Clinical Analyzers. Immunoassays - Analytical Chemistry (ACS


Clinical Analyzers. Immunoassays - Analytical Chemistry (ACS...

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Anal. Chem. 1999, 71, 356R-362R

Clinical Analyzers. Immunoassays Lori J. Sokoll* and Daniel W. Chan*

Department of Pathology, Johns Hopkins University, 600 North Wolfe Street, Meyer B-121, Baltimore, Maryland 21287 Immunoassay automation continues to be one of the most dynamic and innovative areas for research and development in the clinical diagnostics industry. Analyzers, both recently introduced and those in the development process, are being designed to help meet the numerous challenges faced by the clinical laboratory. The laboratory is now faced with internal challenges resulting from shrinking resources and limitations on space and external challenges as a result of managed care competition, cost compression, and increased regulation of the testing laboratory. Hospitals are also merging, forming alliances, and reengineering. To remain competitive, the hospital laboratory must also merge and reengineer. Pressures to decrease hospital lengths of stay have necessitated accelerated turnaround times for many laboratory tests, now including immunoassay-based tests. Despite these many challenges, users have higher expectations for quality laboratory services. To meet these challenges, the clinical laboratory has to become more efficient by incorporating innovations to adapt to these changes. One approach is the introduction of system integration and automation. There are many benefits to automation including the ability to consolidate testing and workstations, including manual testing, batch, selective, and random access analyzers. Automation can therefore reduce labor requirements and reduce testing costs. Turnaround times can also be improved as a result of shorter incubation and assay times and the ability to increase testing frequencies with random access capability. Quality testing can be achieved with immunoassay automation with improved assay performance resulting from improved precision, sensitivity, and wide dynamic ranges, as well as from the elimination of sample handling and processing errors resulting from use of primary tubes and from the elimination of manual data errors from implementation of barcoding and bidirectional interfaces. In this review, the focus is on immunoassay automation as well as on the integration of immunoassay testing with other areas of the clinical laboratory. This review, covering the time period of October 1, 1996October 1, 1998, will present an overview of current immunoassay systems and their features and describe systems launched during this time. Integrated and modular systems and other laboratory automation issues will also be covered. Finally, test menu and future trends will be discussed. Three books, which formed the basis for the last two reviews (J1, J2), two edited by one of us (D.W.C.), Immunoassay Automation: A Practical Guide (J3) and Immunoassay Automation: An Updated Guide to Systems (J4), and one edited by Wild, The Immunoassay Handbook (J5), still provide relevant information on some of the current immunoassay analyzers available. An updated revision of the Wild book is expected this year. Several in-depth surveys of automated immunoassay analyzers (J6-J8) contain 356R Analytical Chemistry, Vol. 71, No. 12, June 15, 1999

more recent information; however, details on some of the newest analyzers may need to be obtained directly from the manufacturer. Several other books, Principles and Practice of Immunoassay (J9), edited by Price and Newman, Immunoassay (J10), edited by Diamandis and Christopoulos, Handbook of Clinical Automation, Robotics, and Optimization (J11), edited by Kost, and Automated Integration of Clinical Laboratories: A Reference (J12), edited by Bissell and Petersen, contain relevant and timely material on general and theoretical aspects of immunoassays, immunoassay automation, and laboratory automation. Finally, two issues of the Journal of Clinical Ligand Assay, one edited by Kricka, devoted to luminescent detection systems (J13) and one we have edited on immunoassay systems and applications (J14) are comprehensive compilations containing the most up-to-date information on the field of immunoassay automation. AUTOMATED IMMUNOASSAY SYSTEMS Automated Immunoassay Systems and Features. Table 17 lists currently available automated immunoassay systems. It is notable that the number of systems has increased since the last review despite the considerable numbers of mergers and acquisitions that have recently taken place in the diagnostics industry (J15). Within the last several years, Roche Diagnostics acquired Boehringer Mannheim’s diagnostics division while Bayer Corp. acquired Chiron’s diagnostics division and Dade Behring is now composed of former Dade, Behring, Syva, and DuPont divisions. At this point in time, manufacturers are committed to supporting those analyzers currently in the field; however, it is clear from this table that many manufacturers already have new systems available or have systems near launch as well as have overlapping products and will not be able to support all analyzers for extended periods of time. Y2K compliance is another important consideration. Important features of immunoassay analyzers are presented in Table 17. Fully automated analyzers designed to provide comprehensive immunoassay analysis for medium to large laboratories are now uniformly random access in design. Several older models or analyzers intended for satellite or main laboratories with small to medium volumes are selective in design in which specimens are analyzed for multiple tests in a batch mode. Assay formats include both heterogeneous and homogeneous approaches. Homogeneous assays do not require separation of bound and free components. Numerous approaches have been taken as a separation mechanism in heterogeneous assays with a common approach using magnetic particles. Numerous signals for detection have been employed as a replacement for radioactive signals in early manual assays with the majority of newly introduced analyzers using luminescence approaches such as chemiluminescence, which allows for increased assay sensitivities 10.1021/a1999910i CCC: $18.00

© 1999 American Chemical Society Published on Web 05/20/1999

Table 17. Features of Automated Immunoassay Systems

Analytical Chemistry, Vol. 71, No. 12, June 15, 1999 357R

system

AxSYM/AxSYM2

ACS:Centaur

Abbott C

ARCHITECT ACS:180 SE i2000 Abbott Bayer (Chiron) C C

manufacturer automationa assay homogeneous heterogeneous competitive immunometric reagents/methodb labelc signald separatione analytes number in U.S.f number on-boardg typeh reagents typei open stabilityj on-board stability left on system tests per vial/kitk on-board refrigeration sampling tray capacity primary tube stat add-on specimen volume (µL) autodilution autorepeat reflex testing clot detection disposable tips throughput incubation time (min) first result time (min) time between results (s) maximum tests/h calibration/controls stabilityl number calibrators information management/diagnostics barcoding bidirectional interface on-board diagnostics diagnostics by modem modelm

Immuno 1 ACCESS

VIDAS

KRYPTOR aca PLUS

Opus Plus

Stratus II

Bayer (Chiron) Bayer C C

Beckman Coulter bioMerieux CIS bio C C C

Dade Behring C

Dade Behring Dade Behring S B

Y Y Y Y EIA, FPIA, IC, REA

N Y Y Y LIA

N Y Y Y LIA

N Y Y Y LIA

Y Y Y Y EIA, T

N Y Y Y EIA

N Y Y Y FIA

Y N Y N FIA

N Y Y Y FIA

N Y Y Y EIA

E, F F PC, NA

A L MP

A L MP

A L MP

E, L S, T MP, NA

E L MP

E F CT

F tF NA

Y Y Y Y EIA, EMIT, PETINIA, PETIA, T E, L S, T MP, P

E F CF, MF

E F CF

54 20 all

15 25 H, I, M, T

39 29 13 30 C, D, H, M, P, T all

47 22 all

38 32 (17) 24 15-30 15 C, D*, H, I, M, T C, D*, H, I H, P, T

44 1-42 D, H, M, P, T

23 NA C, D, H, T

30 NA C, D, H, M, P

Li 3-12 mos 112-336 h Y, N 100 N

Li 30-500 d 30 d Y 100, 500 Y

Li 9-12 m 40 h N 50 N

Li 28 d 28 d Y 50-100 Y

Li 7-60 d 7-60 d Y 100-200 Y

Li 28 d 28 d Y 50 Y

Li 6-12 m NA N NA N

Li, Ly 14 d 14 d Y 25-100 Y

Li, Ly NA NA N NA N

NA NA NA N NA NA

Li 60-120 d NA N 120 N

60-90 Y Y 10-100 Y Y Y Y N

125-250 Y Y 10-150 Y Y Y Y N

60 Y Y 10-200 Y Y N Y N

180 Y Y 10-200 Y Y Y Y N

72 Y Y 2-65 N N N Y N

60 Y Y 10-220 Y N N N N

30 N Y 100-200 N N N N na

50 Y Y 50 Y Y N Y N

16-40 N Y 10-480 N N N N N

20 N Y 10-40 N N N N Y

30 N Y 200 Y N N N N

10 10-15 30-60 60-120

18 29 18 200

7.5 15 20 180

7.5 18 15 240

1-79 5-88 30 120

10-25 15-75 36 100

20-45 20-150 NA 60

9-59 20 45 100

4.2-15 7-30 40-150 60

6-21 10-25 30-60 60

8 8 60 40

4w 2, 6

30 d 2

to 4 w 2

to 28 d 2

7-60 d 3-6

4w 1, 6, 7

2w 1

2w 1

8-12 w 3-5

2-8 w 2-6

g2 w 6

Y Y Y N/Y F

Y Y Y Y F

Y Y Y N B

Y Y Y Y F

Y Y Y N F

Y Y Y N B

Y Y Y N B

Y Y Y Y B

Y Y Y N B

N Y Y N B

Y N Y N B

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Table 17 (Continued)

Analytical Chemistry, Vol. 71, No. 12, June 15, 1999

system manufacturer automationa assay homogeneous heterogeneous competitive immunometric reagents/methodb labelc signald separatione analytes number in U.S.f number on-boardg typeh reagents typei open stabilityj on-board stability left on system tests per vial/kitk on-board refrigeration sampling tray capacity primary tube stat add-on specimen volume (µL) autodilution autorepeat reflex testing clot detection disposable tips throughput incubation time (min) first result time (min) time between results (s) maximum tests/h calibration/controls stabilityl number calibrators information management/diagnostics barcoding bidirectional interface on-board diagnostics diagnostics by modem modelm

Dimension RxL Dade Behring C

IMMULITE IMMULITE 2000 Copalis I Advantage Diag. Prod. Corp. Diag. Prod. Corp. DiaSorin Nichols C C B C

Vitros ECi Elecsys 1010 Ortho-Clinical Roche C S

Elecsys 2010 Roche C

AIA 1200DX AIA NexIA Tosoh Tosoh C C

AutoDELFIA Wallac S

Y Y N Y EIA, EMIT, PETINIA, PETIA, T E, L S, T MP

N Y Y Y LIA

N Y Y Y LIA

Y N Y Y Copalis

N Y Y Y LIA

N Y Y Y LIA

N Y Y Y ECLIA

N Y Y Y ECLIA

N Y Y Y EIA

N Y Y Y EIA

N Y Y Y tFIA

E L CB

AE, E L CB

L MP, P NA

A, LU L MP

E L CW

R L MP

R L MP

E F MP

E F MP

F tF CW

26 44 C, D, H, M, T

58 12 all

21 24 H, M, P, T

3 NA I

15 15 H, M, T

25 20 C, H, M, T

19 23 30 30 22 6 15 21 20 8 C, D*, H, I, M, T C, D*, H, I, M, T C, H, M, P, T C, H, M, P, T H, I, P, T

Li, Ly 10 mos 30 d Y 15-240 Y

Li 30 d 30 d Y, N 100 N

Li 30 d 30 d Y 200 Y

NA NA NA NA 50 NA

Li 48 h-3 mos g48 h Y 100 Y

Li 2 mos 2 mos Y 100 Y

Li 12 w 8w Y 100 or 200 N

Li 12 w 8w Y 100 or 200 Y

Ly 30 d 24 h Y NA N

Ly 30 d 24 h Y NA N

Li AD 24 h N 96 Y

44 Y Y 40-60 Y Y Y Y N

60 N Y 5-75 N N N N N

90 Y Y 5-100 Y Y Y Y N

24 N N 40-200 N N N N N

120-180 Y Y 10-200 Y N N Y N

60 Y Y 10-80 Y Y Y Y Y

66 Y Y 10-50 Y Y N Y Y

30 or 100 Y Y 10-50 Y Y N Y Y

80 Y Y 10-125 N N N Y Y

80 Y Y 10-125 Y Y N Y Y

432 Y N 25-50 Y N N Y Y/N

15 15-25 8 167-500

30 40-70 30 120

30 35-65 18 200

10 12 2 72

30 37 18 170

12-30 16-36 40 90

9-18 15 62 58

9-18 10-20 42 88

40 50 30 120

10, 40 15, 50 30 120

60 75 NA 192

8-12 w 3-6

2w 2

2w 2

30 d 2, 3

1-4 w 2

4w 2, 3

1w 2

4w 2

4w 2, 6

4w 2, 6

L 2

Y Y Y Y F

Y Y N N B

Y Y Y Y F

Y N Y Y B

Y Y Y Y, N B

Y Y Y N F

Y Y Y N B

Y Y Y N B

Y Y Y Y F

Y Y Y Y F

Y Y Y Y B

a B, batch; C, continuous access; S, selective. b Copalis, coupled particle light scattering; EIA, enzyme immunoassay; ECLIA, electrochemiluminescent immunoassay; EMIT, enzymemultiplied immunoassay technique; FIA, fluorescent immunoassay; FPIA, fluorescence polarization immunoassay; IC, ion capture; LIA, luminescent immunoassay; PETIA, particle-enhanced turbidimetric immunoassay; PETINIA, particle-enhanced turbidimetric inhibition immunoassay; REA, radiative energy attenuation; tFIA, time-resolved fluorescent immunoassay; T, turbidimetric. c A, acridinium ester; E, enzyme; F, fluorescence; L, latex; LU, luminol; R, ruthenium. d F, fluorometric; tF, time-resolved fluorometric; L, luminescence; S, spectrophotometric; T, turbidimetric. e CB, coated bead; CF, coated filter paper; CT, coated tube; CW, coated well; MF, multilayer film; MP, magnetic particle; P, particle; PC, particle capture; PF, particle filter; TB, turbidimetric; NA, not applicable, homogeneous. f Tests in the United States. Numbers in parentheses, non-U.S. tests. g NA, not applicable. h C, cardiac; D, drug; D*, limited drug: H, hormone; I, infectious disease; M, metabolism; P, protein, specific; T, tumor marker. i Li, liquid; Ly, lyophilized; NA, not applicable (dry). j AD, assay dependent. k NA (unit packaging). l L, lot specific. m B, benchtop; F, floor.

and dynamic ranges (J16). Examples of labels include enzymes such as alkaline phosphatase and horseradish peroxidase as well as direct chemiluminescent compounds such as acridinium ester and luminol. The number of analytes available on immunoassay analyzers is growing rapidly and is discussed in further detail later in this article. U.S. and worldwide menus can vary significantly due to FDA approval requirements necessitating lengthy and costly analytical and clinical studies for some analytes. Operation is limited, however, by the number of assays resident on-board the analyzer at one time. Number of tests on-board, reagent and sample capacity, with on-board refrigeration or stable reagents, and large reserves of disposables such as tips and reaction vessels also affect walk-away capability. Operational efficiency is also gained with long-term calibration stability, primary tube sampling, autodilution, stat, repeat, reflex, and clot detection capabilities. Analyzer throughput is determined by the assay incubation times, time to first result, and time between results. Throughput will vary among laboratories due to test mix for analyzers with variable assay incubation times. Therefore, simulation studies need to be performed when an analyzer is being evaluated. Manufacturer throughput may be difficult to obtain. Efficiencies are also gained and manual entry and reporting errors diminished with now standard barcoding capabilities and bidirectional interfaces in automated systems. On-board diagnostics are also essential to limit down time in order to meet service expectations. Finally, analyzers with modular designs and/or automation ready, defined as the ability to be incorporated into total or modular laboratory automation systems, are features of newer systems allowing for flexibility in immunoassay testing and integration with other laboratory testing or specimen processing and handling (J17). New Automated Immunoassay Systems. A significant number of immunoassay analyzers have been launched in the time period covered by this review. Those analyzers include the Abbott AxSYM2 and ARCHITECT (Abbott Diagnostics), Bayer (formerly Chiron) ACS:180 SE and ACS:Centaur (Bayer Corp.), Dade Behring Dimension RxL (Dade Behring, Inc.), DPC Immulite 2000 (Diagnostic Products Corp.), Nichols Advantage (Nichols Institute Diagnostics), Ortho Vitros ECi (Ortho-Clinical Diagnostics, Inc.), Roche Elecsys 1010 (Roche Diagnostics), and the Tosoh Nex‚IA (Tosoh Medics). The ARCHITECT, a modular system, and the Dimension RxL, a combination of homogeneous and heterogeneous components, will be described in subsequent sections. The AxSYM2 is an updated version of the Abbott AxSYM analyzer (J18) designed to simplify operations for the user. Minor hardware enhancements were made to the instrument, specifically related to the computer keyboard and computing speed and capacity, with major software enhancements related to the operator interface. User-friendly icons were instituted in a Windows NT operating system with a reduction in the number of screens required for use. On-line troubleshooting and help functions were also enhanced. Similarly, the Bayer ACS:180 SE is an updated version of the 1991 ACS:180 analyzer with major differences related to the user interface. The ACS:180 system, the first fully automated chemiluminescent system developed, is a benchtop instrument with a throughput of 180 tests/h (J19). In the ACS:180 SE system, the

Windows NT software format allows for simplified software navigation and faster and easier scheduling of stat tests. The operator’s manual is also accessible via the built-in CD-ROM. The ACS:Centaur is the latest addition to the ACS line. Similar to the ACS:180:SE, the ACS:Centaur utilizes direct chemiluminescence with an acridinium ester label and a magnetic particle separation and has clot and sample integrity detection capabilities. In contrast to the ACS:180, the ACS:Centaur (J20) is a floor model using individual specimen tips with increased reagent stability due to refrigeration, increased number of assays on-board (30), and increased processing speed of up to 240 tests/h with an operator walk-away time of up to 840 tests. In addition, the analyzer can operate continuously without stopping or pausing for addition of samples, reagents, or supplies or for disposal of wastes. The analyzer is also is designed for specimen sampling from automated track transport systems. The DPC Immulite (J21) and Immulite 2000 are benchtop and floor model analyzers, respectively, which utilize chemiluminescent technology and antigen- or antibody-coated beads as a solid phase. Detection and a proprietary wash technique have combined to allow development of third-generation ultrasensitive assays such as for TSH and PSA. In contrast to the Immulite, the recently introduced Immulite 2000 has a throughput of 120 tests/h, primary and secondary tube sampling, on-board refrigeration, autodilution, reflex testing, and a remote diagnostics program. Ninety specimen tubes can be accommodated in the sample carousel. DPC is partnering with LAB-InterLink, Inc. to develop an interface to allow the Immulite 2000 to directly link to any laboratory automation system and to develop a mechanism to link two or more analyzers to create a modular workcell. The Nichols Advantage is benchtop analyzer designed for use in specialty testing. The analyzer can operate in random access, batch, or stat modes with a throughput of 90-170 tests/h. Some analyzer features include on-board refrigeration, primary tube sampling, automatic clot and bubble detection, and on-board capacity for 15 reagents and 120 specimen tubes. Detection is accomplished through direct chemiluminescence with an acridinium ester label while separation is accomplished via magnetic particles. The streptavidin-coated particles have a high affinity for biotinylated antibodies. Many of the assays developed for the Advantage, primarily endocrine-related analytes, are not available on any other automated immunoassay analyzer. Currently available assays include IGF-I, ACTH, calcitonin, and PTH. The Vitros ECi, manufactured by Ortho-Clinical Diagnostics, a Johnson & Johnson company, is another recently introduced free-standing immunoassay analyzer. The Vitros ECi uses enhanced chemiluminescence with a horseradish peroxidase label and a luminol substrate. Streptavidin-coated wells constitute the solid phase. Integrated assay packs containing reagents and assay microwells are refrigerated on-board. Specimens are sampled using individual sample tips from either primary or secondary tubes. Specimens can also be sampled directly from a track system. The analyzer holds 6 universal circular sample trays of 10 positions each and reagents for up to 15 assays with a throughput of 90 tests/h. The Vitros ECi can also be integrated into a LAB-Frame SELECT sample processor and conveyor system. Analytical Chemistry, Vol. 71, No. 12, June 15, 1999

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The Elecsys 1010 is part of the Elecsys family of electrochemiluminescent immunoassay analyzers. Both benchtop models, the 1010 model is designed for routine and stat use in small to medium and specialty laboratories while the 2010 is designed for medium to large labs. The electrochemiluminescent detection technology allows for extended dynamic assay ranges resulting in fewer repeats and dilutions. The instrument can hold 6 assays on-board with a throughput of 50 tests/h. In addition, the analyzer has autodilution, auto rerun, liquid level sensing, and clot detection capabilities. The Tosoh Nex‚IA is the most recent addition to the Tosoh automated immunoassay line. In contrast to many of the analyzers previously discussed, the Nex‚IA uses fluorescence detection, measuring the conversion of 4-methylumbelliferyl phosphate to 4-methylumbelliferone by antibody- or antigen-labeled alkaline phosphatase. Magnetic beads, used as the solid phase, and other necessary reagents are present in a lyophilized form in uniform unit dose test cups. Reconstitution is performed by the analyzer. Specimens can be sampled from primary tubes or sample cups and the analyzer has a throughput of 120 tests/h. Compared to the previous Tosoh model, the AIA-1200DX (J22), the Nex‚IA has automated daily maintenance and tip loading and reduced incubation times to 10 min for BhCG and cardiac markers. Specimens can be loaded through an 80-position sample carousel. A rack loading unit with 270 positions can also be added. The analyzer can also be configured to be compatible with total laboratory automation systems and track operations and can accommodate specimen racks from Hitachi systems. System Integration. A continuing trend in the clinical laboratory is consolidation of testing based on technology as opposed to segregation by the traditional clinical pathology disciplines such as chemistry, special chemistry, drug assay, hematology, and microbiology. Consolidation is an essential step in the development of a core laboratory for high-volume testing as well as in planning for total or limited robotic laboratory automation. With instrument consolidation, productivity and efficiency gains are realized through decreased labor costs, the elimination of training, documentation, and maintenance on multiple analyzers, and decreased sample handling and splitting. The ability to consolidate is dependent upon the type of automation as well as specific tests available on the system. Currently, sufficient numbers of homogeneous immunoassays such as therapeutic drugs, drugs of abuse, special proteins, and limited hormone tests are now available on many chemistry analyzers to warrant instrument elimination (J23). Conversely, consolidation onto platforms utilizing heterogeneous immunoassay technology is now possible with menus that now include therapeutic drugs, drugs of abuse, and infectious disease tests. With the recent introduction of the Dimension RxL by Dade Behring, consolidation of homogeneous and heterogeneous immunoassays is now possible. The Dimension RxL performs greater than 60 general chemistry, electrolyte, therapeutic drug, and drugs of abuse tests and has an added heterogeneous immunoassay module (HIM). A limited number of high-volume immunoassay tests, including TSH, PSA, CK-MB, troponin I, and HCG have been developed. These heterogeneous assays incorporate enzyme labels, such as alkaline phosphatase and β-galactosidase, with a spectrophotometric signal and chromium dioxide particles for 360R

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separation. Analyzer throughput is 167 tests/h and 500 tests/h for the HIM and combined modules, respectively. Modular Automation. Laboratory automation can impact all facets of the laboratory process from the preanalytical procedures of test ordering, specimen collection, specimen transport, and specimen processing to the analysis of the specimen, and finally to postanalytical result reporting and interpretation and specimen storage. However, the laboratory size, present and future testing volume, and financial resources will influence the ability of the individual testing facility to take advantage of available robotics and other automation. Thus, a number of strategies are possible. Automation may constitute a total, partial, or modular system either closed or open to instruments from a number of specific manufacturers. A number of immunoassay analyzers are designed for use with specific systems (J23) while others are designed to be flexible in nature allowing the instrument to sample directly from any track system. In total laboratory automation (TLA), the entire laboratory testing process is automated. These systems include a number of components and methods to connect them, such as tracks or conveyor belts, as well as system controllers to track and direct the specimens and to communicate to the system elements and the LIS (J12). There are several systems available on the market including those from Roche Diagnostics, Beckman Coulter, and MDS Autolab (J17); however, the investment needed for a TLA system has been estimated at between 1 and 5 million dollars with a payback period of 1-4 years (24). Clearly the cost is prohibitive for most labs. Another approach to laboratory automation is modular systems. In these systems, multiple analytical components can be linked together with a common specimen transport system and specimen and data management unit allowing for increased or decreased testing depending upon present and future testing needs. Systems can be customized on the basis of individual workflow requirements and space considerations. Modular systems can include analytical units as well as preanalytical processing units. The overall implementation of the modular automation strategy has been termed modular stepwise automation (J25). This approach implies that all automation is not implemented at one time and instead pieces are added as the need arises and when there is fiscal justification. For example, many laboratories have adopted the core laboratory approach and have consolidated workstations. Front-end automation may therefore be a consideration. Individual preanalytical components are manufactured by a number of companies and can be used as stand-alone units. Some of these manufacturers include Labotix, MDS/Autolab, and Lab Interlink. A potential disadvantage of the modular strategy is compatibility among modules, specifically with respect to LIS and LAS communication and other electronic and mechanical interfaces. The NCCLS (J26) and international organizations are currently in the process of developing automation standards. Incompatibility may potentially be avoided by using components from one manufacturer. Modular systems with an immunoassay component have been introduced, or are in development, from three manufacturers. The Abbott Diagnostics ARCHITECT, the Roche Diagnostics Modular System, and the Bayer Corp. Advia Integrated Modular System (IMS) all have a common specimen handling and transport

mechanism and the ability to tailor the number and type of analytical units based on test and workflow requirements. The first Abbott ARCHITECT analytical unit to reach the market is the i2000 immunoassay module analyzer. One individual unit is capable of generating 200 tests/h with an on-board capacity of 25 tests. Up to four individual modules can be linked together (i4000, i6000, i8000) to achieve up to 800 tests/h and operated through a single user interface and control center. Adding additional modules results in combined throughput and test capacity of the individual units. Specimens are continuously added to the system in the sample handling center in 5-position carriers. A single queue can accommodate 25 carriers (125 tubes) while a double queue can accommodate 50 carriers (250 tubes). The supply center for consumables has a 5-h walk-away capacity. The i2000 uses a patented acridinium label (J27), providing an improved light yield compared to traditional chemiluminescence detection and paramagnetic microparticles as a capture mechanism. The majority of assays on the i2000 will be true two step in format in order to increase assay performance; however, as a result of instrument design, throughput is not affected by assay format including multiple wash steps and specimen pretreatment. The combination of instrument and assay design, termed CHEMIFLEX by Abbott, is intended to provide enhanced sensitivity and extended linear ranges. ARCHITECT workstations, consolidating immunoassay analysis with chemistry testing, are planned with the addition of a chemistry module (c8000) to the i2000. The ARCHITECT can also be integrated into a track operation. Roche Diagnostics has introduced the MODULAR System incorporating chemistry, immunoassay, and preanalytic components. Currently available modules include two ISE, D, and P modules. The D module, for high-throughput chemistry testing, has 16 channels and dispenses reagents similar to the Boehringer Mannhiem/Hitachi 747 analyzer. The P module, for chemistry, special protein, and drug testing, has 44 channels and pipets reagents similar the Boehringer Mannhiem/Hitachi 917 analyzer. The E module, in development, will provide immunoassay testing similar to the Elecsys analyzer. A total of 25-100 assays can be accommodated on-board the E module with 170-680 tests analyzed per hour for combinations of between one and four modules. Preanalytical units for centrifuging, decapping, aliquoting, barcoding, labeling, recapping, and sorting will also be incorporated into the MODULAR system. The workstation, with numerous configurations and module combinations, has one sample and user interface and one host connection. Five specimen position sample racks are transported to the analytical units via a high-speed primary transport lane where specimens are sampled from separate processing lanes within each module. An additional rerun lane allows automatic rerouting of specimens for reflex or repeat testing. Throughput and stat processing are optimized by software which prioritizes analysis by directing racks to available modules. Bayer Corp. also has a modular system in development for chemistry and immunoassay testing. The ADVIA IMS is part of the ADVIA line which includes hematology (ADVIA 120) and chemistry (ADVIA 1650) instrumentation, and a laboratory automation system (ADVIA LabCell). The IMS will initially consist of three modules, a base unit, a homogeneous clinical chemistry module, and a heterogeneous immunoassay module. Similar to

the other modular systems, individual components can be combined in various configurations and modules can be added to adapt to changing workflow requirements. The base module consists of the sample handler and the predilution/pretreatment ISE (PDI) module. Specimens are loaded in the sample handler via 8 position racks with a capacity of 144 specimens. There is also a stat queue where stat specimens as well as assay reagents, controls, and predilution/pretreatment materials enter the system. Controls and predilution/pretreatment materials are stored in a refrigerated carousel in the PDI module. Specimens, reagents, calibrators, controls, and other materials are transported individually to the appropriate modules by the single overhead robotic transport system. Following analysis, specimens not requiring dilution, repeat, or reflex testing are returned to an output queue in the base module. The analytical units are similar in design with the exception of detection method, colorimetry for the chemistry module and chemiluminescence for the heterogeneous immunoassay module. Units have a refrigerated compartment containing 36 two-reagent locations. Reagents are reconstituted on-board. The IMS design allows connection to automated track systems including the ADVIA LabCell (J28). Test Menu. The number of assays available on immunoassay platforms continues to grow in number with increases in depth as well as breadth. As an example, through 1998, 76 assays have been launched on the Abbott AxSYM compared to 32 in 1994. Tests now cover categories including thyroid, fertility, cardiac, anemia, tumor markers, therapeutic drugs, drugs of abuse, toxicology, adrenal/pituitary, reproductive, allergy, infectious disease, transplant, bone metabolism, cytokines, and other special proteins. Many new tests have been developed in the infectious disease arena, particularly those for hepatitis. A number of novel tests have also been automated including complexed PSA (cPSA) and Her2/neu on the Bayer Immuno 1, IGF-1 and calcitonin on the Nichols Advantage, crosslaps on the Elecsys 2010, and homocysteine on the Abbott IMx. The number of homogeneous assays, particularly for therapeutic drugs and drugs of abuse, have also been increasing in order to consolidate testing onto chemistry analyzers. Homogeneous assay techniques currently employed include EMIT, FPIA, cloned enzyme donor immunoassay (CEDIA), and kinetic interaction of microparticles in solution (KIMS), as well as turbiditry, nephelometry, agglutination, and flow cytometry. Flow cytometry is the basis of the coupled particle lightscattering (Copalis) analyzer by DiaSorin. This homogeneous technique measures changes in light-scattering properties of particles when they form antibody-mediated complexes (J29). Pulses of scattered light are produced as particles or aggregates flow past the incident light beam in a focused laser channel. The ability to discriminate between multiple particles of different sizes allows simultaneous testing and thus the analysis of multiple analytes in the same specimen. This approach has been applied to an assay for antibodies to toxoplasma, rubella, and cytomegalovirus (ToRC assay) which is now commercially available in the United States. The ability to test for multiple analytes, although not simultaneously, is the concept behind the recently launched Stratus CS by Dade Behring. This dedicated analyzer, designed as a point of care device, measures CK-MB, myoglobin, and troponin I in plasma using individual TestPaks for the three Analytical Chemistry, Vol. 71, No. 12, June 15, 1999

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analytes. An on-board centrifuge spins a whole blood sample prior to analysis. Similar to this approach, analyzers for specific tests and applications are being developed by a number of manufacturers. Future Trends. Significant progress has been made in immunoassay technology and automation on both the large scale and the small scale (J30, J31). On the large scale, it is likely that current trends of integration of immunoassays and immunoassay systems with other laboratory testing and instruments will continue. Although currently prohibitive in price, laboratory automation will become more attainable through the modular approach. The ability to consolidate analyzers will be aided by increased test availability and development while multiple analyte testing will increase to provide more efficient and timely testing. On the small scale, multiple analyte testing has also been proposed using the microspot approach (J32). Miniaturized analytical devices being developed such as microarrays and microchips will move immunoassay testing to the bedside (J33-J35). Therefore, the next several reviews may introduce products from new startup companies in addition to reviewing those from the traditional diagnostics industry manufacturers. Lori J. Sokoll, Ph.D., is a clinical chemist at the Johns Hopkins Medical Institutions. Dr. Sokoll received a B.A. in biological sciences from Cornell University, a master of clinical chemistry degree from Hahnemann University, and a Ph.D. in nutrition from Tufts University. She joined the faculty of the Johns Hopkins University following completion of their postdoctoral training program in Clinical Chemistry. Daniel W. Chan, Ph.D., DABCC is the Director of the Clinical Chemistry Division of the Johns Hopkins Hospital and Professor of Pathology, Oncology, Urology, and Radiology at the Johns Hopkins University School of Medicine. Dr. Chan received his B.A. in biology from the University of Oregon and his Ph.D. in biochemistry from the State University of New York at Buffalo. After completion of postdoctoral training in clinical chemistry at the Erie County Laboratories in Buffalo, he joined the faculty of the Johns Hopkins University. Dr. Chan is on the Board of Editors of Clinical Chemistry, the Journal of Clinical Ligand Assay, Journal of Immunoassay, Clinica Chimica Acta, and International Journal of Biological Markers. His current research interests include tumor markers, prostate and breast cancer, endocrine assays and immunoassay automation. Dr. Chan is the editor of three books on immunoassays and automation and has published over 140 articles.

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(J3) Chan, D. W., Ed. Immunoassay Automation: A Practical Guide; Academic: San Diego, CA, 1992; pp 1-367. (J4) Chan, D. W., Ed. Immunoassay Automation: An Updated Guide to Systems; Academic: San Diego, CA, 1996; pp 1-312. (J5) Wild, D., Ed. The Immunoassay Handbook; Stockton: New York, 1994; pp 137-239. (J6) CAP Today 1998, 12, 54-72. (J7) Advance/Lab. 1998, 7, 96-107. (J8) Laboratorian Desk Reference; Clinical Ligand Assay Society: Wayne, MI, 1997; pp 1-112. (J9) Price, C. P., Newman, D. J., Eds. Principles and Practice of Immunoassay; Stockton: New York, 1997; pp 1-667. (J10) Diamandis, E. P., Christopoulos, T. K, Eds. Immunoassay; Academic: San Diego, CA, 1996; pp 1-579. (J11) Kost, G. J., Ed. Handbook of Clinical Automation, Robotics, and Optimization; Wiley-Interscience: New York, 1996; pp 1-952. (J12) Bissell, M. G., Petersen, J. R., Eds. Automated Integration of Clinical Laboratories: A Reference; American Association for Clinical Chemistry: Washington, DC, 1998; pp 1-152. (J13) Kricka, L. J., Ed. J. Clin. Ligand Assay 1998, 21, 347-391. (J14) Chan, D. W., Sokoll, L. J., Eds. J. Clin. Ligand Assay 1999, 22, 1-60. (J15) Kisner, H. J. Clin. Lab. Man. Rev. 1999, 13, 53-61. (J16) Li, D. J.; Sokoll, L. J.; Chan, D. W. J. Clin. Ligand Assay 1999, 21, 377-385. (J17) Felder, R. A. J. Clin. Ligand Assay 1999, 22, 13-24. (J18) Painter, P. C. In Immunoassay Automation: An Updated Guide to Systems; Chan, D. W., Ed.; Academic: San Diego, CA, 1996; pp 13-28. (J19) Klee, G. G.; Hinz, V. S. In Immunoassay Automation: An Updated Guide to Systems; Chan, D. W., Ed.; Academic: San Diego, CA, 1996; pp 63-101. (J20) Day, R. G.; Horschke, W. A.; Hallahan, M.-T.; Jackson, T.; Williams. J. S. J. Clin. Ligand Assay, in press. (J21) Witherspoon, L. R.; Babson, A. L.; Olson, D. R. In Immunoassay Automation: An Updated Guide to Systems; Chan, D. W., Ed.; Academic: San Diego, CA, 1996; pp 103-130. (J22) Gupta, M. K. In Immunoassay Automation: An Updated Guide to Systems; Chan, D. W., Ed.; Academic: San Diego, CA, 1996; pp 201-214. (J23) Blick, K. E. J. Clin. Ligand Assay 1999, 22, 6-12. (J24) Bauer, S.; Teplitz, C.; Bissell, M. G.; Petersen, J. R.; Wozniak, A. A. In Automated integration of clinical laboratories: a reference; Bissell, M. G., Peterson, J. R., Eds; AACC Press: Washington, DC, 1998; pp 134-144. (J25) Felder, R. A.; Kost, G. J. Med. Lab. Observer 1998, 30, 23-27. (J26) AUTO3-P. Laboratory automation: communications with automated clinical laboratory systems, instruments, devices, and information systems; proposed standard; National Committee for Clinical Laboratory Standards: Malvern, PA, 1998. (J27) Adamczyk, M.; Chen, Y.-Y. J. Org. Chem. 1998, 63, 56365639. (J28) Campanelli, M. J. Assoc. Lab. Autom. 1998, 3, 46-48. (J29) Benecky, M. J.; McKinney, K. L.; Peterson, K. M.; Kamerud, J. Q. Clin. Chem. 1998, 44, 2052-2054. (J30) Wheeler, M. J. J. Int. Fed. Clin. Chem. 1997, 9, 98. (J31) Price, C. P. Clin. Chem. Lab. Med. 1998, 36, 341-347. (J32) Ekins, R. P. Clin. Chem. 1998, 44, 2015-2013. (J33) Kricka, L. J. Clin. Chem. 1998, 44, 2008-2014. (J34) Silzel, J. W.; Cercek, B.; Dodson, C.; Tsay, T.; Obremski, R. J. Clin. Chem. 1998, 44, 2036-2043. (J35) Chiem, N. H.; Harrison, D. J. Clin. Chem. 1998, 44, 591-598.

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