KR102708819B1 - Systems for plasma collection and methods of operation thereof - Google Patents

Abstract

A plasmapheresis system and a method for operating the plasmapheresis system are provided, whereby a volume of a plasma product (i.e., anticoagulated plasma) is determined based on donor-specific characteristics, such that a target volume of pure plasma in the plasma product is determined. In particular, the target volume of pure plasma to be collected is based on the body weight of the donor, or the body weight and the height of the donor. The target volume of pure plasma to be collected, TVP, may be a multiple of the body weight of the donor. Alternatively, the TVP may be a multiple of the total blood volume, TBV, of the donor, where the TBV of the donor is determined based on the body weight and the height of the donor. The target volume TVPP for the plasma product to be collected is established, and separation of the whole blood into a plasma component and a second component continues until the volume of the plasma product within the collection vessel is equal to the TVPP.

Description

Systems for plasma collection and methods of operation thereof

Cross-reference to related applications

This application claims priority to US 17/306,099 (05/03/2021) and US 63/140,534 (01/22/2021), which are further incorporated herein by reference in their entireties. US 17/078,824 (10/23/2020); US 17/062,368 (10/2/2020); US 17/041,701 (9/25/2020); US 16/739,441 (10/10/2020); PCT/US 2019/033318 (5/21/2019); US 62/846,400 (10/10/2019); US 62/752,480 (10/30/2018); and US 62/674,144 (05/21/2018), each of which is incorporated herein by reference in its entirety.

background

The present application relates to systems and methods for performing plasmapheresis, and more particularly to plasmapheresis systems and methods in which the volume of pure plasma that may be collected from a particular donor is optimized.

Plasmapheresis is an apheresis procedure in which whole blood is withdrawn from a donor, the plasma is separated from other cellular blood components (red blood cells, platelets, white blood cells), preserved, and the cellular blood components are returned to the donor. The separation of the plasma from the cellular components is typically accomplished by an automated procedure, such as centrifugation or membrane filtration.

In automated plasmapheresis, whole blood is withdrawn from a donor, mixed with an anticoagulant in a specific ratio, and then separated into plasma, red blood cells, and other cellular components. Once a target volume of anticoagulated plasma (or "plasma product") has been collected, as determined by a weight scale associated with the plasma collection vessel, withdrawal of whole blood from the donor is stopped and the red blood cells and other cellular components are returned to the donor. Often, plasma product is collected in multiple collection and reinfusion cycles until the total target volume of anticoagulated plasma has been collected. The anticoagulated plasma may be used for later transfusion or for additional manufacturing.

Plasma collected to serve as source material for further manufacturing (“source plasma”) is collected from multiple donors and combined or pooled for this purpose. To improve consistency in procedures for manufacturing source plasma and minimize opportunities for personnel error, FDA has issued guidance to registered blood collection centers regarding the volume of plasma that may be collected as source plasma during plasmapheresis (FDA Memorandum: “Volume Limits-Automated Collection of Source Plasma (11/4/92)”).

The FDA memo presents a simplified plasma volume nomogram in which the volume (or weight) of pure (or unprocessed) plasma that may be collected from a particular donor is limited to ensure donor safety and comfort. More specifically, the FDA nomogram limits the volume (or weight) of plasma based on the donor's body weight, and establishes a volume of anticoagulant that may be added to a 1:16 ratio of anticoagulant to anticoagulated blood, or 0.06 parts anticoagulant to 1 part anticoagulated blood, to reach a maximum collection volume for the total amount of plasma and anticoagulant for the particular donor.

The simplified nomogram presented in the FDA memo has been the primary method for determining plasma product collection volumes used by blood collection centers. Accordingly, plasmapheresis devices used in these centers are typically programmed to collect a specified volume/weight of anticoagulated plasma (assuming a known density) according to the maximum collection volume allowed by the FDA nomogram, and anticoagulant is added to whole blood at a ratio of 1:16 or 0.06.

One simplification made in the FDA nomogram is to exclude consideration of donor hematocrit in determining the target collection volume for plasma products. However, the relative proportions of pure plasma and anticoagulant in plasma products vary depending on the donor blood hematocrit and the proportion of anticoagulant that is combined with the donor's whole blood. As a result, higher hematocrit donors reach the maximum collection volume suggested in the FDA nomogram before the maximum pure plasma volume that can be safely collected from the donor is reached. This represents an inefficiency for plasma collection centers, as the volume of pure plasma collected is less than the maximum possible.

Additionally, the amount of pure plasma that can be safely collected from a donor may depend on factors other than hematocrit that affect the donor's total blood volume, such as donor weight and donor height.

Since source plasma from multiple donors is pooled, it is important to maximize the volume of pure plasma that can be collected from each individual donor, since even small gains in volume collected from each individual donor, when added together, result in meaningful increases in the total volume of pooled plasma. If the plasmapheresis device can better target the volume of pure plasma, more plasma proteins can be collected from each donor, improving the overall efficiency of the plasma collection center. Accordingly, the present disclosure provides systems and methods for optimizing the volume of collected plasma consistent with donor safety and comfort.

United States Patent Publication No. 2003/0125881 (published on July 3, 2003)

summation

In a first aspect of the present disclosure, a system for collecting plasma from a donor is provided, the system comprising: a venipuncture needle for withdrawing whole blood from the donor, a blood separator for separating the whole blood into a plasma product and a second blood component comprising red blood cells, a donor line coupled to the venipuncture needle for introducing whole blood from the donor into the blood separator, a first pump for controlling flow through the donor line, an anticoagulant line coupled to an anticoagulant source for combining an anticoagulant with the whole blood, and a second pump for controlling flow through the anticoagulant line.

A touchscreen is provided for receiving input from an operator with a controller programmed to control the operation of the system. The controller is configured to control the system to operate a withdrawal and return cycle to determine a target volume of plasma product (TVPP) to be collected based on the donor's body weight and donor hematocrit, or based on the donor's body weight and height and donor hematocrit, withdraw whole blood from the donor, add an anticoagulant to the whole blood at a predetermined ratio (ACR), separate the anticoagulated whole blood into a plasma product and a second component and return the second component to the donor, and stop withdrawing whole blood from the donor and initiate final return of the second blood component when the measured volume of plasma product within the plasma collection vessel reaches the target volume for plasma product.

In a second aspect, the controller is programmed to calculate i) a target volume of pure plasma (TVP) to be collected based on the body weight of the donor and ii) a percentage of anticoagulant within the target volume of the plasma product to be collected (%AC _TVPP ) based on a predetermined anticoagulant ratio ACR and donor hematocrit, where TVPP = TVP/(1 - %AC _TVPP ).

In a third aspect, the controller is programmed to calculate a total blood volume (TBV) of the donor based on a body weight and height of the donor, a target volume of pure plasma (TVP) to be collected as a percentage of the TBV, and a percentage of anticoagulant in the target volume of plasma product to be collected (%AC _TVPP ) based on a predetermined anticoagulant ratio (ACR) and donor hematocrit, where TVPP = TVP/(1 - %AC _TVPP ).

In the fourth aspect, the controller is programmed to calculate the total blood volume (TBV) of the donor based on the donor's weight and height to calculate the body mass index (BMI) for the donor such that TBV = 70/(sqrtBMI/22) (Lemmens equation).

In the fifth aspect, the controller is programmed to calculate the total blood volume (TBV) of the donor based on the donor's weight ( ^Wt ), height (Ht) and gender (male or female) such that for a male TBV = (0.3669 * Ht ³ ) + (0.03219 * Wt) + 0.6041 and for a female TBV = (0.3561 * Ht 3 ) + (0.03308 * Wt) + 0.1833, where Ht is in meters and Wt is in kilograms (Nadler's formula).

In a sixth aspect, methods are provided for performing plasmapheresis to collect a volume (VPP) of plasma product (i.e., anticoagulated plasma) such that a targeted volume of pure plasma (TVP) of the plasma product is determined based on donor-specific characteristics consistent with the safety and comfort of the donor. In particular, the target volume TVP of pure plasma to be collected is based on the body weight, or body weight and height, of the donor.

In the seventh aspect, the target volume of pure plasma to be collected, TVP, may be a multiple of the donor's body weight. Alternatively, the TVP may be a multiple of the donor's total blood volume, TBV, where the donor's TBV is determined based on the donor's body weight and height using well-established methodologies such as the Lemmens equation or the Nadler formula.

The target volume TVPP for the plasma product to be collected is established based on the target volume/weight of pure plasma and the percentage of anticoagulant AC in the plasma product, %AC _TVPP , so that TVPP = TVP/(1-%AC _TVPP ), where %AC _TVPP is based on the donor's hematocrit and AC ratio ACR.

Once the TVPP is determined, the plasmapheresis process begins, where whole blood is withdrawn from the donor, mixed with an anticoagulant in a specific ratio, and separated into plasma, red blood cells, and other cellular components. Once the TVPP is collected, the withdrawal of whole blood from the donor is stopped, as determined, for example, by a weigh scale associated with the plasma collection vessel, and the red blood cells and other cellular components are returned to the donor.

In a seventh aspect, in determining the target volume of plasma product to be collected, the hematocrit of the donor may be determined prior to the collection phase of each cycle, either by calculation or based on a signal from a sensor or the like indicative of the hematocrit of the donor. Additionally, the amount of plasma product within the plasma collection vessel may be determined, for example, by a weight scale associated with the plasma collection vessel or an optical sensor that directly measures the volume.

In another aspect, a method is provided for operating a plasmapheresis system to collect a plasma product volume comprising a maximum allowable volume/weight of raw plasma, based on donor body weight and as defined by the FDA nomogram.

To collect the maximum volume/weight of raw plasma acceptable by the FDA nomogram, a modified nomogram is provided that uses the hematocrit of the donor to calculate a target volume/weight for a plasma product having the maximum volume of raw plasma acceptable by the FDA nomogram. The calculated volume/weight of raw plasma is compared to the maximum volume/weight for raw plasma acceptable by the FDA nomogram. If the calculated volume/weight of raw plasma is less than the maximum allowable volume/weight, the volume/weight of plasma product to be collected is adjusted upward by an amount equal to the maximum volume/weight of raw plasma acceptable by the FDA nomogram for the plasma product plus an additional amount of anticoagulant added to process the additional volume/weight of plasma.

Therefore, with knowledge of the donor's hematocrit and the AC ratio of the device, the volume of additional raw plasma that can be safely collected from the donor consistent with the limits suggested by the FDA nomogram is determined, and the total volume/weight of plasma product to be collected is then adjusted accordingly based on the donor's body weight as suggested by the FDA nomogram.

Typically, plasmapheresis procedures involve sequential cycles of alternating phases, in which whole blood is withdrawn from the donor and the plasma separated and collected, and in which the separated red blood cells and any other non-RBC cellular components are returned to the donor. The donor's hematocrit varies over the course of the plasmapheresis procedure, affecting the amount of anticoagulant in the plasma product collected from one cycle to the next.

Consequently, in the first aspect of the present invention, prior to the start of each subsequent extraction/separation phase, a new hematocrit value for the donor is determined, and the target volume/weight of plasma preparation for that procedure is recalculated prior to the start of each extraction/separation phase to ensure that the maximum amount of raw plasma acceptable by the FDA nomogram is collected.

In another aspect, an additional method for collecting a volume of plasma during a plasmapheresis procedure is provided. The steps of the method include: determining a total whole blood volume V _b for the donor; determining a volume of raw plasma (V _RP ) that may be collected from the donor based on V _b ; determining a target volume of plasma product to be collected (V _PP ) - V _PP is equal to the volume of raw plasma to be collected (V _RP ) plus the volume of anticoagulant added to the V _RP during apheresis (V _AC ), based on the donor Hct and the established anticoagulant ratio (ACR, defined as the ratio of donor blood volume to anticoagulant volume for donor blood without anticoagulant) for the procedure, V _PP = V _RP *K , where K = (ACR*(1-Hct/100) + 1)/(ACR*(1-Hct/100)) -; withdrawing whole blood from a donor; adding an anticoagulant to the whole blood in an amount that matches the ACR; separating a plasma product from the whole blood; and, delivering the plasma product to the collection vessel until the volume of the plasma product in the collection vessel reaches V _PP . Since the plasmapheresis procedure includes multiple extraction/separation and return phases, the V _PP for the procedure is recalculated based on the value for the donor's hematocrit determined prior to the start of each extraction/separation phase, and the target volume for the plasma preparation adjusted accordingly. Alternatively, V _RP is V _b and may also be determined based on a calculated value for the total plasma volume of the donor based on the donor's hematocrit.

In another aspect, a method is provided for determining a volume (V _PP ) of a plasma product that may be collected during an apheresis procedure, wherein V _PP is equal to a volume (V _RP ) of raw plasma that may be collected plus a volume (V _AC ) of an anticoagulant added to the V _RP during the apheresis procedure. The steps of the method include: determining a weight (W _kg ) and sex (M or F) of a donor, and determining a hematocrit (Hct) for the donor; determining a volume (V _RP ) of raw plasma that may be collected based on the weight (W _kg ) and sex (M or F) of the donor; determining a ratio K between V _PP and V _RP such that K = V _PP /V _RP based on the Hct and anticoagulant ratio (ACR) of the donor; V _PP = V _RP *K, and includes a step of determining V _PP such that K = (ACR*(1-Hct/100) + 1)/(ACR*(1-Hct/100)). After V _PP is determined, whole blood is withdrawn from a donor; an anticoagulant is added to the whole blood in an amount equal to the ACR; a plasma product is separated from the whole blood; and the plasma product is delivered to a collection vessel. After the desired amount of whole blood is withdrawn from the donor, the red blood cells are returned to the donor. The donor's Hct and V _PP are then determined prior to each withdrawal step.

In a related embodiment, the withdrawal and separation steps are repeated until the volume of plasma product within the collection vessel reaches V _PP .

In a related aspect, the donor's hematocrit after the first collection phase may be calculated by volume balance, assuming that the donor's red blood cell volume is the same at the start of each withdrawal cycle, but that the total volume of blood decreases from one cycle to the next by an amount equal to the amount of raw plasma collected. Alternatively, the donor's hematocrit at the start of each withdrawal cycle may be measured by optical or other sensors.

In a further embodiment, the volume of raw plasma that may be collected from a particular donor may be determined by any one of several different means. Such means include, for example, an FDA nomogram that considers only the donor's body weight; a modified FDA nomogram that additionally considers the donor's hematocrit and a portion of the total blood volume or total plasma volume calculated for the particular donor. The total blood volume or total plasma volume may be determined, for example, using Nadler's equations, Gilcher's Rule of Five, tables provided by the International Council for Standardization in Hematology (ICSH), or any other generally accepted method using the donor's height, weight, sex, and age, which is consistent with the safety and comfort of the donor.

In another aspect, an automated system for separating plasma from whole blood is provided, comprising reusable hardware components and a disposable kit. The disposable kit further comprises: i) a separator for separating whole blood into a plasma fraction and a concentrated cell fraction, the separator having an input port, the input port having a blood line integrally connected to a whole blood line for transporting whole blood from a donor to the separator, a plasma outlet port integrally connected to a plasma collection vessel by the plasma line, and a concentrated cell outlet port integrally connected to a reservoir for receiving the concentrated cells prior to reinfusion into the donor; ii) a donor line terminating in a venipuncture needle for transporting whole blood from the donor to the blood line; iii) an anticoagulant line integrally connected to the blood line and configured to be connected to a source of anticoagulant for transporting the anticoagulant to the donor line; and iv) a reinfusion line for transporting the concentrated cells from the reservoir to the donor line.

The reusable hardware components further include a programmable controller including i) a first peristaltic pump for delivering an anticoagulant into the blood line at a controlled rate during the collection phase, ii) a second pump for delivering anticoagulated whole blood to a separator during the collection phase and returning concentrated cellular components during the reinfusion phase, iii) a third pump for delivering the concentrated cellular components from the separator to a reservoir during the collection phase, iv) clamps associated with each of the blood line, the plasma line and the reinfusion line, v) weigh scales for weighing each of the plasma collection vessels, the reservoir and the source of anticoagulant, and vi) a touch screen for receiving input from an operator, wherein the programmable controller is configured to receive signals from each of the weigh scales and to automatically operate the first, second and third pumps and clamps to separate the whole blood into a plasma fraction and a concentrated cell fraction during the collection phase and to return the concentrated cells to the donor during the reinfusion stage. The programmable controller is further configured to determine a target amount of plasma product to be collected in the plasma collection vessel according to any of the methods described herein, and to terminate the collection phase upon receiving a signal that the amount of plasma product within the plasma collection vessel is equal to the target amount of plasma product determined by the controller. In determining the target amount of plasma product to be collected, the controller may be configured to calculate a hematocrit of the donor prior to the collection phase of each cycle. Alternatively or additionally, the controller may receive a signal indicative of the hematocrit of the donor, such as from a sensor. Additionally, the amount of plasma product within the plasma collection vessel may be determined, for example, by a weight scale associated with the plasma collection vessel or an optical sensor that directly measures volume.

Brief description of the drawings
FIG. 1 is a perspective view of an exemplary plasmapheresis device suitable for use in the systems and methods of the present application.
FIG. 2 is a perspective view of a spinning membrane separator of the type included in a disposable set, partially disassembled to show details, usable with the plasmapheresis system of FIG. 1.
FIG. 3 is a perspective view of the front panel of the plasmapheresis system of FIG. 1 showing components of a disposable set into which the disposable set is mounted.
Figure 4 is a schematic diagram showing the operation of the plasma separation system in the collection phase.
Figure 5 is a schematic diagram showing the operation of the plasmapheresis system in the reinfusion phase.
Figures 6a and 6b are flowcharts illustrating steps of the methods used in the present application to collect a target volume of pure plasma.
Figure 7 is a table showing the volume of pure plasma, based on donor hematocrit, contained within the plasma preparation volume limits established by the FDA nomogram using a 1:16 ratio of anticoagulant to whole blood.
Figure 8 is a table showing the volume of "unrequested" pure plasma in plasma products based on the difference between the values presented in Figure 7 and the maximum volume of pure plasma that could be collected based on the FDA nomogram.
Figure 9 is a table showing the volumes of plasma products that may be collected from donors resulting in the maximum allowable volume of pure plasma acceptable by the FDA nomogram, based on the donor's body weight and hematocrit.
FIG. 10 is a table showing inputs to a programmable controller for performing a hypothetical plasmapheresis procedure according to the method of the present application.
Figures 11a and 11b include two-part tables showing how a donor's hematocrit increases over the course of a hypothetical plasmapheresis procedure based on inputs from the table in Figure 10, and consequently the increase in total collection volume of plasma product required to collect a target volume of pure plasma.
Figure 12 is a graph illustrating IgG dilution during plasmapheresis.

details

A more detailed description of the systems and methods according to the present disclosure is set forth below. It should be understood that the description of specific devices and methods below is intended to be illustrative and does not encompass all possible variations or applications. Accordingly, the scope of the present disclosure is not intended to be limiting, but should be understood to encompass variations or embodiments that would occur to those skilled in the art. Various aspects of the systems and methods are described in more detail in US 2020/0147289, which is incorporated herein by reference.

In the context of the present application, plasmapheresis is performed on an automated system including hardware components, generally designated 10, and a disposable set, generally designated 12, to collect plasma to be processed as source plasma. With reference to FIGS. 1-5 and as described in more detail below, the disposable set (12) comprises a separator, a container, and tubing integrally connected to transport blood and solutions within a sterile fluid path.

The separator (14), best illustrated in FIG. 2, has a spinning membrane filter (16) mounted on a rotor (18) to rotate within a case (20) to separate blood into its components. A detailed description of a spinning membrane separator may be found in U.S. Pat. No. 5,194,145 to Schoendorfer, which is incorporated herein by reference. As will be appreciated, in other systems, separation of whole blood may also be accomplished by centrifugation. See, for example, U.S. Pat. No. 5,360,542 to Williamson et al.

During plasmapheresis, anticoagulated whole blood enters the separator (14) through the whole blood inlet port (22). The plasma is separated by a spinning membrane filter and then passes from the plasma outlet port (24) through the plasma line (26) into the plasma collection vessel (28). The concentrated cells are pumped from the concentrated cell output port (30) into the reservoir (32), where they are maintained until reinfusion into the donor.

The disposable set (12) also includes a donor line (34) terminating at a venipuncture needle (36) for introducing whole blood from a donor into the system during collection and returning concentrated cells to the donor during reinfusion, a blood line (38) for transferring anticoagulated whole blood to a separator, a cell line (40) for transferring concentrated cells to a reservoir, a cell line (40) for transferring concentrated cells from the reservoir to the donor line (reinfusion line (42)), a plasma line (44) for transferring plasma into a plasma collection vessel, a saline solution (saline solution line (46)), and an anticoagulant (AC line (48)).

The hardware component (10) includes a programmable controller (50) and a touch screen (52) having a graphical user interface (“GUI”) through which an operator controls the procedure. For example, the GUI allows for entry of any of donor ID, donor sex, donor height, donor weight, donor age, donor hematocrit/hemoglobin; target saline infusion volume (if a saline protocol is selected), and target plasma volume. The touch screen (52) also allows the operator to gather status information and handle error conditions.

Three peristaltic pumps, including an AC pump (54), a blood pump (56), and a cell pump (58), are positioned on the front panel of the hardware component (10). The AC pump (54) delivers an anticoagulant solution (AC) into the blood line (38) at a controlled rate as whole blood enters the set from a donor. The blood pump (56) delivers anticoagulated whole blood to the separator during the collection phase of the procedure and returns the concentrated cellular components and, if desired, replacement fluid to the donor during the reinfusion phase of the procedure. The cell pump (58) delivers the concentrated cellular components from the separator (14) to the reservoir during the collection phase.

The front panel also includes four clamps into which tubing from the disposable set (12) is installed, including a reinfusion clamp (60), a blood clamp (62), a saline clamp (64), and a plasma clamp (66). The reinfusion clamp (60) is closed to occlude the reinfusion line (42) during the collection phase (FIG. 5) and opened during the reinfusion phase (FIG. 5) to allow the blood pump to reinfuse concentrated cellular components from the reservoir (32) into the donor. The blood clamp (62) is opened during the collection phases to pump anticoagulated whole blood into the separator (14) and closed during the reinfusion phase to occlude the blood line (38). The saline clamp (64) is closed to occlude the saline line (46) during the collection phase and during the reinfusion of the separated cellular components. If saline is used as the replacement fluid, the saline clamp (64) is opened during the reinfusion phase. The plasma clamp (66) is opened during the collection phase to allow plasma to flow into the plasma collection vessel (28) and closed during the reinfusion phase.

The hardware components (10) include three weigh scales to monitor the current plasma collection volume (scale (68)), AC solution volume (scale (70)), and concentrated cell content volume (scale (72)). The system also includes various sensors and detectors including a venous pressure sensor (74), a separator pressure sensor (76), optical blood detectors (78), and an air detector (80).

The donor is connected to the system throughout the procedure. As illustrated, the disposable set (12) includes a single venipuncture needle (36) through which whole blood is aspirated from the donor in the collection phase (FIG. 4) and the concentrated cells are returned to the donor in the reinfusion phase (FIG. 5). As described above, the plasmapheresis procedure may include multiple cycles, each having a collection/separation phase followed by a return or reinfusion phase. During the collection phase, the whole blood is separated into plasma and concentrated cells. The disposable set includes a plasma collection vessel (28) for receiving the separated plasma and a reservoir (32) for receiving the concentrated cells. During the reinfusion phase, the concentrated cells from the reservoir (32) are reinfused into the donor through the venipuncture needle (36). Plasmapheresis performed with a single venipuncture needle (36) may involve multiple cycles of collection and reinfusion.

Referring again to FIG. 4, during the collection phase, an anticoagulant solution (AC) is pumped at a controlled rate and mixed with the whole blood as it enters the disposable set (12). The anticoagulated blood is pumped to a separator (14) where the plasma is separated from cellular components and sent to a plasma collection vessel (28).

Cell components are pumped from the separator (14) into the reservoir (32). The collection phase is stopped when the reservoir (32) reaches the expected volume of concentrated cells or the target plasma collection volume is achieved.

Next, the re-infusion phase begins. Referring to FIG. 5, during the re-infusion phase, the blood pump (56) reverses direction to pump the concentrated cells from the reservoir (32) back to the donor through the aspiration needle (36). If a saline protocol is selected in which saline is returned to the donor as a replacement fluid for the collected plasma, the final refusion phase is followed by saline re-infusion.

An automated plasma collection device is configured to collect a volume/weight of anticoagulated plasma (i.e., plasma product) having a maximum volume/weight of source plasma acceptable for the donor under the restrictions set forth in the FDA nomogram. To maximize the volume of source plasma including the plasma product, the device is programmed with a nomogram that takes into account the hematocrit of the donor. With knowledge of the hematocrit of the donor and the AC ratio of the device, the total volume/weight of plasma product to be collected can be determined such that the plasma product contains the maximum volume/weight of source plasma fraction that may be collected from the donor, which is consistent with the restrictions on total volume/weight of source plasma set forth in the FDA nomogram. By having the calculations programmed into the controller, the possibility of operator error is reduced compared to offline calculations of the collection volume that are subsequently input into the device.

During plasmapheresis, when an anticoagulant is mixed with whole blood, such as that drawn from a donor, the anticoagulant is distributed uniformly in the pure/raw plasma of the blood. However, the amount of pure/raw plasma in the whole blood depends on the hematocrit (Hct) of the whole blood. The following relationships are established:

RBC volume = whole blood volume * Hct/100. [1]

Volume of pure/raw plasma = Volume of whole blood * (1 - Hct/100). [2]

When an anticoagulant is mixed with whole blood, it may be quantified as an AC ratio (ACR), which is 16 parts whole blood to 1 part AC, or 1 part whole blood to 0.06 parts AC.

ACR = volume of whole blood/volume of anticoagulant (donor blood without anticoagulant) [3]

(This produces slightly different results than the FDA nomogram, which, as noted above, standardizes the volume of anticoagulant that may be added to a 1:16 ratio of anticoagulant to anticoagulated blood, or 0.06 parts anticoagulant to 1 part anticoagulated blood.)

Volume of anticoagulated blood = volume of anticoagulant + volume of whole blood [4]

The combination of these formulas gives:

Volume of pure/raw plasma = ACR * volume of anticoagulant * (1 - Hct/100). [5]

Because the red blood cells are given back to the donor:

Volume of plasma product collected = Volume of pure/raw plasma + volume of anticoagulant. [6]

Equations [5] and [6] can be combined to calculate the amount of anticoagulant in a given amount of collected plasma:

Anticoagulant volume = volume of plasma product collected / (1 + ACR*(1 - Hct/100)). [7]

also:

Volume of collected plasma product = Volume of pure/raw plasma * K, where K = (ACR*(1-Hct/100) + 1)/(ACR*(1-Hct/100)). [8]

In view of the relationships expressed in the above equations, the volume of pure/source plasma contained within the volume of plasma product allowed under the FDA nomogram can be determined based on the donor hematocrit. The results of these calculations are presented in Fig. 7, which shows the volume of pure/source plasma based on donor hematocrit contained within the plasma product volume limits set by the FDA nomogram.

As can be seen with reference to FIG. 7, for donors weighing 110 to 149 lbs. (for which the maximum plasma product volume according to the FDA nomogram is 690 mL) the volume of collected source plasma is less than the 625 mL allowed by the FDA nomogram if the donor has a hematocrit of 42 or greater. This situation is similar for donors weighing 150 to 174 lbs. (for which the maximum plasma collection volume according to the FDA nomogram is 825 mL) and for donors weighing 175 lbs. or greater if the donor's hematocrit is 40 or greater (for which the maximum plasma collection volume according to the FDA nomogram is 880 mL).

The table presented in FIG. 8 represents the volume of "unrequested" raw plasma in the plasma product based on the difference between the values presented in FIG. 7 and the maximum volume of pure/source plasma that may be collected based on the FDA nomogram. Thus, as illustrated in the table presented in FIG. 9, the plasma product collected from any particular donor may be adjusted from that presented in the FDA nomogram by an amount corresponding to the amount of "unrequested" raw/source plasma presented in FIG. 8 plus the amount of anticoagulant required to process the additional volume.

Alternatively, the volume of plasma product to be collected may be calculated by first determining the body weight and hematocrit (Hct) for the donor; determining the volume of source plasma (V _RP ) that may be collected based on the body weight (W _kg ) of the donor; determining the ratio K between V _PP and V _RP such that K = V _PP /V _RP based on the donor Hct and anticoagulant ratio (ACR; 1:16 or 0.06:1, according to FDA nomogram); and determining V _PP such that V _PP = V _RP *K . Furthermore, K = (ACR*(1-Hct/100) + 1)/(ACR*(1-Hct/100)).

In a further alternative, the volume of plasma product to be collected (V _PP ) may be calculated by first determining the body weight (W _kg ) and hematocrit (Hct) of the donor; determining the volume of source plasma (V _RP ) that may be collected based on the body weight (W _kg ) of the donor; determining the volume of anticoagulant to be added (V _AC ) based on the hematocrit and anticoagulant ratio (ACR; 1:16 or 0.06:1, according to FDA nomogram) of the donor such that V _AC = V _RP *(ACR * (1-Hct/100)); and determining the collection volume such that V _PP = V _RP + V _AC .

According to one aspect of the present invention, the automated plasma collection device is configured to collect a volume/weight of plasma product (pure plasma + anticoagulant) having a volume/weight of pure plasma acceptable for the donor as determined by one of two methods described in more detail below.

Referring to FIG. 6A, a first method (70) for collecting a target volume of plasma product TVPP is illustrated. The method comprises first calculating a target volume of pure plasma (TVP) to be collected based on a donor's body weight (step 72), and then determining a percentage of anticoagulant in the target volume of plasma product to be collected (% AC _TVPP ) based on the donor's hematocrit (ACR) and a predetermined anticoagulant ratio (ACR), as TVPP = TVP/(1 - % AC _TVPP ) (step 74). In this method, no intervening calculations are required for either the donor's total blood volume or total plasma volume prior to determining the target collection volume of plasma for the donor, although in alternative embodiments such calculations may be included.

A variety of methods may be used to determine the target volume of pure plasma that may be collected directly from the donor's body weight. For example, the donor's body weight may be multiplied by an established constant "K ₁ " (e.g., 10 mL/kg). Alternatively, the donor's body weight may be divided into weight categories or ranges (e.g., at least 3 categories, at least 6 categories, etc.) and a fixed volume is established for each category (as in the FDA nomogram discussed above, where the range of donor body weights is divided into 3 categories).

The anticoagulant ratio, ACR, may be defined in one of two different ways. In the first method, the ACR is the ratio of the volume of whole blood to the volume of anticoagulant (ACR = WB/AC). In the second method, the ACR is the ratio of the volume of whole blood plus the volume of anticoagulant to the volume of anticoagulant (ACR = (WB + AC)/AC). When ACR = WB/AC, the percentage of anticoagulant in the target volume of plasma product, %AC _TVPP, is determined by the following formula: %AC _TVPP = 1/(1 + ACR(1-Hct)), where ACR and Hct are expressed as percentages. When ACR = (WB + AC)/AC), the percentage of anticoagulant in the target volume of plasma product, %AC _TVPP, is determined by the following formula: %AC _TVPP = 1/(1 + (ACR-1)(1- Hct)). ACR may be expressed as a ratio or percentage and may vary from 7:1 to 20:1, or from about 5% to 14%. An exemplary ACR is 16:1, or 6.25%.

Returning to FIG. 6a, once the TVPP is determined, whole blood is withdrawn from the donor (step 76) and combined with an anticoagulant based on a predetermined ratio ACR as described above (step 78). The anticoagulated whole blood is then introduced into a separator (14) where it is separated into plasma and concentrated (red) cells (step 80). The plasma product (pure plasma and anticoagulant) is collected into a plasma collection vessel (28) (step 82) and the separated red cells are collected into a reservoir (32). As the plasma product is collected, the volume of the plasma product within the plasma vessel, VPP (pure plasma and anticoagulant), is determined (step 84). When the VPP equals the target volume of plasma product (TVPP), the withdrawal of whole blood is stopped and any remaining blood components (e.g., red cells) are returned to the donor (step 86).

Referring to FIG. 6B , a second method (90) for collecting a target volume TVPP of a plasma product is illustrated. In this method, the target volume TPPV of the plasma product is determined by first calculating the total blood volume (TBV) of the donor based on the body weight and height of the donor (step 92), calculating the target volume TVP of the pure plasma to be collected as a percentage of the TBV (step 94), calculating the percentage of anticoagulant in the target volume of the plasma product to be collected (%AC _TVPP ) based on the predetermined anticoagulant ratio (ACR) and the hematocrit of the donor (step 96), and calculating the TVPP as TVPP = TVP/(1 - %A _TVPP ) (step 98). The %ACT _VPP may also be determined as described above with respect to the first method. In this method, calculation of the total plasma volume of the donor is not required to determine the target collection volume of plasma for the donor.

The donor plasma volume may be estimated based on the donor's total blood volume, and the volume of plasma that may be collected, consistent with the donor's safety and comfort, may be based on this estimate. Methods that utilize donor parameters are commonly used to estimate the donor's total blood volume. The donor's total blood volume may be determined using one or more of the Lemmens equation (which uses the donor's body mass index to determine total blood volume), the Nadler equation (which takes into account the donor's height, sex, and weight), the Gilcher's five-rule (which takes into account sex, weight, and morphology (obese, lean, normal, or muscular)), or the standards of the International Counsel for Standardization in Hematology (ICSH) as set forth in Br. J. Haem. 1995, 89:748-56) (which takes into account the donor's height, weight, age, and sex). Any other methodologies for determining the donor's total blood volume may also be used. In other embodiments, multiple such methodologies may be used, and an average, mean, or weighted average of the methodologies may be taken as the total blood volume of the donor. For example, once the total blood volume of the donor is determined, the plasma volume of the donor may be estimated by multiplying the total blood volume by a constant "K ₂ ", where K ₂ is equal to (1 - Hct of the donor).

From an analysis of demographic, laboratory and laboratory data from the 2015-2016 National Health and Nutrition Examinvection Survey extracting sex, age, height, weight, pregnancy data and hematocrit as presented in Pearson et al., Interpretation of measured red cell mass and plasma volume of measured red red red cell mass and plasma volume in adults: Expert Panel on the Radionuclides of the International Council for Standardization in Hematology, British J. Hematology, 89:748-756 (1995) (from which the ICSH recommended formula was derived), it was determined that for donors with defined characteristics (i.e., underweight women with elevated hematocrits), up to 36% of available plasma could be collected while maintaining current regulations. Plasmapheresis procedures using these donors have been routinely performed without adverse effects and are therefore considered safe. This suggests that up to 36% of a donor's available plasma can be safely collected during the plasmapheresis procedure.

Considering that only a negative deviation of the donor's actual blood volume from the predicted/calculated total blood volume represents a potential risk, further downward adjustment of the harvestable volume of plasma may be appropriate, based on consideration of the deviation between calculated blood volumes as determined by Pearson et al., cited above.

Therefore, the total blood volume (TBV) of the donor can also be calculated based on the donor's weight (Wt) and height (Ht) to calculate the body mass index (BMI) for the donor, such that TBV = 70/sqrt(BMI/22), where BMI = Wt/Ht ² , where Ht is in meters and Wt is in kilograms (Lemmens equation). See “ Estimating Blood Volume in Obese and Morbidly Obese Patients ,” Lemmens et al., Obesity Surgery 16, 2006, pp. 773-776.

Alternatively, the donor's total blood volume (TBV) may be calculated based on the donor's weight (Wt), height (Ht) and sex (male or female) as TBV = (0.3669 * Ht ³ ) + (0.03219 * Wt) + 0.6041 for males and TBV = (0.3561 * Ht ³ ) + (0.03308 * Wt) + 0.1833 for females, where Ht is in meters and Wt is in kilograms (Nadler's formula).

The percentage by which the TBV is multiplied to obtain the TVP (and ultimately the TVPP) is selected to maximize the volume of pure plasma collected from the donor consistent with the comfort and safety of the donor. In various embodiments the percentage range can vary from about 1% to about 15% of the TBV, at least 15%, less than 18%, about 15% to 17%, about 12%, about 16% or about 18%. The TVPP can also be applied to a maximum volume to be collected regardless of the TBV of the donor, for example, 1000 mL or 1050 mL.

Based on regression analysis of experimental blood volume data presented in Retzlaff et al., Erythrocyte Volume, Plasma Volume, and Lean Body Mass in Adult Men and Women , J. Haematology, 33, 5:649-667 (1969), an adjustment V C to the calculated whole blood volume _TBV may be made prior to calculating the target volume of pure plasma TVP such that TVP = 0.36(1-Hct)(TBV - V _C ), where V _C = 523 mL. There is 95% confidence that an individual's expected blood volume will differ by no more than 20.5%. Therefore, a scaling factor of 0.795 may be applied to the determination of harvestable source plasma, which is 36% of the donor's total plasma volume described above, such that 28.6% of the donor's calculated source plasma volume may be harvested, which is consistent with donor safety and comfort.

Referring again to FIG. 6b, once the TVPP is determined as described above (based on the TBV), whole blood is withdrawn from the donor (step 100) and combined with an anticoagulant based on a predetermined ratio (step 102). The anticoagulated whole blood is then introduced into a separator (14) where it is separated into plasma and concentrated (red blood) cells (step 104). The plasma product (pure plasma and anticoagulant) is collected into a plasma collection vessel (28) (step 106) and the separated red blood cells are collected into a reservoir (32). As the plasma product is collected, the volume of plasma product within the plasma vessel, the VPP (pure plasma and anticoagulant), is determined (step 108). When the VPP equals the target volume of plasma product (TVPP), withdrawal of whole blood is stopped and any remaining blood components (e.g., red blood cells) are returned to the donor (step 110).

Therefore, the collection volume (volume of plasma product) is determined based on the volume of raw plasma volume that can be collected from a particular donor, the donor's hematocrit, and the defined anticoagulant ratio (ACR). As a result, this method allows for more consistent control of the donor's raw plasma volume, which is the variable most relevant to donor safety.

In an exemplary method, the operator inputs into the system controller a collection volume for a plasma product for a particular donor based on a target volume of raw plasma that may be harvested. The target plasma collection volume may be, for example, based on the donor's body weight and hematocrit for the initial collection phase, as illustrated in FIG. 9 , or by any other method described above. Alternatively, the controller is configured to calculate the target plasma product collection volume for the initial collection phase according to a methodology such as described above when the operator inputs, for example, the donor's body weight and hematocrit, and/or the donor's total blood volume, total plasma volume, and any of the additional donor-specific information required by the methodology used to determine the target volume of harvestable plasma that may be collected (e.g., the donor's sex, height, and age).

In practice, the operator inputs into the system controller a collection volume for a plasma product for a particular donor based on a target volume of raw plasma that may be harvested. The target plasma collection volume may be as set forth in FIG. 9 based on the donor's body weight and hematocrit for the initial collection phase, or by any other method as described above. Alternatively, the controller is configured to calculate the target plasma product collection volume for the initial collection phase according to a methodology as described above when the operator inputs, for example, the donor's body weight and hematocrit, and/or the donor's total blood volume, total plasma volume, and any of the additional donor-specific information required by the methodology used to determine the target volume of harvestable plasma that may be collected (e.g., the donor's sex, height, and age).

Preferably, the system administrator will initially set an indication of whether the target collection volume of the plasma product, TVPP, is determined by the system (e.g., according to one of the methods described above) or is entered directly into the system by the operator. If the operator enters the TVPP, the system administrator will disable the ability of the controller to calculate the TVPP. The system administrator will also set the AC ratio to be used for all procedures. If the controller determines the TVPP, the administrator will set the system so that appropriate donor-specific characteristics are entered into the controller by the operator or the donor management system for calculating the TVPP according to any of the methods described above, thereby allowing donor parameters used for eligibility screening (e.g., weight, height, and hematocrit) to be transmitted electronically to the device, thereby avoiding operator error in entering donor parameters. The donor management system may also utilize the donor screening measurements, along with the relationship between the pure plasma volume and the collection volume, to automatically calculate the TVPP to be transmitted to the controller of the plasmapheresis device. Otherwise, the controller will calculate the TVPP prior to initiating collection of whole blood from the donor. Additionally, if the controller/donor management system calculates the TVPP, the administrator will configure the system to allow the operator to enter a TVPP other than the calculated volume. Additionally, the system will allow the operator to change the TVPP from the calculated TVPP prior to or during the procedure, for example, if the estimated time to perform/complete the procedure needs to be shortened due to donor comfort or convenience reasons. Upon completion of the procedure, the actual volume of plasma product collected, VPP, and target volume, TVPP, as well as the actual volume of pure plasma collected and target volume of plasma, TPV, will be displayed.

As mentioned above, the plasmapheresis procedure may be performed as multiple cycles of collection/draw phases and return/reinfusion phases. If the return/reinfusion phase does not include reinfusion of replacement fluid, the donor's hematocrit will increase from one cycle to the next. Consequently, if the target volume for the plasma product is determined based solely on the donor's initial hematocrit and does not take into account the donor's increasing hematocrit, the percentage of anticoagulant in the plasma product will be greater than predicted by the initial calculations for determining the target volume of the plasma product (and the volume of pure plasma will be less). Therefore, to ensure that the volume of plasma product collected contains the maximum volume of source plasma determined to be withdrawn from a particular donor, the target volume for the plasma product is recalculated periodically throughout the plasmapheresis procedure, such as prior to the start of the collection phase of each cycle, to account for variations in the donor's hematocrit.

Therefore, after a target volume for the plasma product based on the starting hematocrit of the donor has been determined, the plasmapheresis procedure begins with a first withdrawal phase in which a specific volume of whole blood (e.g., approximately 500 mL) is withdrawn from the donor. An anticoagulant is added to the whole blood and the anticoagulated whole blood is separated into plasma product, red blood cells and other non-RBC blood components. At the end of the first withdrawal phase, the red blood cells and non-RBC blood components are returned to the donor. The current volume of plasma product collected after the first withdrawal phase is determined, for example, by a weighing scale. The current value for the donor's hematocrit is then established, a new target volume of plasma product to be collected is determined, and a second cycle of withdrawal and return phases is performed. The cycle of draw phases and return phases is repeated until the target volume of plasma product for the plasmapheresis procedure is collected, as recalculated prior to the start of each draw phase. After the final collection phase, the controller initiates the final red blood cell reinfusion phase, after which the donor is disconnected.

The advantages of performing a plasmapheresis procedure with multiple collection/reinfusion cycles according to the method described above may be seen with reference to the tables in FIGS. 10 and 11a, 11b. FIG. 10 displays input data for a hypothetical plasmapheresis procedure for a donor weighing 190 lbs (86.4 kg) and having an initial hematocrit of 44. Referring to the table in FIG. 1, the simplified FDA nomogram would limit the volume of plasma that could be collected from such a donor to 800 mL, and the total collection volume for plasma products to 880 mL. In this example, the FDA nomogram limits for the volume of source plasma that may be collected are for illustrative purposes only. As noted above, other methodologies may be used to determine the amount of source plasma that may be safely extracted from a donor that differs from that indicated by the FDA nomogram.

The number of collection and reinfusion cycles in a plasmapheresis procedure may vary from 3 to 12. In a hypothetical plasmapheresis procedure, there are five collection and reinfusion cycles selected for illustrative purposes.

Prior to initiation of the first collection cycle, the volume of source plasma to be collected and the total target volume of plasma product to be collected are determined based on the initial hematocrit of the donor, according to the methodology described above. As shown in the first row of the table (start of Cycle 1), the initial target volume for the plasma product to be collected is 889 mL, which is the same as that shown in the table of FIG. 9 for a donor weighing 175 lbs. or more and having a hematocrit of 44 to harvest the FDA limit of 800 mL of source plasma from the donor.

During each collection phase, 500 mL of whole blood is withdrawn from the donor, to which an anticoagulant is added in a predetermined ratio (i.e., 1:16), 31 mL being added during each 500 mL collection cycle. The whole blood plus anticoagulant is separated into a plasma fraction and a red blood cell fraction.

During the first return phase (end of cycle 1 return), the red blood cells and "non-RBC" blood components are returned to the donor, such that at the end of the first return cycle, the donor's hematocrit has increased to 45.6% as calculated by the controller based on the reduced blood volume by the amount of source plasma collected, while the amount of red blood cells in the total blood volume remains the same as at the start of the procedure. The controller may also consider the volume of anticoagulant reinfused with the red blood cells in each return phase, as well as any residual anticoagulant in the donor's whole blood withdrawn in cycle 2 and subsequent cycles, when determining a new hematocrit value for the next cycle. The volume of source plasma and the total target volume of plasma product to be collected for the procedure are then recalculated based on the new, increased hematocrit of the donor and the source plasma volume. This provides a new total target collection volume of 891 mL.

Subsequently, a second collection phase was performed, collecting a total of 430 mL of plasma product containing 386 mL of source plasma over the first two collection phases (end of cycle 2 withdrawal). The red blood cells and “non-RBC” blood components were returned back to the donor, after which the donor’s hematocrit was calculated to be 47.2%.

Two or more collection phases of 500 mL each are performed, followed by a return phase, wherein new values for the volume of source plasma and the total volume of plasma product to be collected are determined prior to the start of each collection phase. As the donor's hematocrit increases, the recalculated target collection volume for the procedure is increased to 893 mL (for the third collection phase) and then to 894 mL (for the fourth collection phase). A fifth "mini" collection cycle is performed to bring the volume of source plasma collected to 800 mL, which is acceptable by the FDA nomogram for the hypothetical donor. The recalculated target collection volume of plasma product for the fifth collection phase remains at 894 mL.

Thus, when the target collection volume for the plasma product is recalculated for each collection phase as illustrated in the above example, a target collection volume for plasma product of 894 mL is obtained which is required to collect the target volume of 800 mL of source plasma. Conversely, if the target collection volume is determined solely based on the donor's initial hematocrit, 889 mL of plasma product would have been collected, and if the target collection volume is based on the simplified FDA nomogram, 880 mL would have been collected. In both cases, less than the target volume of 800 mL would have been collected.

The greater the accuracy with which a donor's hematocrit can be determined before and during the procedure, the more likely it is that the target volume of plasma product collected will encompass the maximum volume of source plasma that can be collected for a particular donor. As described above, donor hematocrit during the procedure is based on the assumption that 100% of the red blood cells withdrawn in each withdrawal cycle are reinfused in each return cycle, along with the volume of anticoagulant and 100% of the non-red blood cell product. However, it has been determined that during the course of a blood separation procedure, interstitial fluid shifts into the intravascular space, which can restore as much as half of the volume withdrawn. See Saito et al., Interstitial fluid shifts to plasma compartment during blood donation , Transfusion 2013; 53(11):2744-50 . The shifted interstitial fluid is in addition to the red blood cells, non-RBC cell product, and anticoagulant that are reinfused in each return phase. Therefore, taking into account the shift in interstitial fluid will lead to more accurate hematocrit determinations and therefore more accurate determination of target volumes for plasma preparations that will result in the maximum amount of source plasma.

Interstitial fluid shifts during plasmapheresis have been demonstrated by tracking donor immunoglobulin G (IgG) levels over the course of the plasmapheresis procedure. See, e.g., Burkhardt et al., Immunoglobulin G levels during collection of large volume plasma for fractionation ; Transfusion 2017; 56:417-420. In the absence of interstitial fluid shifts, donor IgG levels would remain stable over the course of the plasmapheresis procedure. However, IgG levels have been shown to decline, and the amount by which IgG levels decline is a function of the volume of interstitial fluid shifted into the blood system.

Referring to Figure 12, an experimentally developed plot of collected plasma volume (along the X-axis) versus IgG concentration (along the Y-axis) is shown. A 9% drop in donor IgG is observed from a baseline of zero plasma collected (at the start of the procedure) to 200 mL of plasma collected, and an additional 4% drop from 200 mL to 800 mL collected. This was attributed to a shift in interstitial fluid equal to approximately 9% of the donor's initial total blood volume (after 200 mL of plasma was collected) to approximately 13% of the donor's initial total blood volume (after 800 mL of plasma was collected).

The following relationship holds between the donor's IgG concentration and the volume of plasma collected: y = 1.0017x ^-0.02 , where y = IgG concentration and x = volume of plasma collected. Therefore, the percentage of the donor's blood volume that is replaced by the shift of interstitial fluid is equal to V _b (1-y), where V _b is the initial volume of the donor's whole blood. Thus, the shifted volume of interstitial fluid can be calculated based on the volume of plasma collected, and this amount can be added to the volume of the reinfused red blood cells, non-RBC cell preparation, and anticoagulant in each return phase to determine the donor's current total blood volume, and therefore hematocrit. As can be appreciated, the controller can be configured to automatically determine the shifted volume of interstitial fluid based on the volume of plasma collected, and to include the shifted volume when determining the donor's hematocrit prior to each withdrawal phase.

Alternatively, other methods of directly measuring the donor's hematocrit may be used, such as an optical sensor or, if a centrifuge is used, measuring the volume of red blood cells within the centrifuge.

Additionally, the anticoagulant may be introduced into the disposable kit prior to initiation of the plasmapheresis procedure, such as during pre-processing steps such as priming the disposable kit, performing one or more pre-cycles, or performing other pre-procedure steps. To the extent that the anticoagulant used for these purposes is ultimately directed to the plasma product collection vessel, it may be taken into account in determining the volume contained within the plasma collection vessel that will allow the target volume of source plasma to be collected. This may be accomplished, for example, by measuring the weight of a "full" container of anticoagulant and the weight of the container of anticoagulant prior to the start of the first withdrawal cycle, and adding the volume of anticoagulant to the target volume of plasma product. The controller may be configured to automatically perform the steps necessary to take into account anticoagulant introduced into the plasma collection vessel separately from the anticoagulated plasma.

The methods and systems presented above have several aspects. In a first aspect, a method of collecting plasma is provided, wherein a plasma product is collected in a plurality of collection phases, and red blood cells separated between the plurality of collection phases are reinfused into a donor. The method of the first aspect comprises the steps of: a) determining a volume of whole blood (V _b ) and a hematocrit (Hct) for the donor; b) determining a volume of source plasma (V _RP ) that may be collected from the donor; c) determining a volume of plasma product (V _PP ) that may be collected, the plasma product comprising the volume of source plasma plus a volume of an anticoagulant; d) withdrawing whole blood from the donor; e) introducing an anticoagulant to the withdrawn whole blood at a specified ratio (ACR); f) separating the withdrawn whole blood into a second component comprising a plasma product and red blood cells; g) collecting the plasma product into a plasma collection vessel; h) returning red blood cells to the donor after the desired amount of whole blood has been withdrawn from the donor; and i) determining the Hct and V _PP of the donor prior to each collection phase.

In a second embodiment, steps d) to i) are continued until the measured volume of plasma product within the collection vessel is equal to V _PP .

In a third aspect, a method of collecting plasma is provided, wherein the plasma product is collected in a plurality of collection phases, and red blood cells separated between the plurality of collection phases are reinfused into the donor. The method of the second aspect comprises: a) determining a total whole blood volume V _b and a hematocrit for the donor; b) determining a volume of source plasma (V _RP ) that may be collected from the donor based on V _b ; c) V _AC = V _RP * (ACR * (1-Hct)); d) determining a volume of plasma product (V _PP ) that may be collected _, the plasma product comprising a volume of source plasma (V _RP ) plus a volume of anticoagulant (V _AC ); e) withdrawing whole blood from the donor; f) introducing an anticoagulant into the withdrawn whole blood at a specified ratio ( _ACR ); g) separating the withdrawn whole blood into a second component comprising a plasma product and red blood cells; h) collecting the plasma product into a plasma collection vessel; i) after the desired amount of whole blood has been withdrawn from the donor, returning the red blood cells to the donor; and j) determining V _PP and the Hct of the donor prior to each collection phase.

In a fourth embodiment, steps d) to j) are continued until the measured volume of plasma product within the collection vessel is equal to V _PP .

In a fifth aspect, V _b is determined based on one or more donor specific characteristics including donor weight, height, sex, age and morphology.

In a sixth aspect, a method is provided for collecting a volume of plasma product (V _PP ) in an apheresis procedure in which the plasma product is collected in a plurality of collection phases, wherein the separated red blood cells between the plurality of collection phases are reinfused into the donor. In the method of the fourth aspect, V _PP is equal to the volume of raw plasma (V _RP ) that may be collected from the donor plus the volume of anticoagulant (V _AC ) added to the V _RP during the apheresis procedure. The method comprises the steps of: a) determining the body weight (W _kg ) and sex (M or F) of the donor; b) determining the hematocrit (Hct) of the donor; c) determining the volume of raw plasma (V _RP ) that may be collected based on the body weight (W _kg ) and sex (M or F) of the donor; d) determining the ratio K between V _PP and V _RP such that K = V _PP /V _RP based on the Hct and anticoagulant ratio (ACR) of the donor; e) V _PP = V _RP *K; determining V _PP such that; f) withdrawing whole blood from a donor; g) introducing an anticoagulant into the withdrawn whole blood at a specified ratio (ACR); h) separating the withdrawn whole blood into a second component comprising a plasma product and red blood cells; i) collecting the plasma product into a plasma collection vessel; j) after the desired amount of whole blood has been withdrawn from the donor, returning the red blood cells to the donor; and k) determining a target V _PP and a Hct of the donor prior to each collection phase.

In a seventh aspect, steps c) to k) are repeated until the measured volume of plasma product within the collection vessel is equal to V _PP . Preferably, K = V _PP /V _RP = (ACR*(1-Hct/100) +1)/(ACR*(1-HCT/100)).

In an eighth aspect, a method is provided for collecting a volume of plasma product (V _PP ) in an apheresis procedure in which the plasma product is collected in a plurality of collection phases, wherein the separated red blood cells between the plurality of collection phases are reinfused into the donor. In the method of the fifth aspect, V _PP is equal to the volume of raw plasma (V _RP ) that may be collected from the donor plus the volume of anticoagulant (V _AC ) added to the V _RP during the apheresis procedure. The steps of the method are: a) determining the body weight (W _kg ) and sex (M or F) of the donor; b) determining the hematocrit (Hct) of the donor; c) determining the volume of raw plasma (V _RP ) that may be collected based on the body weight (W _kg ) and sex (M or F) of the donor; d) adding the V _AC based on the Hct and anticoagulant ratio (ACR) of the donor. = V _RP * (ACR * (1-Hct)) Step of determining V _AC to be added to V _RP ; e) V _PP = V _RP + V _AC ; f) withdrawing whole blood from a _donor ; g) introducing an anticoagulant into the withdrawn whole blood at a specified ratio (ACR); h) separating the withdrawn whole blood into a second component comprising a plasma product and red blood cells; i) collecting the plasma product into a plasma collection vessel; j) after the desired amount of whole blood has been withdrawn from the donor, returning the red blood cells to the donor; and k) determining V _PP and Hct of the donor prior to each collection phase.

In a ninth aspect, steps d) to k) are continued until the measured volume of plasma product within the collection vessel is equal to V _PP .

In the tenth aspect, V _RP V _RP for each of the multiple ranges of donor body weight Establish the V _RP for a range of weights that includes the donor's weight. is determined by selecting the donor weight. Donor weight can range from 110 to 149 lbs., 150 to 174 lbs., and 175 lbs. and above in three categories.

In the 11th aspect, V _RP = K ₁ * W _kg .

In the 12th aspect, V _RP is less than or equal to 28.6% of (1-Hct)*(V _b ).

In the 13th aspect, V _b is determined using one of Nadler's equations, Gilcher's five rules, the standards of ICSH, or any other generally accepted methodologies.

In the 14th aspect, V _RP = W _kg * 10 mL/kg.

In aspect 15, when donor parameters are used to estimate the total blood volume (V _b ) for the donor, V _RP = K ₂ * V _b .

In a sixteenth aspect, an automated system for separating plasma from whole blood is provided, comprising reusable hardware components and a disposable kit. The disposable kit comprises: i) a separator for separating whole blood into a plasma fraction and a concentrated cell fraction, the separator having an input, the input having a blood line integrally connected to a whole blood line for transporting whole blood from a donor to the separator; a plasma outlet port integrally connected by the plasma line to a plasma collection vessel, and a concentrated cell outlet port integrally connected to a reservoir for receiving the concentrated cells prior to reinfusion into the donor; ii) a donor line terminating in a venipuncture needle for transporting whole blood from the donor to the blood line; iii) an anticoagulant line integrally connected to the blood line and configured to be connected to a source of anticoagulant for transporting an anticoagulant to the donor line; iv) a saline line configured to be attached to a source of saline for transporting saline to the blood line; and v) additionally comprising a reinfusion line for transporting concentrated cells from the reservoir to the donor line. The reusable hardware components further include a programmable controller including i) a first peristaltic pump for delivering an anticoagulant into the blood line at a controlled rate during the collection phase, ii) a second pump for delivering anticoagulated whole blood to a separator during the collection phase and returning concentrated cellular components during the reinfusion phase, iii) a third pump for delivering the concentrated cellular components from the separator to a reservoir during the collection phase, iv) clamps associated with each of the blood line, the plasma line and the reinfusion line, v) weight scales for weighing each of the plasma collection vessels, the reservoirs and the sources of anticoagulant, and vi) a touch screen for receiving input from an operator, wherein the programmable controller is configured to receive signals from each of the weight scales and to automatically operate the first, second and third pumps and clamps to separate the whole blood into a plasma fraction and a concentrated cell fraction during the collection phase and to return the concentrated cells to the donor during the reinfusion stage. The programmable controller is further configured to determine a weight of a plasma fraction to be collected in the plasma collection vessel according to any aspect described herein, and to terminate the collection phase upon receiving a signal from a weight scale for the plasma collection vessel that is equal to the weight of the plasma fraction determined by the controller. In determining the target amount of plasma product to be collected, the controller may be configured to calculate a hematocrit of the donor prior to the collection phase of each cycle. Alternatively or additionally, the controller may receive a signal indicative of the hematocrit of the donor, such as from a sensor. Additionally, the amount of plasma product within the plasma collection vessel may be determined, for example, by a weight scale associated with the plasma collection. In one embodiment, the separator comprises a spinning membrane separator.

It will be appreciated that the described embodiments are illustrative of some of the applications of the principles of the present subject matter. Many modifications may be made by those skilled in the art without departing from the spirit and scope of the claimed subject matter, including combinations of features individually disclosed or claimed herein. For this reason, the scope of the claims is not limited to the above description, but is set forth in the following claims.

Claims (29)

A system for collecting plasma from a donor,
A blood separator for separating whole blood from said donor into a first blood component comprising plasma products and a second blood component comprising red blood cells;
A donor line for introducing whole blood from said donor into said blood separator;
An anticoagulant line coupled to an anticoagulant source to combine the above whole blood and anticoagulant;
a touch screen for receiving input from the operator; and
Includes a programmable controller,
The above programmable controller:
The system is configured to control the system to operate a withdrawal and return cycle to determine a target volume (TVPP) of plasma product to be collected based on the weight of the donor, or based on the weight and height of the donor, a percentage of anticoagulant in the target volume of plasma product to be collected (%AC _TVPP ) based on the hematocrit (Hct) of the donor and a predetermined anticoagulant ratio (ACR), withdraw whole blood from the donor, add an anticoagulant to the whole blood at the predetermined ratio (ACR), separate the anticoagulated whole blood into the plasma product and the second blood component, and return the second blood component to the donor, and stop withdrawing whole blood from the donor and initiate a final return of the second blood component when the measured volume of plasma product within the plasma collection vessel reaches the target volume (TVPP) for the plasma product, wherein the controller further comprises: i) A system for collecting plasma from a donor, wherein the controller is further programmed to calculate a target volume of pure plasma (TVP) to be collected from said body weight of the donor and ii) a percentage of said anticoagulant in said target volume of said plasma product to be collected (%AC _TVPP ) based on said hematocrit (Hct) and said predetermined anticoagulant ratio (ACR) of said donor, wherein TVPP = TVP/(1 - %AC _TVPP ), and wherein the controller is further programmed to calculate the target volume of pure plasma (TVP) to be collected as a multiple of said body weight of the donor. In the first paragraph,
A system for collecting plasma from a donor, wherein the controller is further programmed to calculate a total blood volume (TBV) of the donor based on a body weight and height of the donor, a target volume of plasma (TVP) to be collected as a percentage of the TBV, and a percentage of anticoagulant in the target volume of plasma to be collected (%AC _TVPP ) based on a hematocrit (Hct) of the donor and the predetermined anticoagulant ratio (ACR), wherein TVPP = TVP/(1 - %AC _TVPP ). In the second paragraph,
The controller is further programmed to calculate total blood volume (TBV) of the donor based on the weight and height of the donor to calculate a body mass index (BMI) for the donor such that TBV = 70/sqrt(BMI/22), where BMI = Wt/Ht ^2. A system for collecting plasma from a donor. In the second paragraph,
A system for collecting plasma from a donor, wherein the controller is further programmed to ^calculate the total blood volume (TBV) of the donor based on the weight (Wt), height (Ht) and gender (male or female) of the donor such that for a male TBV = (0.3669 * Ht ³ ) + (0.03219 * Wt) + 0.6041 and for a female TBV = (0.3561 * Ht 3 ) + (0.03308 * Wt) + 0.1833, wherein Ht is in meters and Wt is in kilograms. In the first paragraph,
A system for collecting plasma from a donor, wherein ACR is the ratio of the amount of whole blood to the amount of anticoagulant (ACR = WB/AC), and the controller is further configured to determine the percentage of anticoagulant in the target volume of the plasma product (%AC _TVPP ) such that %AC _TVPP = 1/(1 + ACR(1-Hct)). In paragraph 1,
A system for collecting plasma from a donor, wherein ACR is the ratio of the volume of whole blood plus the volume of said anticoagulant to the volume of said anticoagulant (ACR = (WB + AC)/AC), and the controller is further configured to determine the percentage of said anticoagulant in the target volume of said plasma product (%AC _TVPP ) such that %AC _TVPP = 1/(1 + (ACR-1)(1- Hct)). A method of operating a system for collecting a target volume of plasma product (TVPP) from a donor, comprising:
TVPP includes the target volume of pure plasma (TVP) plus the volume of anticoagulant,
The above system:
A blood separator for separating whole blood from said donor into a first blood component comprising plasma products and a second blood component comprising red blood cells;
A donor line for introducing whole blood from said donor into said blood separator;
An anticoagulant line coupled to an anticoagulant source to combine the above whole blood and anticoagulant;
a touch screen for receiving input from the operator; and
Includes a programmable controller,
The above method is:
a) first calculating the target volume of pure plasma (TVP) to be collected from the donor as a multiple of the body weight of the donor, and determining the percentage of anticoagulant in the TVPP (%AC _TVPP ) such that TVPP = TVP/(1-%AC _TVPP ), wherein %AC _TVPP is based on the hematocrit (Hct) and anticoagulant ratio (ACR) of the donor, thereby determining the TVPP;
b) withdraw whole blood from said donor;
c) mixing an anticoagulant with the whole blood at the anticoagulant ratio (ACR);
d) separating the anticoagulated whole blood into plasma products, red blood cells and other cellular components;
e) collecting said plasma product into a container;
f) determining the volume (VPP) of the plasma product within the vessel; and
g) a method of operating a system for collecting a target volume (TVPP) of plasma product from a donor, comprising the step of operating the programmable controller to stop withdrawal of whole blood from the donor and return the red blood cells and other cellular components to the donor when VPP = TVPP. In paragraph 7,
Further comprising the step of operating the programmable controller to determine the percentage (%AC _TVPP ) of the anticoagulant in the target volume of the plasma preparation such that %AC _TVPP = 1/(1 + ACR(1-Hct)),
A method of operation of a system for collecting a target volume of plasma product (TVPP) from a donor, wherein ACR is the ratio of the amount of said whole blood to the amount of said anticoagulant (ACR = WB/AC). In paragraph 7,
A method of operating a system for collecting a target volume ( _TVPP ) of plasma product from a donor, further comprising the step of operating the programmable controller to determine a percentage (%AC _TVPP ) of the anticoagulant in the target volume of the plasma product such that %AC TVPP = 1/(1 + (ACR-1)(1- Hct)), wherein ACR is a ratio of the volume of whole blood plus the volume of anticoagulant to the volume of the anticoagulant (ACR = (WB + AC)/AC). In paragraph 7,
A method of operating a system for collecting a target volume (TVPP) of plasma product from a donor, comprising: collecting a target volume (TVPP) of plasma product in a plurality of cycles, each cycle including a collection phase in which whole blood is withdrawn from the donor and a return phase in which the red blood cells and other cellular components are returned to the donor; further comprising: determining a hematocrit (Hct) of the donor prior to the collection phase of each cycle, and operating the programmable controller to recalculate the target volume (TVPP) of plasma product to be collected based on the hematocrit (Hct) of the donor determined prior to the collection phase of each cycle. As a system for collecting plasma,
A blood separator for separating whole blood from a donor into a first blood component comprising a plasma product and a second blood component comprising red blood cells, the blood separator having a plasma outlet port coupled to a plasma line configured to direct the plasma product to a plasma product collection vessel;
A donor line configured to introduce said whole blood from said donor into said blood separator;
An anticoagulant line coupled to an anticoagulant supply source, said anticoagulant line configured to combine an anticoagulant with said whole blood from said donor;
a touch screen configured to receive input from an operator; and
comprising a controller programmed to control the operation of said system;
The above controller:
Receiving the weight, height, and hematocrit of a donor, and determining a target volume of plasma product to be collected (TVPP), comprising pure plasma and an anticoagulant, based on the weight of the donor, or based on the weight and height of the donor, and determining a percentage of anticoagulant in the target volume of plasma product to be collected (%AC _TVPP ) based on the hematocrit (Hct) of the donor and a predetermined anticoagulant ratio (ACR),
Control the system to operate a withdrawal and return cycle to withdraw whole blood from said donor, add an anticoagulant to said whole blood at said predetermined ratio (ACR), separate said anticoagulated whole blood into said plasma product and said second blood component, and return said second blood component to said donor, and stop withdrawing whole blood from said donor and initiate final return of said second blood component when a measured volume of plasma product within the plasma collection vessel reaches said target volume for plasma product (TVPP).
Programmed,
The controller is further programmed to calculate a total blood volume (TBV) of the donor based on the body weight and height of the donor, a target volume of plasma (TVP) to be collected as a percentage of the TBV, and a percentage of the anticoagulant in the target volume of the plasma product to be collected (%AC _TVPP ) based on the hematocrit (Hct) of the donor and the predetermined anticoagulant ratio (ACR), wherein TVPP = TVP/(1 - %AC _TVPP ). In Article 11,
A system for collecting plasma, wherein the controller is further programmed to calculate i) a target volume of plasma to be collected (TVP) based on the body weight of the donor and ii) a percentage of anticoagulant in the target volume of the plasma to be collected (%AC _TVPP ) based on the hematocrit (Hct) and the predetermined anticoagulant ratio (ACR) of the donor, wherein TVPP = TVP/(1 - %AC _TVPP ). In Article 12,
A system for collecting plasma, wherein said controller is further programmed to calculate a target volume of pure plasma (TVP) to be collected as a multiple of said body weight of said donor. In Article 12,
A system for collecting plasma, wherein the controller is programmed to repeat the withdrawal and return phases until the target volume of the plasma product to be collected is collected, wherein the target volume of the pure plasma to be collected is re-determined prior to the start of each withdrawal phase. In Article 11,
The controller is further programmed to calculate a total blood volume (TBV) of the donor based on the body weight and height of the donor, a target volume of plasma (TVP) to be collected as a percentage of the TBV, a percentage of the anticoagulant in the target volume of plasma product to be collected (%AC _TVPP ) based on the hematocrit (Hct) of the donor and the predetermined anticoagulant ratio (ACR), wherein TVPP = TVP/(1 - %AC _TVPP ). In Article 15,
The controller is further programmed to calculate total blood volume (TBV) of the donor based on the weight and height of the donor to calculate a body mass index (BMI) for the donor such that TBV = 70/sqrt(BMI/22), where BMI = Wt/Ht ² . In Article 15,
^The system for collecting plasma is further programmed to calculate the total blood volume (TBV) of the donor based on the weight (Wt), height (Ht) and gender (male or female) of the donor such that for male TBV = (0.3669 * Ht ^{3 ) + (0.03219 * Wt) + 0.6041 and for female TBV = (0.3561 * Ht 3} ) + (0.03308 * Wt) + 0.1833, wherein Ht is in meters and Wt is in kilograms. In Article 11,
A system for collecting plasma, wherein ACR is the ratio of the amount of whole blood to the amount of anticoagulant (ACR = WB/AC), and the controller is further configured to determine the percentage of anticoagulant in the target volume of the plasma product (%AC _TVPP ) such that %AC _TVPP = 1/(1 + ACR(1-Hct)). In Article 11,
A system for collecting plasma, wherein ACR is a ratio of the volume of whole blood plus the volume of said anticoagulant to the volume of said anticoagulant (ACR = (WB + AC)/AC), and the controller is further configured to determine the percentage of said anticoagulant in the target volume of said plasma product (%AC _TVPP ) such that %AC _TVPP = 1/(1 + (ACR-1)(1- Hct)). In Article 11,
A system for collecting plasma, wherein the controller is programmed to initiate final return of the second blood component when the volume of plasma product within the plasma collection vessel reaches a target volume of plasma product. In Article 11,
A system for collecting plasma, wherein the controller is programmed to electronically receive donor parameters from a donor management system to determine a target volume for the plasma product based at least in part on the donor parameters. In Article 21,
A system for collecting plasma, wherein the donor management system is programmed to calculate a target volume for the plasma product, and the controller is programmed to determine the target volume for the pure plasma by receiving the target volume for the pure plasma from the donor management system. In Article 11,
A system for collecting plasma, wherein said controller is programmed to determine said target volume for the plasma product prior to withdrawing said whole blood from said donor. In Article 11,
A system for collecting plasma, wherein said controller is further programmed to take into account an anticoagulant introduced into said plasma collection vessel separately from said plasma product. A system for collecting plasma from a donor,
A blood separator for separating whole blood from said donor into a first blood component comprising plasma products and a second blood component comprising red blood cells;
A donor line for introducing whole blood from said donor into said blood separator;
An anticoagulant line coupled to an anticoagulant source for combining the anticoagulant with said whole blood;
a touch screen for receiving input from the operator; and
Includes a programmable controller,
The above programmable controller:
Based on the body weight of the donor, or based on the body weight and height of the donor, a target volume of plasma product to be collected (TVPP) is determined, and based on the hematocrit (Hct) and the predetermined anticoagulant ratio (ACR) of the donor, a percentage of anticoagulant in the target volume of plasma product to be collected (%AC _TVPP ) is determined.
Control the system to operate a withdrawal and return cycle to withdraw whole blood from said donor, add an anticoagulant to said whole blood at a predetermined ratio (ACR) to said whole blood, separate said anticoagulated whole blood into said plasma product and said second blood component, return said second blood component to said donor, and stop withdrawing whole blood from said donor and initiate final return of said second blood component when a measured volume of plasma product within the plasma collection vessel reaches said target volume for plasma product (TVPP).
Composed of,
The controller is further programmed to calculate a total blood volume (TBV) of the donor based on a body weight and height of the donor, a target volume of plasma to be collected (TVP) as a percentage of the TBV, and a percentage of anticoagulant in the target volume of the plasma product to be collected (%AC _{TVPP) based on the hematocrit (Hct) of the donor and the predetermined anticoagulant ratio (ACR), wherein TVPP = TVP/(1 - %AC TVPP )} . In Article 25,
The controller is further programmed to calculate total blood volume (TBV) of the donor based on the weight and height of the donor to calculate a body mass index (BMI) for the donor such that TBV = 70/sqrt(BMI/22), where BMI = Wt/Ht ^2. A system for collecting plasma from a donor. In Article 25,
A system for collecting plasma from a donor, wherein ACR is the ratio of the amount of whole blood to the amount of anticoagulant (ACR = WB/AC), and the controller is further configured to determine the percentage of anticoagulant in the target volume of the plasma product (%AC _TVPP ) such that %AC _TVPP = 1/(1 + ACR(1-Hct)). In Article 25,
A system for collecting plasma from a donor, wherein ACR is the ratio of the volume of whole blood plus the volume of said anticoagulant to the volume of said anticoagulant (ACR = (WB + AC)/AC), and the controller is further configured to determine the percentage of said anticoagulant in the target volume of said plasma product (%AC _TVPP ) such that %AC _TVPP = 1/(1 + (ACR-1)(1- Hct)). In Article 25,
A system for collecting plasma from a donor, wherein the controller is further programmed to ^calculate the total blood volume (TBV) of the donor based on the weight (Wt), height (Ht) and gender (male or female) of the donor such that for a male TBV = (0.3669 * Ht ³ ) + (0.03219 * Wt) + 0.6041 and for a female TBV = (0.3561 * Ht 3 ) + (0.03308 * Wt) + 0.1833, wherein Ht is in meters and Wt is in kilograms.

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