Source: http://www.google.com/patents/US8158341?dq=6,998,619
Timestamp: 2014-09-18 02:26:02
Document Index: 164616331

Matched Legal Cases: ['Application No. 90', 'Application No. 90', 'Application No. 90', 'Application No. 90', 'Application No. 90', 'Application No. 90']

Patent US8158341 - Efficient algorithm for PCR testing of blood samples - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign in<nobr>Advanced Patent Search</nobr>PatentsA method is provided for identifying viral positive biological fluid donations in the fewest number of test cycles. The method comprises providing biological fluid donations and defining an n-dimensional matrix comprising a multiplicity of elements, each element being identified by a matrix notation...http://www.google.com/patents/US8158341?utm_source=gb-gplus-sharePatent US8158341 - Efficient algorithm for PCR testing of blood samplesAdvanced Patent SearchPublication numberUS8158341 B2Publication typeGrantApplication numberUS 11/374,484Publication dateApr 17, 2012Filing dateMar 9, 2006Priority dateApr 10, 1995Also published asCA2276570A1, CA2276570C, CN1246158A, CN100354431C, DE69840358D1, EP0975810A1, EP0975810A4, EP0975810B1, US5780222, US6063563, US6566052, US20030204321, US20060136148, US20060160073, US20090263788, WO1998030723A1Publication number11374484, 374484, US 8158341 B2, US 8158341B2, US-B2-8158341, US8158341 B2, US8158341B2InventorsLorraine B. Peddada, Charles M. Heldebrant, Andrew J. Conrad, Peter SchmidOriginal AssigneeBaxter International Inc.Export CitationBiBTeX, EndNote, RefManPatent Citations (30), Non-Patent Citations (150), Classifications (21), Legal Events (1) External Links: USPTO, USPTO Assignment, EspacenetEfficient algorithm for PCR testing of blood samplesUS 8158341 B2Abstract A method is provided for identifying viral positive biological fluid donations in the fewest number of test cycles. The method comprises providing biological fluid donations and defining an n-dimensional matrix comprising a multiplicity of elements, each element being identified by a matrix notation comprising an index for each dimension of the array. Samples are taken from each fluid donation and mapped to a matrix element with each sample identified by its corresponding element's notation; n aliquots being taken from each sample and subpools formed from the aliquots with each subpool containing an aliquot from all samples mapped to elements in which one of the dimensional indices is fixed. Subpools are tested for viral indication and the dimensional index of each subpool that returns a positive viral indication is determined. The dimensional indices are combined to identify a subset of matrix elements that contain a viral positive sample.
1. A method for identifying viral positive biological fluid donations in the fewest number of high-sensitivity test cycles, the method comprising:
(a) providing a multiplicity of biological fluid donations;
(b) taking a single aliquot from each of the multiplicity of fluid donations and combining said aliquots into a single master pool;
(c) testing the master pool for viral indication using a high-sensitivity PCR test;
(d) providing an indication to a user as to whether the master pool contains a viral positive sample;
(e) where the master pool is found to contain a viral positive sample, defining an n-dimensional matrix, where n is an integer 2 or higher, the matrix comprising a multiplicity of elements, each individual element identified by a unique matrix notation, the matrix notation comprising at least a separate dimensional index for each dimension of the array;
(f) taking a sample from each of the multiplicity of biological fluid donations; (g) mapping each sample to one of said multiplicity of elements of the matrix, each individual sample identified by its corresponding element's respective matrix notation;
(h) taking at least n aliquots from each sample;
(i) forming from the at least n aliquots of each sample one unique subpool for each group of elements having matrix notations with one common dimensional index, each of the subpools containing sample aliquots taken exclusively from samples mapped to elements in which one of the dimensional indices is fixed;
(j) testing all of the subpools for viral indication using a high-sensitivity PCR test;
(k) determining the fixed dimensional index of each subpool that returns a positive viral indication;
(l) combining said fixed dimensional indices to identify a subset of matrix elements that contain a viral positive sample, thereby reducing the number of elements that may contain a viral positive sample;
(m) providing an indication to a user as to the identities of the subset of matrix elements that may contain a viral positive sample; and
(n) where positive indications are provided in more than one subpool in more than one dimensional index of the matrix then directly testing each of the potentially positive samples with a high-sensitivity PCR test to detect the presence of the viral contamination, and producing a positive indication when the sample containing the presence of the viral contamination is detected.
2. The method according to claim 1 wherein n is 3, and the matrix is subdivided into rows, columns, and layers, wherein each element is characterized by a matrix notation Xrcs, where the dimensional indices r, c, and s, respectively, identify elements comprising a row, a column, and a layer of the matrix.
3. The method according to claim 2, wherein the subpool formation step (f) further comprises:
forming r-subpools of aliquots from samples identified by a fixed r index but different c and s indices;
forming c-subpools of aliquots from samples identified by a fixed c index but different rand s indices;
forming s-subpools of aliquots from samples identified by a fixed s index but different rand c indices.
determining the fixed r index of each r-subpool which returned a positive viral indication;
determining the fixed c index of each c which returned a positive viral indication; and
determining the fixed s index of each s-subpool which returned a positive viral indication.
5. The method according to claim 4, further comprising the step of substituting the fixed r, c, and index of each r-, c-, and s-subpool which returned a positive viral indication for the dimensional indices r, c, and s of the matrix notation, thereby identifying a unique matrix element defined by said matrix notation, thus identifying the corresponding viral positive sample.
6. The method according to claim 1 wherein n is 2, and the matrix is subdivided into rows, and columns, wherein each element is characterized by a matrix notation Xrc where the dimensional indices r, and c, respectively, identify elements comprising a row and a column of the matrix.
7. The method according to claim 6, wherein the subpool formation step (f) further comprises:
forming r-subpools of aliquots from samples identified by a fixed r index but different c indices;
forming c-subpools of aliquots from samples identified by a fixed c index but different r indices.
determining the fixed r index of each r-subpool which returned a positive viral indication; and
determining the fixed c index of each c-subpool which returned a positive viral indication.
9. The method according to claim 8, further comprising the step of substituting the fixed r and c index of each r- and c-subpool which returned a positive viral indication for the dimensional indices r and c of the matrix notation, thereby identifying a unique matrix element defined by said matrix notation, thus identifying the corresponding viral positive sample.
10. The method according to claim 1, wherein said samples are collected concurrently with the collection of said multiplicity of biological fluid donations.
11. The method according to claim 2, wherein said samples are collected concurrently with the collection of said multiplicity of biological fluid donations.
12. The method according to claim 3, wherein said samples are collected concurrently with the collection of said multiplicity of biological fluid donations.
13. The method according to claim 4, wherein said samples are collected concurrently with the collection of said multiplicity of biological fluid donations.
14. The method according to claim 5, wherein said samples are collected concurrently with the collection of said multiplicity of biological fluid donations.
15. The method according to claim 6, wherein said samples are collected concurrently with the collection of said multiplicity of biological fluid donations.
16. The method according to claim 7, wherein said samples are collected concurrently with the collection of said multiplicity of biological fluid donations.
17. The method according to claim 8, wherein said samples are collected concurrently with the collection of said multiplicity of biological fluid donations.
18. The method according to claim 9, wherein said samples are collected concurrently with the collection of said multiplicity of biological fluid donations.
19. The method according to claim 1, wherein said samples are collected after the collection of said multiplicity of biological fluid donations.
20. The method according to claim 2, wherein said samples are collected after the collection of said multiplicity of biological fluid donations.
21. The method according to claim 3, wherein said samples are collected after the collection of said multiplicity of biological fluid donations.
22. The method according to claim 4, wherein said samples are collected after the collection of said multiplicity of biological fluid donations.
23. The method according to claim 5, wherein said samples are collected after the collection of said multiplicity of biological fluid donations.
24. The method according to claim 6, wherein said samples are collected after the collection of said multiplicity of biological fluid donations.
25. The method according to claim 7, wherein said samples are collected after the collection of said multiplicity of biological fluid donations.
26. The method according to claim 8, wherein said samples are collected after the collection of said multiplicity of biological fluid donations.
27. The method according to claim 9, wherein said samples are collected after the collection of said multiplicity of biological fluid donations.
28. The method according to claim 1, wherein said multiplicity of donations is more than 500 donations.
29. The method according to claim 2, wherein said multiplicity of donations is more than 500 donations.
30. The method according to claim 3, wherein said multiplicity of donations is more than 500 donations.
31. The method according to claim 4, wherein said multiplicity of donations is more than 500 donations.
32. The method according to claim 5, wherein said multiplicity of donations is more than 500 donations.
33. The method according to claim 6, wherein said multiplicity of donations is more than 500 donations.
34. The method according to claim 7, wherein said multiplicity of donations is more than 500 donations.
35. The method according to claim 8, wherein said multiplicity of donations is more than 500 donations.
36. The method according to claim 9, wherein said multiplicity of donations is more than 500 donations.
37. The method according to claim 1, wherein the biological fluid is blood.
38. The method according to claim 2, wherein the biological fluid is blood.
39. The method according to claim 3, wherein the biological fluid is blood.
40. The method according to claim 4, wherein the biological fluid is blood.
41. The method according to claim 5, wherein the biological fluid is blood.
42. The method according to claim 6, wherein the biological fluid is blood.
43. The method according to claim 7, wherein the biological fluid is blood.
44. The method according to claim 8, wherein the biological fluid is blood.
45. The method according to claim 9, wherein the biological fluid is blood.
46. The method according to claim 1, wherein the biological fluid is plasma.
47. The method according to claim 2, wherein the biological fluid is plasma.
48. The method according to claim 3, wherein the biological fluid is plasma.
49. The method according to claim 4, wherein the biological fluid is plasma.
50. The method according to claim 5, wherein the biological fluid is plasma.
51. The method according to claim 6, wherein the biological fluid is plasma.
52. The method according to claim 7, wherein the biological fluid is plasma.
53. The method according to claim 8, wherein the biological fluid is plasma.
54. The method according to claim 9, wherein the biological fluid is plasma.
55. The method according to claim 1, wherein the viral indication is an indication of a virus selected from the group consisting of HIV and HCV.
56. The method according to claim 2, wherein the viral indication is an indication of a virus selected from the group consisting of HIV and HCV.
57. The method according to claim 3, wherein the viral indication is an indication of a virus selected from the group consisting of HIV and HCV.
58. The method according to claim 4, wherein the viral indication is an indication of a virus selected from the group consisting of HIV and HCV.
59. The method according to claim 5, wherein the viral indication is an indication of a virus selected from the group consisting of HIV and HCV.
60. The method according to claim 6, wherein the viral indication is an indication of a virus selected from the group consisting of HIV and HCV.
61. The method according to claim 7, wherein the viral indication is an indication of a virus selected from the group consisting of HIV and HCV.
62. The method according to claim 8, wherein the viral indication is an indication of a virus selected from the group consisting of HIV and HCV.
63. The method according to claim 9, wherein the viral indication is an indication of a virus selected from the group consisting of HIV and HCV.
64. The method according claim 2, wherein the high-sensitivity test is PCR.
65. The method according claim 3, wherein the high-sensitivity test is PCR.
66. The method according claim 4, wherein the high-sensitivity test is PCR.
67. The method according claim 5, wherein the high-sensitivity test is PCR.
68. The method according to claim 1, wherein, the subset of matrix elements identifies at least one sample as a viral positive sample.
69. The method according to claim 2, wherein, the subset of matrix elements identifies at least one sample as a viral positive sample.
70. The method according to claim 3, wherein, the subset of matrix elements identifies at least one sample as a viral positive sample.
71. The method according to claim 4, wherein, the subset of matrix elements identifies at least one sample as a viral positive sample.
72. The method according to claim 5, wherein, the subset of matrix elements identifies at least one sample as a viral positive sample.
73. The method according to claim 6, wherein, the subset of matrix elements identifies at least one sample as a viral positive sample.
74. The method according to claim 7, wherein, the subset of matrix elements identifies at least one sample as a viral positive sample.
75. The method according to claim 8, wherein, the subset of matrix elements identifies at least one sample as a viral positive sample.
76. The method according to claim 9, wherein, the subset of matrix elements identifies at least one sample as a viral positive sample.
77. The method according to claim 1, wherein, the subset of matrix elements identifies a single sample as a viral positive sample.
78. The method according to claim 2, wherein, the subset of matrix elements identifies a single sample as a viral positive sample.
79. The method according to claim 3, wherein, the subset of matrix elements identifies a single sample as a viral positive sample.
80. The method according to claim 4, wherein, the subset of matrix elements identifies a single sample as a viral positive sample.
81. The method according to claim 5, wherein, the subset of matrix elements identifies a single sample as a viral positive sample.
82. The method according to claim 6, wherein, the subset of matrix elements identifies a single sample as a viral positive sample.
83. The method according to claim 7, wherein, the subset of matrix elements identifies a single sample as a viral positive sample.
84. The method according to claim 8, wherein, the subset of matrix elements identifies a single sample as a viral positive sample.
85. The method according to claim 9, wherein, the subset of matrix elements identifies a single sample as a viral positive sample.
86. The method according to claim 1, wherein, the number of indices in at least one dimension of the array is not equal to the number of indices in the other dimensions of the array.
87. The method according to claim 2, wherein, the number of indices in at least one dimension of the array is not equal to the number of indices in the other dimensions of the array.
88. The method according to claim 3, wherein, the number of indices in at least one dimension of the array is not equal to the number of indices in the other dimensions of the array.
89. The method according to claim 4, wherein, the number of indices in at least one dimension of the array is not equal to the number of indices in the other dimensions of the array.
90. The method according to claim 5, wherein, the number of indices in at least one dimension of the array is not equal to the number of indices in the other dimensions of the array.
91. The method according to claim 6, wherein, the number of indices in at least one dimension of the array is not equal to the number of indices in the other dimensions of the array.
92. The method according to claim 7, wherein, the number of indices in at least one dimension of the array is not equal to the number of indices in the other dimensions of the array.
93. The method according to claim 8, wherein, the number of indices in at least one dimension of the array is not equal to the number of indices in the other dimensions of the array.
94. The method according to claim 9, wherein, the number of indices in at least one dimension of the array is not equal to the number of indices in the other dimensions of the array. Description
CROSS-REFERENCE TO RELATED APPLICATION(S) This application is a divisional of patent application Ser. No. 10/442,780, filed May 20, 2003 now abandoned which is a divisional of patent application Ser. No. 09/549,477, filed Apr. 14, 2000, now U.S. Pat. No. 6,566,052, which is a divisional of patent application Ser. No. 09/081,926, filed May 20, 1998, now U.S. Pat. No. 6,063,563, which is a divisional of patent application Ser. No. 08/778,610, filed Jan. 6, 1997, now U.S. Pat. No. 5,780,222; which is a continuation-in-part of patent application Ser. No. 08/683,784, filed Jul. 16, 1996, now U.S. Pat. No. 5,834,660; which is a divisional of patent application Ser. No. 08/419,620, filed Apr. 10, 1995, now U.S. Pat. No. 5,591,573.
FIELD OF THE INVENTION The present invention relates generally to systems and processes for preparing and analyzing samples taken from plasma donations to uniquely identify donations which are virus contaminated. In particular, the invention relates to an apparatus and process for forming individual, separately sealed, and connected containers holding samples of the same plasma as is contained in the donation. The invention also relates to an apparatus and process for forming initial screening test pools from the containers and testing the pools for the presence of a virus in accordance with an algorithm to identify individual contaminated donations in the fewest number of testing cycles.
BACKGROUND OF INVENTION Blood, plasma, and biological fluid donation programs are essential first steps in the manufacture of pharmaceutical and blood products that improve the quality of life and that are used to save lives in a variety of traumatic situations. Such products are used for the treatment of immunologic disorders, for the treatment of hemophilia, and are also used in maintaining and restoring blood volume in surgical procedures and other treat protocols. The therapeutic uses of blood, plasma, and biological fluids require that donations of these materials be as free as possible from viral contamination. Typically, a serology test sample from each individual blood, plasma, or other fluid donation is tested for various antibodies, which are elicited in response to specific viruses, such as hepatitis C (HCV) and two forms of the human immunodeficiency virus (HIV-1 and HIV-2). In addition, the serology test sample may be tested for antigens designated for specific viruses such as hepatitis B (HBV), as well as antibodies elicited in response to such viruses. If the sample is serology positive for the presence of either specific antibodies or antigens, the donation is excluded from further use.
Whereas an antigen test for certain viruses, such as hepatitis B, is thought to be closely correlated with infectivity, antibody tests are not. It has long been known that a blood plasma donor may, in fact, be infected with a virus while testing serology negative for antibodies related to that virus. For example, a window exists between the time that a donor may become infected with a virus and the appearance of antibodies, elicited in response to that virus, in the donor's system. The time period between the first occurrence of a virus in the blood and the presence of detectable antibodies elicited in response to that virus is known as the �window period.� In the case of HIV, the average window period is approximately 22 days, while for HCV, the average window period has been estimated at approximately 98 days. Therefore, tests directed to the detection of antibodies, may give a false indication for an infected donor if performed during the window period, i.e., the period between viral infection and the production of antibodies. Moreover, even though conventional testing for HBV includes tests for both antibodies and antigens, testing by more sensitive methods have confirmed the presence of the HBV virus in samples which were negative in the HBV antigen test.
One method of testing donations, which have passed available antibody and antigen tests, in order to further ensure their freedom from incipient viral contamination, involves testing the donations by a polymerase chain reaction (PCR) method. PCR is a highly sensitive method for detecting the presence of specific DNA or RNA sequences related to a virus of interest in a biological material by amplifying the viral genome. Because the PCR test is directed to detecting the presence of an essential component of the virus itself its presence in a donor may be found almost immediately after infection. There is, theoretically therefore, no window period during which a test may give a false indication of freedom of infectivity. A suitable description of the methodology and practical application of PCR testing is contained in U.S. Pat. No. 5,176,995, the disclosure of which is expressly incorporated herein by reference.
SUMMARY OF INVENTION There is, therefore, provided in the practice of this invention a cost-effective and efficient process for preparing and testing samples from a multiplicity of blood or plasma donations to uniquely identify donations which are infected with virus as well as systems and devices for practicing the process.
In a further embodiment of the present invention, an additional process for testing a multiplicity of plasma donations to uniquely identify donations having a positive viral indication in a single PCR testing cycle includes the steps of defining an n-dimensional grid which defines internal elements at the intersections of each of the n-dimensions of the grid. A sample from each of a number of plasma donations is mapped to a corresponding element of the grid, with each sample being defined by a matrix notation, Xres, where the subscript of the matrix element notation defines dimensional indices of the grid. Aliquots are taken from each sample of each of the plasma donations and formed into subpools. Each subpool includes an aliquot of all plasma donation samples in which one of the dimensional indices is fixed. The subpools are all tested at once, in a single PCR testing cycle, and the dimensional indicia of each subpool which tests positive is evaluated in accordance with a reduction by the method of minors, thereby unambiguously identifying a unique element defined by the dimensional indicia of each positive subpool, and thus unambiguously identifying a uniquely positive sample.
FIG. 2 a is a semi-schematic perspective view of a tubing segment connected between a plasma donation bottle and sample container and including a series of linked-together Y-sites in accordance with the present invention;
FIG. 3 a is an enlarged top plan view of a portion of the tubing segment shown in FIG. 2 showing additional details of the seals which separate the pouches;
FIG. 3 b is a semi-schematic cross-sectional view of a tubing segment seal;
FIG. 4 a is a semi-schematic perspective view of a top and bottom platens of a heat sealing device provided in accordance with practice of the present invention for mounting onto a commercially available heat sealer;
FIG. 9 a is a semi-schematic partial cross-sectional view of a screen plate against which sample-containing packets are crushed;
FIG. 9 b is a semi-schematic top view of a screen plate showing radial and concenthc fluid gutters for collecting sample fluid from crushed sample containers;
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to systems, processes and devices useful for testing blood or plasma donations to detect those specific donations which have a viral contamination above a pre-determined level. Such contaminated donations are then disposed of to thereby prevent their incorporation into the raw material stream for pharmaceutical products or their transfusion into human patients. The viral detection tests used in accordance with practice of the present invention can be any that directly detect a virus instead of antibodies elicited in response to the virus. The tests include polymerase chain reaction (PCR) tests and other tests which are sufficiently sensitive to directly detect a virus even after pooling samples from multiple donations.
Turning to FIG. 1, an exemplary embodiment of a system provided in accordance with practice of the present invention for effecting the sampling process is shown. The system includes a standard plasma donation container 20, constructed of a nonreactive material such as polyvinyl chloride (PVC). The donation container 20 includes a cap 22 having two hollow elbow shaped fittings 23 and 24, respectively, attached to the top surface thereof The fittings communicate with the interior of the donation bottle through orifices provided in cap 22 for such purpose. A flexible hollow filler tube 26, constructed of a biologically neutral material, such as PVC plastic, is connected at one end to the elbow fitting 23 and connected at the other end to, for example, a needle which is inserted into a donor in order to procure a donation. In the illustrated embodiment, a test container 28, is also provided, for collecting a sample from the donation to be serology tested. The test container 28 is generally test tube shaped and is also constructed of a biologically nonreactive material. The test container 28 includes an integral cap member 30 through which orifices are provided in order to communicate with the interior of the test container.
A second orifice may also be provided in the cap member 30, to which a vent tube 34 is connected in a manner similar to tubing segment 32. The vent tube is typically no more than one to two inches in length, and is typically terminated with an inserted, friction fit bacteria excluding filter 36.
The tubing segment is sealed in a manner to provide from 5 to 15, individual and connected pouches. Sealing, to define the pouches, may be done either after the tubing segment has been removed from between the plasma donation container and the serology test container or preferably is done while the tubing segment is still attached to the plasma donation container, in order to avoid hydrostatic pressure build-up. Sealing may be done by any known method, such as thermo-compression sealing (heat sealing), sonic welding or the like, so long as the length of the region compressed and sealed is sufficient to permit the connected pouches to be separated from one another by cutting through the center of the seal without violating the integrity of the pouch on either side, as indicated more clearly in FIGS. 3 a and 3 b. A second embodiment of the tubing segment adapted to be subdivided into blood or plasma sample-containing aliquot portions is depicted in FIG. 2 a which is a semi-schematic perspective view of a collection tubing segment embodiment connected between a plasma donation bottle 20 and sample container 28 and divided into aliquot-containing portions in accordance with the present invention.
After the plasma sample from the donation is drawn into the tubing segment 50, the terminal exit tubing segment 59 is closed off by a heat seal or weld 40 a or other suitable sealing means such as a sonic weld at a suitable location along its length proximate to the terminal exit tubing segments connection to the test container 28.
The filled tubing segment 50 is removed from the test container by cutting the terminal exit tubing segment 59 away from the test container through the center of the seal 40 a. Alternatively, if the tubing segment 50 terminates in a luer-type connector, the tubing segment 50 is removed from the test container 28 by disconnecting the luer. A second heat seal 38 a is applied to the initial entry tubing segment 57 at a location along its length proximate to the initial segment's connection to the donation container 20. The filled portion of the tubing segment 50 is removed from the plasma donation by cutting the initial entry segment 57 away through the center of the seal 38 a, or by disconnecting the luer-type fitting 58, if such is provided. An elongated, hollow, articulated tube, closed off at both ends and comprising a plurality of Y-sites linked-together in series, is thus provided. Each of the linked-together Y-sites contains an aliquot of the blood or plasma donation.
As will be described in greater detail below, the tubing segments connecting a preceding Y-site's outlet port to a subsequent Y-site's branch port are also provided with heat seals 42 a to define sequential, individual, and connected sample aliquots, each suitably comprising an individual Y-site. Each such Y-site contains a particular quantity of blood or plasma needed for a specific generation pool to be formed. Sealing to isolate each Y-site may be performed either after the tubing segment 50 has been removed from the plasma donation container or may be performed while the tubing segment is still attached. Preferably, sealing to isolate the Y-sites is performed while the tubing segment 50 still attached to the plasma donation container so that the volume reduction caused flattening a portion of the tubing during the sealing process does not cause a build-up in the internal hydrostatic pressure of the sample. When the tubing segment 50 remains connected to the plasma donation container, excess fluid created by the volume reduction of the tubing created by the heat seals is allowed to be expressed back into the donation container. Excess hydrostatic pressure, which may lead to dangerous spurting during sample extraction, is thus safely relieved.
Turning now to FIGS. 3 a and 3 b, in a preferred embodiment, the seal between pouches (42 of FIG. 2) and/or Y-sites (51 of FIG. 2 a) includes a flat pad area 46, including a central narrow portion 47 through which the seal is cut or torn in order to separate the connected pouches. Cutting is done through the central portion in order to insure that each separated pouch remains sealed at compressed tab portions 48 at either end after separation. The length of the seal pad may be made greater or smaller, depending on the chosen separation method. Separation may be done by use of a scalpel, a guillotine cutter, or a simple pair of scissors.
The narrow area (47 of FIG. 3 b) through approximately the center of the seal is formed by an elongated ridge structure 67 provided down the center of the extended seal head portion 64 of the seal platens. As the tubing segment is squeezed between the upper and lower sealing heads, the ridge 67 forces an indentation on the top and bottom surface of the seal portion. The indentations narrow the plastic material comprising the center the seal, thus making it easy to separate.
Turning now to FIG. 4 a, there is depicted in semi-schematic view, a specific embodiment of a sealing device 70, useful for providing thermo-compression heat seals at uniform, spaced-apart intervals, so as to form pouches of specific desired sizes, or to isolate linked-together Y-sites into individual sample-containing aliquots. The sealing device 70 suitably comprises top and bottom platens 71 and 72, respectively, adapted to be mounted along the pressure lever and seal band, respectively, of a commercially available impulse sealer, such as one of the ALINE M-series impulse sealers, manufactured and sold by the ALINE Company of Santa Fe Springs, Calif. The specific embodiment depicted in FIG. 4 a is a two-part heat sealing head adapted to be attached to an ALINE MC-15 Impulse heat sealer as an after market modification, and allows the MC-15 to produce pre-filled pouches of plasma for further processing in accordance with the system and method of the present invention.
The bottom platen 72 of the heat sealing head 70 is constructed of a suitable rigid, heat resistant material such as laminated Kevlar� manufactured and sold by the DuPont Corporation. In the illustrated embodiment, the bottom platen 72 is preferably about 15 inches in length in order to fit on the mounting surface of the MC-15 Impulse heat sealer. The bottom platen 72 includes a longitudinal slot 73 which is centrally disposed and runs along the entire length of the bottom platen 72. The width of the longitudinal slot 73 is approximately 0.2 inches in order to accommodate standard medical tubing, which typically has an outer diameter of approximately 0.1875 ( 3/16) inches, in nested fashion along the length of the slot.
A plurality of transverse slots 74 are provided at spaced-apart intervals along the length of the bottom platen 72 which are disposed in a direction orthogonal to that of the central slot 73. The transverse slots 74 have a width of approximately 0.5 inches and are located on 1.125 (1⅛) inch centers. Each transverse slot is, therefore, separated from its neighbors by a residual block of platen material centrally divided by the central longitudinal slot 73 which is about 0.625 (⅝) inches in width.
Both the longitudinal and transverse slots 73 and 74, respectively, are cut only partially through the material of the bottom platen 72, thereby forming a substantially flat bed 75 which defines the bottom surface of both the longitudinal and transverse slots. When the apparatus is used to form heat seals, a length of 0.1875 ( 3/16) standard medical tubing is nested in position along the longitudinal slot 73 and rests on the bed 75 of the bottom platen which functions as a bearing surface during the heat seal process.
A heating element 76, such as a nickel-chromium (NiCr) resistive wire, is provided in a snake-fashion from slot to slot and is disposed lengthwise along each transverse slot comprising the bottom platen in about the center of the slot. Where the heating element 76 traverses the center of the transverse slots 74, the NiCr wire is protected from contacting the thermo-sensitive plastic tubing by covering the wire with a piece of, for example, Teflon� tape. Blood or plasma samples contained in the pouches formed within the sealing device during the seal process are thus not damaged by the high temperatures of the heat seal.
The top platen 71 is also approximately 15 inches in length and is suspended over the bottom platen 72 by the pressure lever of the MC-15 heat sealer. The top platen 71 is constructed from a heat-resistant plastic material such as Lexan� or milled Kevlar� and comprises a set of equally spaced-apart, generally rectangular teeth protruding from its bottom, surface, and extending in a direction toward the bottom platen. The teeth 77 are about 0.5 inches in length and are spaced-apart on 1.125 (1⅛) inch centers. Accordingly, it can be seen that each of the teeth 77 is dimensioned to fit into the cavity defined by the transverse slots 74 of the bottom platen 72. Each of the teeth 72 of the top platen 71 is positioned to be suspended over a corresponding intersection of a transverse slot 74 and the longitudinal slot 73 of the bottom platen 72. Thus, each tooth 77 is configured to fit into the cavity thus defined when the heat seal platens are closed together by removal operation of the MC-15 device.
After a flexible tubing segment is placed within the longitudinal slot 73, the top platen 71 is pushed into contact with the bottom platen 72, by lowering the lid of the MC-15 heat seal apparatus. As the lid is lowered, the teeth 77 of the top platen 71 enter the cavity defined by the transverse slots 74 of the bottom platen 72 and contact that portion of the tubing segment which lies exposed on the bed 75 at the intersection of each transverse slot 74 with the central longitudinal slot 73. Current is provided to the nickel-chromium resistive heating wire which causes the plastic material of the tubing segment to soften. At the san time, the top platen 71 is compressed onto the bottom platen, thus applying pressure to the plastic material being softened by the heating element 76.
After sealing, the tubing segment is labeled on at least one end with a unique identifier that corresponds to the original plasma donation. This may be achieved by, for example, gluing a label onto the segment or by imprinting a bar coded emblem directly onto the tubing material. A prepared recess 78 is suitably provided on the heat sealer 70 for holding and aligning a pre-printed bar code identifier tag. Such a tag is formed from a suitable heat-sealable material and is heat sealed to the tubing segment at the first seal position for identification purposes. The tubing segment, including the sample containing pouches, is then frozen for preservation.
Returning now to FIGS. 3 a, 3 b, and 4, it may be further desirable to have each individual pouch along a segment identified by an alpha or numeric code equal to the position of the pouch along the linear length of the original tubing segment. Such code may be imprinted, for example, on the compressed portion of the seal pad located between adjacent pouches by use of a stamping die. Such a stamping die may comprise an integral part of the sealing device as depicted in FIGS. 4 and 4 a, so that sealing, forming pouches of variable sizes, and providing narrow or perforated areas for easy separation, as well as identification numbers, are all accomplished in a single efficient step. Alternatively, the alpha or numeric identifier could comprise part of a perforating jig or die. Stamping dies are known which include means for advancing the alpha or numeric character to a next sequential one such that sequential pouches in a tubing segment are each identified by a corresponding sequential string of alpha (a, b, c . . . ) or numeric (1, 2,3, . . . ) characters.
As shown in connection with FIG. 6, a terminal (first generation, �number 1�) pouch 84 is removed from each tubing segment that has been identified as belonging to a particular PCR group to be tested. Each terminal pouch 84 is washed, but not opened, and placed in a corresponding sample well 81 of the sampling plate 80. The cover plate 82 is secured over the top of the sampling plate 80 and the plate, cover, and pouches are thawed at an appropriate temperature.
While the method of preparing a PCR test pool has been described in terms of manually extracting a sample by inserting a cannula individually into each sample well, the method may equally be practiced using an automated process. The sampling plate containing pouches in each well may be held so as to allow an array of cannulas, arranged in a manner corresponding to the arrangement of through-holes in the cover plate, to be pressed down onto the sampling plate, thereby allowing all of die sample pouches to be pierced and samples extracted therefrom at the same time. Alternatively, a single cannula or cannula holding device may be automated or programmed to successively pierce and withdraw fluid from each pouch. In order to prevent carryover contamination, a clean cannula is used to withdraw samples for each pool.
In addition, it will be evident to one having skill in the art that the combination of sampling plate, sample wells, cover, through-holes, and cannula, while described in connection with extracting sample fluid from a sample packet, is equally applicable to extracting sample fluid from the Y-site sample containers of FIG. 2 a. The configuration of the sample wells of FIGS. 5 and 6 are determined by the shape of the fluid-holding container, and only minor modifications are required to reconfigure them for Y-sites. For example, the sample wells may comprise an elongated cylinder, oriented vertically, into which each Y-site is inserted. A notch may be provided at some appropriate location about the upper periphery of each sample well which functions as a detent into which the Y-site's branch port may be positioned. This would also function to orient each Y-site and provide additional positional security. In the same manner as described in connection with FIGS. 5 and 6, fluid may be extracted from each Y-site by inserting a cannula through each Y-site's access port and into fluid communication with the sample. As the cannula is removed from the access port, the cover plate material surrounding each through-hole acts as a stop and prevents the Y-site from being withdrawn from the sample well.
An additional embodiment of an apparatus and method suitable for preparing a PCR testing pool in accordance with the present invention will now be described in connection with FIGS. 7, 8, 9 a, 9 b, and 10. Turning first to FIG. 7, a plasma donation pool comprising expressed fluids from a multiplicity of plasma samples is prepared from a number of plasma donation sample packets in an electrically powered hydraulic press 90. The hydraulic press 90 suitably comprises a crushing cylinder 91 in which sample packets are placed, and a hydraulically operated piston 92 which crushes the sample packets. The samples contained within the packets are expressed from the crushing cylinder 91 by a suitable compressed gas, such as compressed air or nitrogen, and collected in a pooling container as a pool.
Initially, a generational pouch (for example, pouch #1) is removed from each tubing segment that has been identified as belonging to a particular PCR group to be tested. Each generational pouch is washed, but not opened, and placed within the crushing cylinder 91 of the press 90. Loading of the crushing cylinder is performed within the environment of a class II biosafety hood and air-flow path so as to ensure against inadvertent contamination of the surrounding environment by a packet which has lost structural integrity. In a manner to be described in greater detail below, the crushing piston 92 is firmly seated into the open throat 91 a of the crushing cylinder 91 in such a manner that containment of the contents of the crushing cylinder 91 is assured and that the cylinder 91 and piston 92 combination completely encloses the sample packets. The manner in which the crushing piston 92 engages the crushing cylinder 91 is designed to ensure that the environment outside of the cylinder 91 is protected from contamination by any harmful viruses that may be present in any of the samples contained by the sample packets.
Turning now to FIGS. 9 a and 9 b, the screen plate 110 is a generally circular, disc-shaped plate against which the sample containing packets are forced when they are crushed by the crushing piston 92. As is depicted in FIG. 9 b, the screen plate 110 includes fluid gutters comprising radial slots 111 and concentric circular slots 112, all approximately 1/32 inches in width, which are cut in the top surface of the screen plate. The radial slots 111 are cut at an angle which slopes toward the center of the screen plate 110 where they terminate into an axially located drain or sump 113 which drains through a � inch drain pipe 114 (best seen in FIG. 8) drilled through the base plate 105.
As is shown in FIG. 10, the crushing piston 92 further includes several O-rings 126 disposed in seal races 178 provided about the periphery of the piston head 120. The O-rings are provided in order to form a tight pressure seal between the exterior circumferential surface of the piston head 120 and the inner circumferential surface of the cylinder wall 107 of the crushing cylinder 91. Multiple O-ring seals provide a measure of safety and security, in order to ensure containment of potentially contaminated sample fluid within the confines of the cylinder 91. While three O-rings 126 are depicted in the illustrated embodiment of FIG. 10, it will be evident that a greater or lesser number of O-ring seals may be provided in accordance with the invention. All that is required is that a seal be formed between the crushing piston 92 and the crushing cylinder 91 so as to ensure containment of potentially contaminated fluid within the cylinder.
Returning now to FIG. 8, the crushing cylinder side wall includes a 0.020 inch beveled step 130 which is machined into the interior surface of the side wall. The first approximately 1.0 inches from the top, of the cylinder side wall 107 is thus, machined to have an inside diameter (ID) approximately 0.040 inches larger than the ID of the remaining portion of the cylinder side wall 107 which extends downwardly towards the screen plate 110 and base 105. The interface between the step and the remaining side wall portion is beveled, so as to provide a relatively smooth, angled transition from the slightly larger upper ID, to the slightly smaller lower ID.
The step on the cylinder side wall 107 is provided so that the crushing piston 92 may be manually inserted into the open throat of the crushing cylinder 91 with wily slight contact being made between the O-rings (126 of FIG. 10) and the ID surface of the cylinder. Once the manually assembled piston and cylinder combination is placed on the cylinder seat (93 of FIG. 7) the hydraulic shaft 94 is advanced to mate with the socket 123 of the piston and is extended until the retaining clips 124 detent against the underside surface of the piston head's annular retaining collar 122. The hydraulic shaft 94 is then further advanced so as to push the piston further into the cylinder, thereby pushing the O-rings beyond the step 130 on the ID of the cylinder wall. When pushed beyond the step, the O-rings fully compress between the ID of the cylinder side wall 107 and the piston seal races 127, forming thereby a tight seal.
In operation, the crushing piston 92 develops pressure of about 800 to 900 psi (4,000 lbs of force point loaded at the hydraulic shaft) which is a sufficient pressure to crush the sample packets contained within the cylinder. Blood or plasma sample fluid flows along the fluid gutter provided in the screen plate and into the central sump, where it is collected and allowed to flow out the extraction port and into a pooling container. Following the crushing operation, the hydraulic cylinder 95 is operated to raise the crushing piston 92 a small distance (approximately � to 1 inches) above the mass of crushed sample packets, thereby creating a chamber within the cylinder. A pressurized gas, such as compressed air, is forced into the chamber through the pop-off valve 102 in the piston 92. Pressurizing the chamber causes any remaining blood or plasma sample fluid to be expressed out of the cylinder through the outlet port 103 into the pooling container.
Once the crushing and pooling operation is completed, the express line connected to the outlet port 103, is clamped, to prevent any additional sample fluid from exiting the cylinder. The express line is placed into a bleach container, and the hydraulic cylinder 95 is caused to raise the piston further in the cylinder, thereby creating a suction which siphons bleach from the container into the cylinder. Preferably, the crushing and bleach siphoning steps are repeated two additional times, in order to ensure that any blood or plasma sample �flash back� fluid is fully expressed from the crushing cylinder 91 and that the bleach has ample opportunity to fill the interior volume of the crushing chamber, thereby reducing any gross viral contamination that may be found within.
Next, the quick release clamps are operated and the piston/cylinder combination is removed from the hydraulic press 90 and subjected to sterilization procedures in, for example, an autoclave. The piston and cylinder may be subsequently chemically cleaned by soaking them in a 10% bleach solution for fifteen minutes, followed by a rinse cycle of H20, 1% SDS (sodium dodecyl sulfate) surfactant, and H20 again, prior to autoclaving. If there is insufficient time for autoclave sterilization, the chemical clean may be concluded with a 70% ETOH and sterile H20 solution. If such additional chemical cleaning is desired, it is performed in a class II biosafety hood which exhausts through a HEPA filter. While under the hood, the crushing cylinder is loaded with a next group of sample packets to be crushed and the crushing piston 92 is manually inserted into the open mouth of the crushing cylinder 91 and forced down until the pistons O-rings make contact with the beveled step formed in the side wall of the cylinder. The newly reloaded cylinder/piston combination is now ready to be placed on the cylinder seat 93 of the crusher 90. The hydraulic cylinder 95 is operated to cause the hydraulic shaft 94 to lower onto the piston 92 such that the quick release clamps engage the annular retaining ring on the piston. The crushing, expressing, and bleach-cleaning process is now repeated.
In addition, it will be apparent to one having skill in the art that a single large scale pool, comprising up to 512 samples or more, can be formed from a crusher apparatus made sufficiently large enough to accommodate the greater number of sample pockets in the cylinder. The hydraulic press portion would also be increased in size to provide greater crushing power to overcome the greater resistance of the increased number of pockets. As was mentioned above, the pool size would only be limited by the desired scale of the crusher.
Referring now to FIG. 11 there is shown a flow chart of a PCR test methodology according to the invention, which allows for the identification of a unique PCR positive donation with the fewest number of individual tests.
For example, if a 0.02 ml sample was prepared from a plasma donation contaminated with viruses at a concentration of 500 viruses per mll of sample, the 0.02 ml sample would comprise, on average, 10 viruses. If this 0.02 ml contaminated sample were pooled with approximately 500 other 0.02 ml samples from uncontaminated donations, the resulting 10 ml pool would comprises viruses at a concentration of 1 per ml. Accordingly, if a 1 ml sample were taken from the pool for PCR testing, there is a significant statistical probability that the PCR sample will contain no viruses.
Such low concentrations of virus contamination pose little threat for products produced from plasma, because several methods are available for inactivating viruses present in such low concentration donations. Such viral inactivation methods include the use of solvent/detergent or heating at over 60� C. for an appropriate time or the like. These methods, generally, are described as being capable of reducing the concentration of viruses by a number of �log units.� For example, the solvent detergent method is capable of reducing the viral contamination of hepatitis C by at least 107 per ml or �7 log units.� Thus, plasma products such as factor VIII, factor IX or prothrombin complex may be prepared from plasma donations routinely treated by, for example, the solvent detergent method after having been PCR tested negative.
In the embodiment illustrated in connection with FIG. 11, the factors discussed above, such as the frequency of occurrence of the virus of interest in the donor population and the likely concentration of the virus alter dilution, are evaluated. An appropriately sized first level PCR testing pool is designed which minimizes the statistical probability that viruses present in low concentrations will go undetected. The pool is prepared at block 201 by pooling the contents of terminal pouches of identified tubing sections, in the manner described above. At block 202, a PCR test is performed on the first level PCR pool.
Block 203 represents a decision point in the methodology of the invention which depends on the results of the PCR test performed in block 202. In the event of a negative result on the test, all of the donations corresponding to samples used to make up the first level PCR pool are presumed to be free of viral contamination and released for further processing into pharmaceutical products. The methodology thus exits on receipt of a negative PCR test result. When the PCR test returns a positive indication, this indicates that a viral contaminant is present in one, or more than one, of the donations which made up the original PCR first level pool. At block 204, an additional sample pouch, the pouch next to the one first removed, is taken from tubing segments which correspond to donations comprising the original PCR first level pool. These additional sample pouches are divided into two approximately equal subgroups, designated A and B herein for purposes of clarity.
These subgroups are then separately pooled using a separate, clean cannula to form each subgroup pool in the same manner as described above, and only one of the subgroup pool is PCR tested, as indicated at block 205. It is immaterial for purposes of the invention which of the two subgroups is tested. In block 205, subgroup A is identified as the subgroup to be tested, but subgroup B could just as easily have been designated without disturbing the methodology of the invention.
At block 206, a decision is made depending on the outcome of the PCR test of subgroup pool A. In the event that subgroup pool A tests negative for a PCR viral indication, no further testing is performed on samples from donations that comprised subgroup A. Rather, as indicated at block 207, the next sample pouches in sequence are taken from tubing segments that comprised subgroup B which are then, in turn, divided into two approximately equal subgroups A′ and B′. Each subgroup in this step comprises approximately half the number of samples as comprised the immediately preceding subgroup. The contents of the subgroup sample pouches are again pooled separately in the same manner as described above. In the event that subgroup A tested PCR positive, indicating at least one of its component donations was virus contaminated, the other untested subgroup (subgroup B in the example of FIG. 11) is now PCR tested at block 108 to confirm that it is not also PCR positive. Subgroup A now becomes the subgroup further subdivided into two approximately equal subgroups (A′ and B′), as indicated at block 209.
At block 210, PCR testing is performed on only one of the subgroup pools, A′ or B′, defined in preceding step 207 or 209. The method now iterates and returns to block 206, wherein the decision step is applied to the results of the PCR test performed at block 210. Again, if the PCR test results prove negative for the tested subgroup, the untested subgroup would be further subdivided into two approximately equal subgroups, each comprising approximately half the samples of the preceding subgroup. If the tested subgroup returned a PCR positive result, the tested subgroup would be further subdivided into two approximately equal subgroups, each of which would comprise one half of the samples of the preceding subgroup. In this case, the untested subgroup would again be PCR tested in order to confirm that it was not also PCR positive.
It is therefore clear from the foregoing that the system and method of the present invention, including the provision of tubing segments comprising individual and connected pouches each containing a sample of a plasma donation, is advantageous in providing a multiplicity of PCR test pools. Unlike conventional pool preparation, in which a sequence of initial and subsequent pools are formed from a single sample of each donation at the same time, the present invention allows for formation of a test pool immediately prior to testing. This manner of �just-in-time� pool formation permits construction of test pools from individual pouches only as needed. The possibility of contamination is eliminated since the pools are constructed at different times, each from sealed sample pouches. Moreover, sample pouches remain frozen until needed to develop a test pool. Multiple freeze-thaw cycles which may adversely affect the recovery of the DNA or RNA of interest are avoided, thus insuring the integrity of the PCR test.
However, a significant amount of time is consumed in each PCR testing cycle (harvesting, subgroup pool formation, and PCR testing). Talking the 512 sample first generational pool as an exemplar, it will be evident that at least 10 PCR testing cycles will be required to identify a unique viral contaminated donation. While highly cost-effective, the above-described method may present challenges to a PCR testing laboratory when time is of the essence.
An example of such a matrix is depicted in FIG. 14, which is a graphical illustration of square matrix, characterized by 3-dimensional; row, column, and slice (r,c,s). In the exemplary matrix of FIG. 14, there are 3 rows, 3 columns, and 3 slices, thereby defining 33, or 27, elements. In the exemplary embodiment, a row is considered as comprising all of the elements defined by taking an imaginary vertical section through the square regular matrix. In the embodiment of FIG. 14, the elements comprising, for example, row 3 of the matrix are identified by the letter r3 on their row faces.
Likewise, a column comprises all of the matrix elements defined by taking a second imaginary vertical section through the matrix, in a direction orthogonal to the direction of a row. In the exemplary embodiment of FIG. 14, the elements that comprise, for example, column 1 have the letter c1 on their column faces. A slice is defined as all elements comprising a horizontal section taken through the exemplary matrix of FIG. 14. In like manner to the row, column, definition, the elements comprising slice 1 are identified with the letter s1 on their slice faces.
Next, an aliquot is taken from each sample, and a multiplicity of minor sub-group pools are formed. Each minor pool comprises the aliquots of all of the samples (Xrcs) in which 1 of the dimensional indices is fixed. In other words, in accordance with the above-described exemplary matrix, all of the samples (Xrcs) which have r=1, regardless of the column or slice value, are formed into a minor pool; likewise for r=2, r=3 . . . r=N; likewise for c=1, regardless of row or slice value, c=2, . . . c=N; likewise for s=1, regardless of row or column value, s=2 . . . s=N. Each minor pool thus represents each row, column, layer, or other dimensional index, such that if an N-dimensional matrix has been defined, there will be N-dimensions times the (total number of samples)1/n minor pools. For the exemplary 3-dimensional 8�8�8 matrix containing 512 samples, there will be 24 minor subgroup pools (8 row pools, 8 column pools, and 8 layer pools). The creation of minor pools, in accordance with the invention, may be viewed as being similar to the mathematical method of reducing a determinant by the method of minors. In like manner, each sample will be understood to be represented in N minor pools, 1 for each dimension of the matrix.
In a manner similar to that described above, the major pool sizes chosen such that the statistical probability of their being more than one positive sample in the major pool (the 512 samples) is small, preferable less than 1 to 2%. This can be done by evaluating the frequency of occurrence of the virus of interest in the general donor population to a 98% to 99% confidence level. For example, if it is determined that only 1 donor out of a general donor population of 1,000 is contaminated with the virus of interest to a 98% confidence level, there is a 2% probability of finding more than 1 contaminated donor in the next 1,000 donors being evaluated. This assures that the algorithm will, in general, be able to identify the single reactive unit in a pool of appropriate size within the PCR testing cycle. In accordance with the invention, given a single positive sample within the matrix, 3 of the minor pools will contain an aliquot of the positive donation, 1 in each dimension. In the exemplary embodiment (the matrix of 512 samples), there are 8 minor row pools, 8 minor column pools, and 8 minor layer pools. If the master pool tests positive, then 1 row, 1 column, and 1 layer pool will test positive during the second PCR testing cycle as shown at 307. The intersection of the row, column, and layer element index unambiguously identifies the reactive donation as shown at 309.
As an example, if the reactive sample has been mapped to matrix element X113 the row 1 minor pool will return a positive PCR test result, while the row 2, and subsequent row minor pools will test negative. Further, the column 1 minor pool will return a positive test result, while the column 2 and subsequent column pools will test negative. Likewise, the layer 1 and 2 minor pools will return a negative result, the layer 3 pool will test positive, and subsequent layer minor pools will test negative. The 3 positive minor pools (row 1, column 1, and layer 3) have only a single element in common, X113. Thus, the positive donation is uniquely identified as represented by the sample mapped to element X113.
In like manner, it is mathematically evident that if there are more than 2 positive donations in the matrix, and their identifiers vary in more than 2 dimensions, there will be, at most zn potentially positive candidate elements identified, where z is the actual number of positive donations, and where n is the number of dimensions which vary. In this circumstance, aliquots are taken of all suspect elements in the matrix and directly tested.
Accordingly, the practice of the present invention results in the blood supply, and blood or plasma products prepared therefrom, being substantially safer by virtue of its being as free as possible from viral contamination. Advantageously, cost-effective, high-sensitivity testing is readily performed for the presence of a virus directly. Thus, false indications of virus contamination usually associated with antibody testing during the infectivity window period is avoided. Moreover, the present invention allows cost-effective use high-sensitivity tests which are capable of detecting the presence of a single virus in the test sample, thus helping to insure the freedom of the blood supply from incipient viral contamination.
Those skilled in the art will appreciate that the foregoing examples and descriptions of various preferred embodiments of the present invention are merely illustrative of the invention as a whole, and that variations in the shape, size, and number of the various components of the present invention, as well as the types of tests implemented, may be made within the spirit and scope of the invention. For example, it will be clear to one skilled in the art that the length of the individual and connected pouches, and therefore their volumetric content, may be progressively increased along the length of the tubing segment. As successive testing subpools are formed from a smaller and smaller number of samples, the volume of plasma comprising the pool necessarily decreases. It should be clear that in order to maintain a sufficient volume of plasma in each successive subpool, successive sample pouches may contain a larger volume in order to accommodate a desired final pool volume. In order to accommodate pools ranging in size from about 1 ml to about 10 ml, it will be clear that the volumes of successive sample pouches will increase from about 0.02 ml to about 0.5 ml, in progressive steps. In one exemplary embodiment, the pouch volume is 0.02 ml the first pouch to be used in the largest pool and is 0.2 ml in the final pouch.
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