 120°C. This amount needed to heat the clean air is communicated by the computer system to heater H01 275, which applies the calculated amount of heat to the clean dry air, thereby obtaining heated dry gas that is used to dry the atomized liquid plasma. Thermocouple sensors TT04 278 and TT05 280 measure the temperature to ensure the proper temperature range is achieved.

[0250] After passing through mass flow controller MVC02 264 and temperature transducer TT03 266, the heated drying air flows through pneumatically controlled ball valve PV03 268 and filter F04 270. The pneumatically controlled ball valve opens and closes the valve using air pressure. Station 1A of air manifold AM01 330 is used to control valve PV03 268. The pneumatically controlled ball valve PV03 268 is activated when MFC02 is commanded to begin flowing. This serves as a safety control in case MFC02 fails to control the air flow and the valve closes. During the spray drying process, pneumatic valve PV03 is opened and solenoid valve PV06 322 is closed to direct air to line B. When the disposable compression line is used after spray drying is complete, air pressure valve PV03 268 is closed and solenoid valve PV06 322 diverts the air flow from clean drying air from line B to line F. Filter F04 270 is a redundant filter to prevent pathogens from being introduced into the plasma during drying. Filter F04 270 is a 0.2 micron hydrophobic polytetrafluoroethylene filter.

[0251] Continuing along line E, the heated drying gas passes through pressure transducer PT05 276, which measures the pressure of the heated drying gas immediately before entering disposable 2 when disposable 2 is installed. The clean air pressure at pressure transducer PT05 276 ranges from about 10 to about 20 psig. In addition to measuring the pressure, temperature transducers TT04 278 and TT05 280 redundantly measure the temperature of the heated drying gas, which ranges from about 110°C to about 120°C. At position G in Figure 46C, the heated drying gas enters inlet deflector 242 (elbow) and enters plenum 6 of spray-drying head 2, which provides uniform air pressure as described herein. The heated drying gas flow rate upon entering the nozzle is about 720 to about 780 slpm, and the temperature is about 110°C to about 120°C.

[0252] Pneumatic piston PP01 324 lowers deflector 242 into spray-drying head 2 during spray drying and raises deflector 242 when spray drying is complete. Piston PP01 can be locked or unlocked and is in an up position (when not in use) and a down position (during spray drying). Piston PP01 324 has sensors OS06 326, which detect when piston PP01 324 is in the up position, and OS05 328, which detect when piston PP01 324 is in the down position. When not moving, the piston is locked to prevent unwanted movement. Before spray drying begins, a computer system signals piston PP01 324 to lower into plenum 6 of spray-drying head 2 to provide uniform air pressure for spray drying. Deflector 242 includes a ball-in-socket style gimble. During manufacturing, the gimble allows deflector 242 to be aligned with disposable 2 to form a leak-tight seal during use.

[0253] The drying gas line has an internal path used for the compression line of the disposable. Once spray drying is complete, removal of moist air is assisted by the bag compression line, line F. The bag compression line actually injects air between the outer wall of the disposable 100 and the inner wall of the plasma drying chamber housing 202, effectively compressing the air within the disposable 100 through line J and out the exhaust port 208.

[0254] The air used for the disposable's compression line branches off from the clean air drying gas line, line B, after passing through mass flow controller MFC02264 and travels through solenoid valve PV06 322 using line F. To divert the air to line F, pneumatic valve PV03 is closed and solenoid valve PV06 322 is opened. Meanwhile, during the spray drying process, pneumatic valve PV03 is opened and solenoid valve PV06 322 is closed to direct the air to line B. As the air travels through line F, the disposable's compression line, the flow enters housing 202 through connector CN05 296. After drying is complete, the disposable's compression line is used, and pneumatic valve PV03 268 is closed and solenoid valve PV06 322 is opened, allowing air to travel into housing 202 and help push the moist air out of disposable 100.

[0255] Pressurized Aerosol Gas Flow Lines The pressurized aerosol gas flow line provides pressurized gas flow at a rate sufficient to atomize donor plasma droplets at the nozzle 20 of the disposable 100. The pressurized aerosol gas flow rate as it enters the nozzle is about 30 to about 50 slpm.

[0256] The aerosol pressurized line also originates from a compressed clean air source. After passing through filter F01 258, the clean air line supply branches off to line A in Figure 46C. A portion of the clean, dry air branches off and follows line D through mass flow controller MFC01 282. A mass flow controller is a device used to measure and control the flow of clean, dry air. In this case, the mass flow controller increases the flow of clean, dry air sufficiently so that when it reaches nozzle 20 in the drying chamber 28 of disposable 2, the donor plasma is atomized. Mass flow controller MFC01 282 pressurizes the clean, dry air flow to a flow rate in the range of approximately 30 to approximately 50 slpm. This results in aerosol pressurized air that atomizes the liquid plasma droplets. The aerosol pressurized air passes through solenoid valve PV02 284 and pressure transducer PT10 286. Solenoid valve PV02 284 has a plunger that, in its rest position, closes the opening in the line. When current is applied, the coil generates a magnetic field that applies a force to the plunger, opening the line. Pressure transducer PT10 286 measures the pressure and provides an output consisting of an electrical signal indicative of the amount of pressure. In one embodiment, pressure transducer PT10 288 measures the pressure of the pressurized aerosol gas in the line and communicates the pressure to a computer system via an electrical signal. The pressure of the purified air measured by pressure transducer PT10 286 ranges from approximately 20 to approximately 40 psig. The pressurized aerosol gas passes through filter F08, a 0.2-micron hydrophobic polytetrafluoroethylene filter to remove pathogens, and continues on line D. Filter F08 is another redundant filter to prevent pathogens in the purified dry air from entering the drying chamber.

[0257] The aerosol pressurized air passes through the aerosol line 216 of the dryer 200, passes through the aerosol filter 12 of the disposable 2, and terminates at location H at the nozzle 20, as shown in FIG. 46C, as further described herein.

[0258] Plasma drying chamber housing 202 of dryer 200 The drying chamber housing 202 of the dryer 200 houses the disposable 100 during use and is described in detail herein.

[0259] With reference to FIG. 46C, baffle filter 94 is designated as filter F05, and lower / trap filter 36 is designated as filter F06, both of which are described in detail herein. A disposable is attached to receiver and drying gas inlet 204, also referred to as connector CN03, which is described further herein. Dryer 200 includes pressure transducer PT08 224A and pressure transducer PT09 224B, which are described further herein. Dryer 200 further includes sensor OS04 292 for determining whether door 228 is closed and sensor OS07 294 for ensuring door 228 is locked with door handle 230 (SS01). Gas exhaust port 208 is designated as connector CN06 and leads to line J for the disposable exhaust line for the exit of wet air. Connector CN05 296 is a connector to a disposable compression line, designated line F, as further described herein, and connector CN07 298 is a connector to an enclosure exhaust line, designated line K, as further described herein.

[0260] Disposable Exhaust Line A disposable exhaust line designated as line J exhausts humid air during spray drying. As described herein, humid air is a mixture of drying gas, pressurized aerosol gas, and evaporated water from the plasma droplets. The humid air within the disposable 100 during spray drying exits through this disposable exhaust line, line J.

[0261] Referring to FIG. 46C, in one embodiment, the disposable exhaust line is a 1-inch internal diameter flowing at 790 slpm. The moist air first exits the gas exhaust port 208 and passes through temperature transducers TT06 300 and TT07 302, which measure the temperature of the moist air as it exits the disposable 100, followed by pressure transducer PT06 304, which measures pressure and flow. During spray drying, the temperature range of temperature transducers TT06 300 and TT07 302 is between about 15°C and about 75°C. During spray drying, pressure transducer PT06 304 measures pressures ranging from about 0 to about 5 psig and flow rates ranging from about 10 to about 790 slpm. The exhaust air passes through normally open pneumatic valve PV04 306, which uses air pressure to open and close the valve. Station 1B of air manifold AM01 330 is used to control valve PV04 306. Air pressure valve PV04 306 is normally open and will remain open in the event of a system shutdown or overpressurization. This acts as a safety control as it allows airflow to exit the system. The moist air passes through filter F07 308 to mix with the ambient air before exiting connector CN02 310. Filter F07 308 is a 0.1 micron hydrophobic polytetrafluoroethylene filter.

[0262] Housing / Enclosure Exhaust Line The enclosure exhaust line is for removing air that is within the plasma drying chamber housing but outside of the disposable 100. Moist air within the disposable 100 is exhausted through line J, while after drying is complete or if there is a failure, residual air within the housing between the outer wall of the disposable 100 and the inner wall of the housing 202 is removed through this path, line K.

[0263] Residual air from the housing 202 exits through connector CN07 298 and flows through pressure transducer PT07 312, which measures pressure and flow. Residual air passes through normally open pneumatic valve PV05 314, which uses air pressure to open and close the valve. Station 2A of air manifold AM01 330 is used to control valve PV05 314. This valve remains open in the event of a system shutdown or overpressurization. This serves as a safety control, allowing air to freely flow out of the system even when power is removed. Before exiting through connector CN02 310, the residual air passes through filter F09 316 before the moist air exits. Filter F09 316 is a 0.1 micron hydrophobic polytetrafluoroethylene filter.

[0264] Line K further includes an internal path for leak detection, methods of which are described further herein. This line measures the flow of residual air between the disposable and the housing. The inner loop includes solenoid valve PV07 318 and flow sensor FS01 320. The solenoid valve has an electric coil with a movable ferromagnetic core and a plunger at its center. During spray drying, solenoid valve PV07 318 remains closed. In the rest position, the plunger remains closed. When current is applied, the coil generates a magnetic field that applies a force to the plunger, opening the line. The FS01 320 flow sensor measures the air flow. Flow sensor FS01 320 includes a pressure transducer that measures the pressure across an internal flow restriction, from which the flow rate can be calculated. In this case, the flow sensor measures the actual mass flow rate of residual air. This inner loop is used for leak detection, as described further herein.

[0265] Dryer Air Manifold The air manifold AM01 330a branch chamber extracts a small amount of clean, dry air to create mechanical motion. The extracted air is used to actuate the pneumatic valves (PV) and pneumatic pistons (PP) within the spray dryer 200. The manifold shows three stations: Station 1, Station 2, and Station 3. Multiple actuators are part of each station. Station 1 actuates pneumatic valves PV03 268 and PV04 306; Station 2 actuates pneumatic valve PV05 314 and piston PP01 324 (unlock); and Station 3 actuates piston PP01 324 (down) and piston PP01 324 (up). Air manifolds are commercially available, including multi-port solenoid valves such as the SMCSY3000 (Airline Hydraulics, North Kingstown, RI). In the unpowered state, pneumatic valve PV03 268 is normally closed, and pneumatic valves PV04 306 and PV05 are normally open. In the unpowered state, pneumatic piston PP01 is locked, and during drying, pneumatic piston PP01 324 is in the down position. The arrangement of stations and actuators can be modified as needed. A pneumatic manifold is used to operate the spray dryer valves and pistons, although any commercially available device such as a motor could be used.

[0266] Leak Detection Method and System 1000 The present invention, in one embodiment, includes a leak detection method 1000 that the dryer 200 undergoes. (FIG. 46D) The dryer 200 is designed to determine if a leak exists in the disposable 100, or, in other words, to determine the integrity of the disposable 100. In one embodiment, the leak detection function of the dryer 200 is performed after installation of the disposable 100 and after spray drying. This test helps determine if the disposable 100 can withstand or has withstood the pressure and flow of the dryer 200. The dryer 200 and method 1000 utilize two methods to determine if a disposable leak exists. The first method is a pressure decay method, i.e., method 1030, and the second method is a flow sensor method, i.e., method 1032. The two leak detection methods can be used individually or together.

[0267] Both methods involve starting the dryer 200 and loading the disposable 100 as described herein. The dryer 200 heats until the exhaust temperature, as measured by temperature transducers TT06 300 and TT07 302, is measured at a set temperature, e.g., 65°C. The temperature transducers signal that the set temperature has been met, and the computer system commands the mass flow controller MFC02 to shut down. In this step 1002, the drying gas is stopped by commanding the mass flow controller MFC02 to stop flow and close the pneumatic valve PV03.

[0268] In addition to stopping the flow of drying gas, the exhaust line is also closed in step 1004. In step 1004, the computer system communicates with pneumatic valve PV04 306 to temporarily close the pneumatic valve during the leak detection test.

[0269] In the pressure decay method, methodology 1030, in step 1006, dry gas slowly pressurizes the disposable container at a flow rate of about 50 SLPM to a pressure of about 2 psig at the dry gas outlet 208 as measured by pressure transducer PT06 304. In this step, the disposable can be pressurized to a range of about 1.5 psig to about 4 psig, and the flow rate can range from about 1 SLPM to about 50 SLPM. This pressurization is accomplished using mass flow controller MFC02 264.

[0270] Next, the pressure decay method includes waiting 1008 for a period of time (e.g., about 30 seconds, 1 minute, 1.5 minutes, 2 minutes, 2.5 minutes, 3 minutes, 3.5 minutes, 4 minutes, 4.5 minutes, 5 minutes). In one embodiment, the method includes waiting about 1 minute.

[0271] After a period of time has elapsed, pressure transducer PT06 304 measures the pressure in step 1010 and sends a digital signal representing the value to the computer system's memory. If the pressure value is such that there is a decrease below a set amount (e.g., a threshold amount), the disposable is discarded in step 1012. If the pressure value in step 1014 is above an acceptable set amount, the disposable is determined to be acceptable for spray drying by this test. The threshold amount of pressure ranges from about 1 psig to about 3.5 psig, and in one embodiment, is about 1.3 psig. In other embodiments, instead of using a set amount, the computer system using a processor can calculate the rate of change of pressure decrease, or can calculate pressure decay by determining the change in volume instead of pressure.

[0272] In a second leak detection method, methodology 1032, the flow sensor method includes closing pneumatic valve PV05 314 in the enclosure's relief line, line K in FIG. 46C, in step 1016. Closing pneumatic valve PV05 314 allows dry gas to flow through the leak detection line, line L. The computer system sends a signal to pneumatic valve PV05 314 to close in step 1016, and then sends a signal to solenoid valve PV07 318 to open in step 1018. Steps 1016 and 1018 can occur simultaneously or sequentially. Once both steps are completed, airflow is measured using sensor FS01 320 in step 1020. Instead of measuring pressure and inferring airflow, airflow is measured directly in this step. The computer system uses a processor to compare the measured airflow to a set airflow. If the average air flow is less than the set amount, then in step 1022 the software determines that the disposable 100 is suitable for use in the spray drying process. However, if the air flow is greater than the set amount, then in step 1024 the computer system determines that the disposable 100 should be discarded. The set air flow rate (e.g., threshold flow rate) for comparing the measured air flow rate is 10 cm 2 / min~30cm 2 / min (e.g., 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30 cm 2 / min). In one embodiment, the set air flow rate is 20 cm 2 / min.

[0273] Once one or both tests are complete, in step 1026 the computer system communicates that the tests are complete and actuates the valves as follows: pneumatic valve PV04 306 is opened on the exhaust line, line J, pneumatic valve PV05 314 is opened on the enclosure / housing exhaust line, line K, and solenoid valve PV07 318 on the leak detection line, line L is closed.

[0274] In one embodiment, the pressure decay method 1030 or the flow sensor method 1032 can be used independently or together. If one of the methods is used in a spray drying system, the results of that test determine whether the disposable 100 is suitable for use in the spray drying process. If both methods are used, as in step 1028, the results of both tests (e.g., leak detection pressure values ​​or leak detection flow rate values) are compared, and if both results indicate the disposable 100 is suitable for use, the computer system communicates that the disposable 100 can be used for spray drying or that spray drying can proceed. If both methodologies are used and one test indicates the spray drying disposable 100 should be used and the other test indicates it should not be used, the disposable 100 should be discarded and not used in the spray drying process. This comparison is embodied in step 1028 and is performed by a processor in the computer system according to a programmed routine. The results of the determination are communicated to the user. In one embodiment, the result is communicated that the disposable 200 is suitable or unsuitable to an output device such as the display 212 on the dryer 200. In other embodiments, the communication may be printed, provided audibly (e.g., by a digital voice instructing the user to remove the disposable 200), or provided visually by an indicator light 224 (e.g., red to stop and remove the disposable 100, or green to go).

[0275] Disposable Pressure Sensing Method and System 1200 The present invention further includes a disposable pressure detection method and system 1200. See FIG. 46E. This methodology allows the dryer 200 to measure the pressure inside the disposable 100 using a pressure sensor located outside the disposable 100. Although the sensor resides within the housing 202, the wall material of the disposable 100 partially conforms to the shape of the inner wall of the housing 202, especially when heated drying gas floods the disposable 100. This is due to the flexibility of the disposable wall. In doing so, the pressure sensor attached to the inner wall of the housing 202 measures the pressure exerted by the outer wall of the disposable 100, which represents the air pressure inside the disposable 100. This test can be performed before, during, and after the spray drying process.

[0276] Disposable pressure sensing methodology 1200 begins at step 1202, where dryer 200 is started and the drying gas is run and heated to an inlet temperature of at least about 65°C or higher (e.g., up to about 130°C), as measured by either temperature transducer TT04 278 or temperature transducer TT05 280, or both. In one embodiment, this method can be performed with or without heated disposables. In another embodiment, the spray dryer is heated to an exhaust temperature of about 55°C to about 75°C, or an inlet temperature in the range of about 110°C to about 120°C. In one embodiment, one, two, or three temperature sensors or transducers can be used.

[0277] As heated dry air from line E enters the dry gas inlet 204, the heated air causes the outer wall of the disposable to exert a force on one or both of pressure transducers PT008224A or PT009224B. The pressure transducers detect the pressure and generate an electrical signal proportional to the detected pressure. The detected pressure is proportional to the amount of mechanical force exerted on the pressure transducer. A proportional digital signal value is generated and transmitted to the computer system's memory. The computer system's processor calculates the amount of pressure within the disposable 100 according to the following equation in step 1206: Drying chamber pressure (PT08 / PT09) = (digital signal mV) x (gain) - offset Where, gain: approximately 2, offset: approximately -0.1

[0278] During manufacturing, the gain and offset of patents 008224A and 009224B are determined by referencing the digital signal to a known, calibrated pressure gauge. The disposable 2 is pressurized to various pressures (e.g., 1.0, 3.0, 5.0, approximately 6.0 psig) as described herein. The output digital signal is then plotted on a chart against the calibrated gauge pressure. A line of the form y=(m)x(x)+b can then be drawn, where (m) is the gain and b is the offset. This is repeated for both PT008224A and PT009224B.

[0279] If the pressure becomes too high, the dryer enters its failsafe mode in step 1210. Specifically, the dryer enters failsafe mode if the set failsafe pressure (e.g., a second threshold pressure amount) is equal to or greater than 7.1 psi to about 8 psi (e.g., about 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, about 8.0 psi). In this case, the computer system communicates that a pressure in this range will enter failsafe mode. This is communicated to the operator via an output device (e.g., display 212), as described herein. In other embodiments, the communication can be printed, provided audibly, or provided visually via indicator light 224. Failsafe mode generally means, in one embodiment, that dryer 200 is shut down, drying gas and plasma are stopped from flowing in, and humid air is allowed to flow out. Step 1212. Thus, the computer system communicates and activates the following valves on the inlet side by closing pneumatic valve PV02 284, pneumatic valve PV03 268, solenoid valve PV06 322, mass flow controller MFC01 264, and mass flow controller MFC02 282, and deactivating heater H01 275 and peristaltic pump PO1 214. On the outlet side, the computer system communicates and activates by opening output valves (PV04, PV05) and disabling PV07 to allow the humid air to be filtered and outflow / mixed with ambient air. If the system detects excessive heater temperature at TS01 272 or TS02 274, excessive aerosol pressure at PT10 286, or excessive dry air pressure at PT05 276, a fail-safe mode can also be entered.

[0280] When the pressure reaches within a set pressure amount (e.g., a first threshold pressure amount), the drying run ends. In one embodiment, the set pressure amount when the drying run ends is in the range of about 5.0 to about 7.0 psi (e.g., about 5.0, 5.5, 6.0, 6.5, and 7.0 psi). In one embodiment, the set pressure amount is about 6.7 psi to about 7.02 psi. Step 1208. In this case, the computer system communicates to the operator via an output device (e.g., display 212) that the drying run of the disposable 100 has ended, as described herein.

[0281] Once the pressure reaches the set pressure amount in step 1208, the computer system determines whether enough pre-processed plasma has been processed for a finished dried plasma unit (e.g., a plasma unit with a sufficient amount of plasma that can be used for transfusion after reconstitution). During the drying operation, the pressure through the disposable 100 gradually increases by approximately 2 psi. The end of the drying run can be determined by the pressure exceeding the limit set forth in step 1208 or by detecting a sudden increase in the exhaust temperature as measured by TT06 300 or TT07 302. When the exhaust temperature increases by approximately 1.5°C above the set point (e.g., 66.5°C), the computer system communicates to the operator via an output device (e.g., display 212) that the drying run of the disposable 100 has ended, as described herein.

[0282] The amount of dried or processed plasma can be measured directly or indirectly. In one embodiment, the amount of dried plasma is measured indirectly by determining the amount of donor plasma remaining in the formulated pre-processed plasma bag 66. The less volume remaining in the plasma bag 66, the more volume will be dried, and vice versa. A minimum amount of plasma remains in the tubing. Thus, in one embodiment, to obtain a processing volume of about 15 grams to about 20 grams (e.g., 15, 16, 17, 18, 19, or 20 grams) of dried plasma without bag weight, the total amount of pre-processed donor plasma to be processed (e.g., a threshold processing plasma mass) ranges from about 280 grams to about 390 grams (e.g., about 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, or 390 grams). In one embodiment, the amount of starting pretreated donor plasma is about 320 grams to about 390 grams (e.g., 320, 330, 340, 350, 360, 370, 380, or 390 grams). Note that the pretreated donor plasma has about 50 to about 60 grams of pretreatment solution and about 220 to about 340 grams of donor plasma.

[0283] In other embodiments, other indirect measurements can determine the amount of plasma processed, including determining the volume moved through plasma tubing 16 or pump 216. Because the density of pre-processed donor plasma is 1.02 grams / milliliter to 1.03 grams / milliliter, the mass of processed plasma can be determined if the volume is known.

[0284] Other embodiments include direct measurement of the processed dried plasma. In such embodiments, the weight of the disposable before and after spray drying can be obtained, and the difference is the weight of the spray-dried plasma.

[0285] The indirect mass measurement of the donor pre-treated plasma bag or the direct measurement of the dried plasma within the disposable 100 is communicated to a computer system whose processor determines whether a sufficient amount of pre-treated plasma has been processed. If a sufficient amount of pre-treated plasma has been processed, as described herein, the drying run is considered complete and successful, step 1214. This result is communicated to an operator as described herein, and optionally, in step 1216, the disposable 100 is expanded and compressed to help remove the dried plasma from the interior walls of the disposable 100. Expansion of the disposable 100 occurs by flowing a drying gas through it, and compression of the disposable 100 occurs via line F, as described herein.

[0286] If an insufficient amount of dried plasma powder has been processed, the drying run fails and the disposable 100 with the partial amount of dried plasma is discarded in step 1212. This result is communicated to the operator as described herein.

[0287] Method and system for detecting spray drying head interface integrity 1400 The present invention includes a method for detecting the integrity of a spray drying disposable 100, including its filter and its interface with the dryer 200. In particular, the present invention includes a method 1400 for determining whether the interface between the bottom filter / trap filter 36, the baffle filter 94, or the deflector 242 and the plenum 6 is compromised. Additionally, the method 1400 also detects seal or integrity defects in the disposable 100.

[0288] This methodology allows for direct detection of spray dried disposable failure and allows for maintaining plasma separation to protect the operator.

[0289] Method 1400 begins by monitoring the pressure above the spray-drying head 2 of the disposable 100 and the pressure within the housing 202 of the dryer 200. Generally, monitoring these pressures and comparing their values ​​at various times allows for a determination of the integrity of the disposable 100 or the integrity of the interface between the disposable 100 and the dryer 200. The pressure generally increases over time in a controlled manner at a constant slope during a spray run. Simply put, if the pressure measurements deviate from this slope, such deviation indicates a failure of the disposable 100 or its interface with the dryer 200.

[0290] Referring to FIG. 46F, step 1402 begins method 1400 by monitoring the pressure with pressure transducer PT05 276 present in dry gas line E just before or as the dry gas enters the disposable 100 at dry gas inlet 242. The method also includes monitoring pressure transducers PT08 224A and PT09 224B, which are located within housing 202 and used to measure the pressure within the disposable 100. Monitoring these pressures refers to measuring pressure at two or more points in time and comparing them to determine a slope step 1404, in step 1402. As described herein, the pressure measurements are converted to a digital value proportional to the amount of pressure sensed. The digital value of pressure from any one of these transducers is communicated to a computer system that performs the comparison of these pressure values ​​and uses its processor to determine the slope.

[0291] In one embodiment, there are two pressure transducers in the housing 202, so the average of the two sensors is used in the calculations below.

[0292] In particular, the formula used to compare pressure values, which is performed periodically, is as follows: Current pressure (psig) - Past pressure (psig) from time X minutes = Y psig / X minutes

[0293] In step 1406, the slope is determined by comparing Y psi / X min at multiple time points from step 1404.

[0294] In other words, the equation that determines the slope is:

number

[0295] Using the slope equation above, the slope is equal to the change in psi over time. The slope of a drying run can be determined, in one embodiment, by performing a drying run, measuring the pressure, and determining the slope, as described herein. After each drying run, the disposable dryer can be visually inspected to determine whether the integrity of the filters and / or interfaces has been compromised. In the inventive spray drying system described herein, if the slope exceeds about 0.02 psig / min or is in the range of about 0.02 psi / min to about 0.2 psig / min (e.g., the slope threshold), the capture / lower filter 36, the baffle filter 94, and the interface between the deflector 242 and the plenum 6 are considered intact, and the drying run is determined to be successful. See step 1408. If the baffle filter 94 and / or the lower filter 36 are defective, the slope will be outside this range. See step 1410. In practice, in certain cases, a momentary drop in pressure (e.g., the slope is still less than 0.02 psig / min) can reflect a defect.

[0296] In one aspect, the slope calculation is determined after at least about 4 minutes of passage and measured periodically over a period of about 35 minutes, which is a typical duration of a spray drying run. In one embodiment, the slope is calculated periodically at time points ranging from every 1 minute to every 10 minutes (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 minutes). In the embodiment shown in Figure 46F, the slope is calculated every 3 minutes (180 seconds).

[0297] An example of a calculated slope for a spray drying run can be seen in Figure 46G, which shows the pressure values ​​(on the left Y-axis) of pressure transducer PT05 176 at the drying gas inlet and pressure transducers PT08 224A and PT09 224B located within housing 202 over time (on the X-axis) from approximately 6 minutes to approximately 32 minutes. The right Y-axis shows the slope or rate of pressure change in psi / min. As can be seen, the slope (e.g., rate of pressure change) is approximately 0.02 psi / min. Figure 46H shows a failure of lower / trap filter 36, and Figure 461 shows a failure of baffle filter 94. In both cases, there is a rapid drop below the 0.02 psi / min slope.

[0298] If the slope is determined to be below a set amount (e.g., 0.02 psi / min), the computer software sends instructions to terminate the drying run and notify the operator via an output device, as described herein. The disposable is discarded.

[0299] Computer Systems In addition to the sensors and actuators described herein (e.g., connectors, differential pressure transducers, flow sensors, heaters, mass flow controllers, sensors, pumps, pneumatic pistons, pressure regulators, pressure relief valves, pressure transducers, valves, scales, solenoids, thermocouples, thermocouple sensors, temperature transducers, etc.), the spray dryer 200 shown in FIGS. 45A-45C and 46A-46B and the finisher 400 or 400′ shown in FIGS. 47-48 further include a computer system. The computer system includes, among other devices, a controller including one or more processors, a bus or other communication mechanism coupled to the one or more processors for communicating information, and a main memory (e.g., RAM) and / or other dynamic storage device coupled to the bus for storing information and instructions executed by the processor. The computer system is integrated with the sensors / actuators and control system to enable computer control of the sensor / actuator operation and data collection and communication. The main memory can also be used to store temporary variables (e.g., pressure, flow rate, time, etc.) or other intermediate information during execution of instructions executed by the controller. Such a computer system also includes a ROM or other static storage device coupled to the bus for storing static information and instructions for the processor. Physical computer-readable storage devices, such as solid-state memory devices, are provided and coupled to the bus for storing information. Output devices of the computer system can be provided, for example, to allow various information to be viewed or perceived in connection with the execution of the instructions. Input devices can be provided, for example, to allow a user to make selections, input data or various other information, or interact in any of a variety of ways with the processor during execution of the instructions. The computer system is also coupled via the bus to one or more display or output devices (e.g., screen displays, touch screens, light beacons, sound indicators, etc.), one or more input devices (e.g., touch screens, etc.).

[0300] In accordance with the disclosed methods, in at least some aspects, the methods are implemented using a computer system in response to a controller executing one or more sequences of one or more instructions contained in a physical memory device attached to a bus, such as a main memory, Execution of the sequences of instructions causes the controller to perform at least some of the process steps described herein.

[0301] The memory device has instructions configured to cause the controller, in combination with inputs from the sensors / actuators, to determine to perform the steps of the dryer 200 or finisher 400 or 400' described herein.

[0302] As used herein, the term "computer-readable medium" refers to any physical medium that participates in providing instructions to a processor for execution (e.g., nonvolatile media, volatile media, magnetic media, optical media, solid-state media, etc.). A computer system utilized in conjunction with dryer 200 or finisher 400 or 400' also advantageously, but optionally, includes a communications module coupled to a bus; such communications interface provides a two-way data communication coupling to a network link (e.g., an Integrated Services Digital Network (ISDN) card, a modem, a Local Area Network (LAN) card, a wireless link, etc.). The network link provides data communication through one or more networks to other data devices (e.g., a network link may provide a connection through a local network to a host computer or to data equipment operated by an Internet Service Provider (ISP)), and the computer system is configured to send and receive data through the networks, network links, and communications interfaces. The communication module can be configured to implement a communication protocol based on Bluetooth® technology, Wi-Fi, Wi-Max, IEEE 802.11 technology, radio frequency (RF) communications, an Infrared Data Association (IrDA) compatible protocol, or a Shared Wireless Access Protocol (SWAP).

[0303] Detailed description of the finishing machine Once spray drying is complete, the disposables with the spray-dried plasma are transferred to a finishing device.

[0304] 47A-47F, finishing devices 400 and 400' are shown. Specifically, the function of the finishing device is to transfer plasma from a designated portion of a disposable, remove excess air, if any, from the disposable, and seal and separate the plasma to provide a plasma unit (dried plasma unit 60) with dried plasma. Plasma unit 60 can be rehydrated and transfused to a patient within, for example, five minutes.

[0305] Specifically, the finishing device 400 or 400' includes a base 440 or 440' and a shuttle 418 or 418'. The base 440 or 440' includes a power source, an impactor 442 or 442', a heat sealer and separator 448 (heat sealer 448' and separator 450'), and an air extractor 456 or 456'. In the illustrated embodiment, the impactor 442 includes a magnet and spring and impactor 442' in Figures 47B and 47C. Figures 47E-H and 47D-F use a pneumatic cylinder. In one embodiment, the impactor 442 or 442' can include any combination of elements that allow it to disposably apply sufficient impact force to move the dried plasma into the desired compartment, as further described herein. The sealer 448 or 448' can be an impulse sealer, a heat sealer, an electric heater, a radio frequency sealer, or the like. Separator 448 or 450', in one embodiment, is a cutting wire or heat cutter, but can be any device capable of separating and cutting the disposable once sealed. The sealer and separator can be the same device, as shown in Figures 47B-47C as sealer / separator 448, or they can be two separate devices, as shown in Figures 47E, 47F, 48E, and 48F as sealer 448' and separator 450'.

[0306] The finishing device 400 has a sliding frame 402 and shuttle 418 that move together, while the finishing device 400' has a fixed frame 402' that guides the movable shuttle 418'. Figures 47A, 47B, and 48A show the finishing device 400 with the shuttle and frame in a lowered position. Figures 47C, 48B, and 48C show the shuttle and frame in specific upper positions. Figures 47F and 48E show the finishing device 400' with the shuttle in a lowered position, while Figures 47D, 47E, 48D, and 48F show the shuttle in specific upper positions. Figure 47G shows the shuttle in an inverted upper position, and Figure 47H shows the shuttle in an inverted lower position. The fixed frame 402' of the finishing device 400' has a rail system that allows the shuttle 418' to move up and down. In particular, rails 472A' and 472B' are attached to backplate 403' and utilize guides 474A' and 474B'. See FIG. 47I. The guides 474A' and 474B' and rails 472A' and 472B' shown in FIG. 47I are tongue and groove fits. The rails 472A' and 472B' are fixed, and the guides 474A' and 474B' move up and down the rails, which in turn move the shuttle 418'. The mechanism that drives the shuttle 418' shown in FIG. 47I is a lead screw 476'. The end of the lead screw is fixed by rotating a nut while moving back and forth along the length of the threaded shaft. The rotation of the nut is driven by a motor. In addition to using a lead screw, the finishing machine can use any method for moving the shuttle, including chains, straps, and any other mechanism that allows the shuttle to move up and down the rails. In embodiments using a rail system and lead screw, the lead screw moves precisely up and down.

[0307] More specifically, the spray drying disposable device 100 is aligned within the finishing apparatus 400 or 400′ as follows. In one aspect, this is accomplished by inserting the plenum 6 of the spray drying head 2 into the spray drying head receiver 404 or 404′ (by aligning the locator notch 26 with the ridge 9), attaching the gas outlet 30 of the disposable to the gas outlet receiver 414 or 414′, and securing the locating pin openings 32A-C around the locating pins 432A-C or 432A′-C′. See FIGS. 48A-48D. In one embodiment, the disposable device is aligned and secured in the finishing apparatus when all three alignment elements—the locator device, the gas port device, and the locating devices on the outer wall of the disposable—are engaged. In other embodiments, any combination of these alignment elements can be utilized, as long as the disposable device is aligned and secured in the finishing apparatus.

[0308] In a further embodiment, the gas outlet receiver is positioned to accommodate any changes in the length or configuration of the disposable gas outlet 30 caused by the thermal and pressure stresses of the spray drying process achieved by the spray dryer apparatus. Similarly, the location of the locating pins 432A-C or 432A'-C' is positioned to accommodate and accommodate any changes in the length of the disposable or configuration of the locating pin openings 32A-C caused by the thermal and pressure stresses of the spray drying process achieved by the spray dryer apparatus.

[0309] As described above, the second locator 26 on the disposable 100 is aligned with the third locator 452 or 452' in the spray dryer head receiver 404 or 404' during the finishing process. In one embodiment, the spray dryer head 2 is inserted into the spray dryer head receiver 404 with the locator aligned when the finisher 400 is in the loading position, as shown in Figures 47A, 47B, and 48A (shown in the loading position with the spray dryer attached). In the finisher 400', the spray dryer head 2 is dropped into the spray dryer head receiver 404' with the locators aligned when the finisher 400' is in the loading position. In the embodiment shown in Figures 47E and 46D, the loading position is approximately two-thirds of the way up the rail. In one aspect, the third locator on the finisher and the first locator on the spray dryer are the same shape and size and align with the locator on the spray dryer disposable. Similar to the spray dry head arrangement, this arrangement axially aligns the finisher and spray dryer disposable. The positioning device can include any device that attaches to, mates with, complements, or communicates with a locator on the disposable and a locator on the finisher. Examples of positioning arrangements include a recess / protrusion arrangement, a complementary shape arrangement, a hook / receiver arrangement, a channel and groove arrangement, a latch and catch arrangement, a magnet arrangement, etc. In the embodiment of Figure 48A, a male locator is on the spray dryer finisher and a complementary female locator is on the disposable, although the arrangement can be reversed.

[0310] The spray drying head receiver 404 or 404' also aligns the spray drying head 2 laterally. The spray drying head receiver 404 allows the spray drying head 2 of the disposable 100 to be aligned laterally relative to the finisher 400 or 400'. In one embodiment, a spray dryer head retaining clip 454 secures the spray dryer head 2 during the finishing process. See FIG. 47A. The retaining clip 454 is optional. The baffle plate ridge 9 of the spray drying head 2 also provides additional support when inserted into the receiver 404 or 404'. Once inserted and aligned, the spray drying disposable 100 can no longer move up and down. When the receiver and arrangement are used, they align the disposable so that it cannot move up and down, and once inserted into the finisher, it cannot move axially as defined by the axis through the center of the spray drying head. As shown in Figure 48A, the spray drying head fits into the receiver 404 such that the fit is snug or tight.

[0311] In one embodiment, the receiver 404' can be further configured to facilitate insertion, alignment, and retention of the spray drying head 2. The finisher 400' has a receiver 404' shown in a top view in FIG. 48G and a perspective view in FIG. 48H. The baffle plate ridge 9 of the spray drying head 2 slides into the receiver 404 or 404'. In the case of the receiver 404', the top and front surfaces have ramps 458A and 458B, which are partially tapered edges, allowing an operator to slide the spray drying head 2 from above into the receiver 404' in an angled downward motion, generally along axis C. The partially tapered surfaces taper from the top surface to the inner surface along the front surface forming the ramp. In one embodiment, the ramps in FIG. 48H are partially tapered, leaving only a portion of the front and inner surfaces, with the untapered inner front surface forming lip 462A' or lip 462B'. Lips 462A' and 462B' form part of bumpers 460A' and 460B', which prevent the spray drying head 2 from being removed along axis D, for example, after baffle plate 8 of the spray drying head 2 is fully inserted and flat.

[0312] Bumpers 460A' and 460B' are curved and configured to receive baffle plate ridge 9. The bumpers are formed when the receiver continues more than 180 degrees around a circular circumference. The receiver has a circular parameter ranging from about 210 degrees to about 260 degrees, including bumpers 460A' and 460B', with bumpers 460A' and 460B' each forming about 15 degrees to about 40 degrees (e.g., about 15, 20, 25, 30, 35, or 40 degrees) of the circumference. Receiver 404' also includes spring-loaded ball detents 464A' and 464B' instead of retaining clips. These detents function as fasteners to secure baffle plate ridge 9 to receiver 404'. The detents are optional and can be other types of fasteners (e.g., used to further secure the baffle plate ridge 9 to the receiver 404'. In one embodiment, the detents 464A' and 464B' provide an audible "click" to notify the operator that the baffle plate ridge is properly secured.

[0313] Positioning devices (e.g., pin and opening arrangements 32A-C and 432A-C or 432A-C') are preferably located at each corner of the plasma unit's outer wall, as well as above and below seal and separation locations 44A and 44B. The positioning devices shown are pin and opening arrangements, but can be any arrangement that allows the side walls of the disposable to be properly secured to the finisher while the finisher is in use. Compare Figures 47C and 48B. In addition to pin and opening arrangements, other examples of positioning devices include hook / receiver arrangements, channel and groove arrangements, latch and catch arrangements, etc. In embodiments, pins are located on the finisher and openings are located on the disposable, although these can be reversed.

[0314] The finisher 400 or 400' can include a tensioning system that stretches the walls of the disposable 100 during sealing and / or separation. In one aspect, stretching the disposable walls helps ensure a better, more complete seal and reduces wrinkles in the seal. In certain embodiments, if the disposable walls do not have enough tension, wrinkles can become embedded in the seal, potentially causing it to break. Increasing the tension in the disposable walls results in fewer wrinkles and / or broken seals compared to untensioned disposable walls. The finisher 400' has two locating pins 432C' attached to each tensioner 466A', 466B', 466C', and 466D'. See FIG. 47D. Any arrangement of locators and tensioners can be used as long as the disposable 100 remains secured to the shuttle frame and the disposable walls are in tension during sealing and / or separation. During sealing and / or separation, the tensioners move apart along axis E, creating tension in the disposable wall.

[0315] In the embodiment of FIG. 48I, the structure of tensioners 466A', 466B', 466C', and 466C' each have a sideways "U" shape with two locating pins 432C'. Tensioner 446C' structure includes ramps that engage with rollers 470A' or 470B' of the sealer and / or separator, and when engaged, the tensioners move away from each other along axis E (FIGS. 47D, 48J). This movement creates tension in the disposable wall during sealing by heat sealer 448' or separator 450', reducing wrinkled seals and / or broken seals. In one embodiment, the tension is measured to be appr...

Claims

1. 1. A method for producing spray-dried plasma, said method comprising: a) combining plasma with a pretreatment solution, said pretreatment solution comprising: i) one or more amino acids in an amount ranging from about 10 μmol / mL plasma to about 110 μmol / mL plasma; ii) one or more spray-dried stable acidic substances (SDSAS) in an amount ranging from about 10 μmol / mL plasma to about 30 μmol / mL plasma; Including, combining the plasma with a pretreatment solution, thereby obtaining formulated plasma; b) drying the formulated plasma using a spray drying system and a spray drying disposable device having a spray drying head and a drying chamber, wherein the spray drying system has a drying gas source for providing a drying gas that is in communication with the drying chamber in use, a plasma source for providing plasma, and a pressurized aerosol gas source for providing a pressurized aerosol gas, and the spray drying disposable device comprises: i) the spray drying head, (1) the spray drying head, comprising a spray drying nozzle assembly that, in use, is in fluid communication with the source of plasma from the spray drying system and the source of pressurized aerosol gas from the spray drying system, and in use, the pressurized aerosol gas flows in a vortex pattern to atomize the plasma entering the drying chamber to obtain atomized plasma droplets; ii) the drying chamber, wherein, in use, the atomized plasma droplets evaporate in the presence of a drying gas emitted from the drying gas source, thereby obtaining dry plasma particles and moist air, and the dry plasma particles are trapped in the drying chamber and the moist air passes through the drying chamber; drying the formulated plasma, thereby producing a spray-dried formulated plasma; Including, A method wherein, when the spray-dried formulated plasma is reconstituted, the amount of functional von Willebrand factor (vWf) recovered in the reconstituted plasma is increased compared to plasma not subjected to step a.

2. 2. The method of claim 1, wherein the one or more SDSAS is selected from the group consisting of ascorbic acid, citric acid, lactic acid, gluconic acid, oxalic acid, halogenated acetic acid, arenesulfonic acid, molybdic acid, phosphotungstic acid, tungstic acid, chromic acid, sulfamic acid, hydrogen chloride (HCl), glycine hydrochloride (glycine HCl), monosodium citrate, and any combination thereof.

3. 2. The method of claim 1, wherein the one or more amino acids are selected from the group consisting of alanine, asparagine, glutamine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

4. 4. The method of claim 3, wherein the pretreatment solution comprises glycine in an amount ranging from about 70 μmol / mL plasma to about 90 μmol / mL plasma.

5. 5. The method of claim 4, wherein the pretreatment solution comprises glycine in an amount of about 84 μmol / mL plasma.

6. 3. The method of claim 2, wherein the pretreatment solution comprises HCl in an amount ranging from about 15 μmol / mL plasma to about 25 μmol / mL plasma.

7. 7. The method of claim 6, wherein the pretreatment solution comprises HCl in an amount of about 20 μmol / mL plasma.

8. 2. The method of claim 1, wherein the amino acid is glycine, the SDSAS is HCl, and the molar ratio of glycine to HCl is about 1.5 to 8.

9. 9. The method of claim 8, wherein the molar ratio of glycine to HCl is about 4.

15.

10. The method of claim 1, wherein the pH of the pretreatment solution is from about 2.0 to about 4.

0.

11. 11. The method of claim 10, wherein the formulated plasma of step a) has a pH of about 6.0 to about 6.

6.

12. 10. The method of claim 1, further comprising reconstituting the spray-dried formulated plasma with a reconstitution solution to produce reconstituted plasma.

13. 13. The method of claim 12, wherein the reconstituted plasma has a pH of about 6.5 to about 7.

8.

14. 13. The method of claim 12, further comprising selecting a subject in need of plasma infusion and infusing the reconstituted plasma.

15. 10. The method of claim 1, wherein a first volume of the plasma is rapidly added to a second volume of the pretreatment solution, thereby obtaining formulated plasma, and wherein the second volume is no more than about 30% of the first volume.

16. 10. The method of claim 1, wherein the method further comprises agitating the formulated plasma prior to step b).

17. 2. The method of claim 1, wherein the amount of C5a is from about 4.7 to about 74 ng / mL.

18. 2. The method of claim 1, wherein the amount of C5a is within 20% of the amount of C5a in reconstituted pre-dried plasma pretreated with amino acid-free SDSAS.

19. 19. The method of claim 18, wherein the amount of C5a is within 10% of the amount of C5a in reconstituted pre-dried plasma pretreated with amino acid-free SDSAS.

20. 20. The method of claim 19, wherein the amount of C5a is within 5% of the amount of C5a in reconstituted pre-dried plasma pretreated with amino acid-free SDSAS.

21. 2. The method of claim 1, wherein the recovery of active von Willebrand factor is about 5% to about 40% higher than the recovery of active von Willebrand factor obtained from otherwise identical spray-dried plasma that has not been subjected to step a.

22. 22. The method of claim 21, wherein the recovery of active von Willebrand factor is about 10% to about 35% higher than the recovery of active von Willebrand factor obtained from otherwise identical spray-dried plasma that has not been subjected to step a.

23. 10. The method of claim 1, wherein the spray drying nozzle assembly comprises a cannula having a cannula opening, a wall having an inner surface and an outer surface, an upper end, and a lower end, the lower end having a bottom surface.

24. 4. The method of claim 3, wherein one or more plasma proteins have levels within corresponding clinical reference ranges.

25. 2. The method of claim 1, wherein the von Willebrand factor (vWf) is measured by a von Willebrand factor antigen assay or a von Willebrand factor ristocetin cofactor assay.

26. 26. The method of claim 25, wherein the von Willebrand factor antigen or von Willebrand factor ristocetin cofactor is about 50 IU / dL to about 200 IU / dL.

27. 1. A method for producing spray-dried plasma, said method comprising: a) combining plasma with a pretreatment solution comprising one or more physiologically compatible spray-dried stable acidic substances (SDSAS) in a final amount of about 1 mM to about 50 mM and one or more amino acids in an amount of about 1 mM to about 150 mM, thereby obtaining formulated plasma; b) drying the formulated plasma using a spray drying system and a spray drying disposable device having a spray drying head and a drying chamber, wherein the spray drying system has a drying gas source for providing a drying gas that is in communication with the drying chamber in use, a plasma source for providing plasma, and a pressurized aerosol gas source for providing a pressurized aerosol gas, and the spray drying disposable device comprises: i) the spray drying head, (1) A spray-drying nozzle assembly, in use, in fluid communication with the source of plasma from the spray-drying system and the source of pressurized aerosol gas from the spray-drying system, wherein, in use, the pressurized aerosol gas flows in a vortex pattern to atomize the plasma entering the drying chamber to obtain atomized plasma droplets. the spray drying head comprising: ii) the drying chamber, wherein, in use, the atomized plasma droplets evaporate in the presence of a drying gas emitted from the drying gas source, thereby obtaining dry plasma particles and moist air, and the dry plasma particles are trapped in the drying chamber and the moist air passes through the drying chamber; and drying the formulated plasma, thereby producing a spray-dried formulated plasma.

28. 28. The method of claim 27, wherein the one or more SDSAS is selected from the group consisting of ascorbic acid, citric acid, lactic acid, gluconic acid, oxalic acid, halogenated acetic acid, arenesulfonic acid, molybdic acid, phosphotungstic acid, tungstic acid, chromic acid, sulfamic acid, hydrogen chloride (HCl), glycine hydrochloride (glycine HCl), monosodium citrate, and any combination thereof.

29. 28. The method of claim 27, wherein the one or more amino acids are selected from the group consisting of alanine, asparagine, glutamine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

30. 1. A spray-dried formulated plasma comprising: a) combining plasma with a pretreatment solution comprising one or more physiologically compatible spray-dried stable acidic substances (SDSAS) in a final amount of about 1 mM to about 50 mM and one or more amino acids in an amount of about 1 mM to about 150 mM, thereby obtaining formulated plasma; b) drying the formulated plasma using a spray drying system and a spray drying disposable device having a spray drying head and a drying chamber, wherein the spray drying system has a drying gas source for providing a drying gas that is in communication with the drying chamber in use, a plasma source for providing plasma, and a pressurized aerosol gas source for providing a pressurized aerosol gas, and the spray drying disposable device comprises: i) the spray drying head, (1) A spray-drying nozzle assembly, in use, in fluid communication with the source of plasma from the spray-drying system and the source of pressurized aerosol gas from the spray-drying system, wherein, in use, the pressurized aerosol gas flows in a vortex pattern to atomize the plasma entering the drying chamber to obtain atomized plasma droplets. the spray drying head comprising: ii) the drying chamber, wherein, in use, the atomized plasma droplets evaporate in the presence of a drying gas emitted from the drying gas source, thereby obtaining dry plasma particles and moist air, and the dry plasma particles are trapped in the drying chamber and the moist air passes through the drying chamber; and drying the formulated plasma, thereby producing a spray-dried formulated plasma, A spray-dried formulated plasma, wherein when the spray-dried formulated plasma is reconstituted, the amount of functional von Willebrand factor (vWf) recovered in the reconstituted plasma is increased compared to plasma not subjected to step a.

31. 1. Reconstituted pre-spray dried plasma, a) combining plasma with a pretreatment solution comprising one or more physiologically compatible spray-dried stable acidic substances (SDSAS) in a final amount of about 1 mM to about 50 mM and one or more amino acids in an amount of about 1 mM to about 150 mM, thereby obtaining formulated plasma; b) drying the formulated plasma using a spray drying system and a spray drying disposable device having a spray drying head and a drying chamber, wherein the spray drying system has a drying gas source for providing a drying gas that is in communication with the drying chamber in use, a plasma source for providing plasma, and a pressurized aerosol gas source for providing a pressurized aerosol gas, and the spray drying disposable device comprises: i) the spray drying head, (1) A spray-drying nozzle assembly, in use, in fluid communication with the source of plasma from the spray-drying system and the source of pressurized aerosol gas from the spray-drying system, wherein, in use, the pressurized aerosol gas flows in a vortex pattern to atomize the plasma entering the drying chamber to obtain atomized plasma droplets. the spray drying head comprising: ii) the drying chamber, wherein, in use, the atomized plasma droplets evaporate in the presence of a drying gas emitted from the drying gas source, thereby obtaining dry plasma particles and moist air, and the dry plasma particles are trapped in the drying chamber and the moist air passes through the drying chamber; drying the formulated plasma, thereby producing a spray-dried formulated plasma; c) combining water with said spray-dried formulated plasma, thereby obtaining reconstituted pre-spray-dried plasma; is obtained by Reconstituted pre-spray-dried plasma, wherein the amount of functional von Willebrand factor (vWf) recovered in the reconstituted plasma is increased compared to plasma not subjected to step a.

Images