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Laboratory Automation

Review Article

Clinical Chemistry Laboratory Automation in the 21st Century -


Amat Victoria curam (Victory loves careful preparation)

David A Armbruster,1 David R Overcash,2 Jaime Reyes2


1
Global Scientific Affairs, Abbott Diagnostics, Chicago, IL, USA; 2Global Marketing, Abbott Diagnostics, Chicago, IL, USA.
*For correspondence: David Armbruster, David.Armbruster@abbott.com

Abstract
The era of automation arrived with the introduction of the AutoAnalyzer using continuous flow analysis and the Robot Chemist
that automated the traditional manual analytical steps. Successive generations of stand-alone analysers increased analytical
speed, offered the ability to test high volumes of patient specimens, and provided large assay menus. A dichotomy developed,
with a group of analysers devoted to performing routine clinical chemistry tests and another group dedicated to performing
immunoassays using a variety of methodologies. Development of integrated systems greatly improved the analytical phase of
clinical laboratory testing and further automation was developed for pre-analytical procedures, such as sample identification,
sorting, and centrifugation, and post-analytical procedures, such as specimen storage and archiving. All phases of testing were
ultimately combined in total laboratory automation (TLA) through which all modules involved are physically linked by some kind
of track system, moving samples through the process from beginning-to-end. A newer and very powerful, analytical methodology
is liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). LC-MS/MS has been automated but a future
automation challenge will be to incorporate LC-MS/MS into TLA configurations. Another important facet of automation is
informatics, including middleware, which interfaces the analyser software to a laboratory information systems (LIS) and/or
hospital information systems (HIS). This software includes control of the overall operation of a TLA configuration and combines
analytical results with patient demographic information to provide additional clinically useful information. This review describes
automation relevant to clinical chemistry, but it must be recognised that automation applies to other specialties in the laboratory,
e.g. haematology, urinalysis, microbiology. It is a given that automation will continue to evolve in the clinical laboratory, limited
only by the imagination and ingenuity of laboratory scientists.

Introduction and integrated laboratories that perform millions of tests each


“In the early 1960s satellites were circling our planet, President year”.2 The present paper attempts a sweeping but concise
Kennedy had committed the US to put a man on the moon by review of clinical laboratory automation. Modern laboratory
the end of the decade, and graduate students in the Department practice in developed nations has long moved beyond
of Biochemistry of the University of Tennessee were making piecework manual procedures and uses fully automated
predictions on the future of analysis (mostly manual at the systems, often integrated platforms coupling clinical chemistry
time) of body fluids. Over a pitcher of cold beer on a hot and and immunoassay analysers, pre- and post-analytical modular
humid summer day, one of us dared to predict that someday systems, and even total laboratory automation (TLA), to join
there would be instruments in which you could put serum or those pre- and post-analytical devices with several analytical
even whole blood at one end and get the results at the other; modules. Overlying this automation, to whatever extent it
‘printed too,’ concluded the optimist of the group”.1 This quote exists, is informatics: comprehensive software to manage
from Doumas is an appropriate opening for a paper on clinical the diverse functions of the modern laboratory, ranging from
chemistry automation. Also apt is an observation from a paper reagent inventory management to optimised sample workflow
presenting an historical perspective of clinical chemistry by to sophisticated result reporting that provides ‘value-added’
Kricka and Savory: “This discipline, which could originally clinical interpretation. A book-sized publication would
be practised in small laboratories in which relatively few be required to do justice to all of these topics and what is
manual tests were performed, now requires highly automated presented here is of necessity only a high level overview.

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Clinical Chemistry is a fairly new specialty, an amalgam of spectrometry (GC-MS), and liquid chromatography-tandem
chemistry and medicine. As observed by Henry Bence Jones mass spectrometry/mass spectrometry (LC-MS/MS), plus
(1813-1873, of Bence Jones protein fame) “Whatever sets various ligand assay methodologies, including fluorescence
forth the union of chemistry and medicine tends to promote polarisation immunoassay (FPIA), enzyme immunoassay
not only the good of science but also the welfare of mankind”.3 (EIA), radioimmunoassay (RIA), and chemiluminescence
“By 1840, approximately 1400 organic compounds were immunoassay(CMIA).4
known, and the period around 1840 is regarded as the point
of origin of the discipline ‘clinical chemistry’, especially Olsen observed in an understatement that: “Laboratory
in the German-speaking world, because it was then the automation today is a complex integration of robotics,
first textbooks, handbooks, and journals appeared”.4 Early computers, liquid handling, and numerous other
on, the discipline was called ‘pathological chemistry’ or technologies”.6 The purpose of automation is to save time
‘chemical pathology’, with ‘clinical chemistry’ eventually and improve performance through the elimination of human
becoming the accepted term after it was introduced by the error. Automated systems are built around the microprocessor
American Association of Clinical Chemistry (AACC) and and computers. Stand-alone automated systems by and large
the International Federation for Clinical Chemistry (IFCC).4 did not appear until the 1950s when they could be reliably
“Clinical Chemistry” (1883) by C.H. Ralfe of the London produced by commercial laboratory equipment manufacturers.
Hospital was the first book in English to carry the title clinical The marriage of clinical chemists working independently
chemistry.3 Current estimates suggest that perhaps about with a new in vitro diagnostics industry meant that “What
200–300 analytes are routinely tested in clinical laboratories was an engineering challenge for one generation of scientists
with about 1,000 analytes in total being subject to analysis in frequently became off-the-shelf technology for the next”.6
various facilities.4 Currently the challenge is to use automation to enhance early
diagnosis and preventive medicine, caring not only for the
Early on, Clinical Chemistry relied on traditional analytical individual patient but society at large.4
methods such as atomic absorption, flame emission
photometry, gasometry, potentiometry and amperometry, We are preconditioned, having enjoyed many years of
spectrophotometry, immunonephelometry (for competitive laboratory automation, not to question its value. But a word
and sandwich immunoassays) and electrophoresis and the of caution is advisable. As Rosenfeld noted, “In the closing
wide variety of analysers needed for these methodologies.5 A decades of the 20th century, automated devices produced an
clinical laboratory might have consisted of a hodge-podge of overabundance, and an overuse and misuse of testing to the
different devices, each devoted to perhaps one or only a few detriment of careful history taking and bedside examination
analytes and each requiring a medical technologist to operate of the patient. This is attributable in part to a fascination with
it. Rosenfeld opined that “Folin’s use of the Duboscq-type machine-produced data.”3 Undoubtedly this is a reference to
colorimeter for colour comparison in the quantitative analysis the widespread use of screening by testing for a large number
of creatinine in urine in 1904 ushered in the modern era of of analytes not because the data is necessary for diagnosis/
clinical chemistry”.3 By the 1960s, colorimetric methods had treatment but because the capability is readily available and
been adapted to the photometer and the manual processes it may be easier to order an extensive panel of tests than to
were being adapted to the continuous-flow autoanalyser, request only the specific analytes pertinent to a given patient’s
displacing some of the individual analysers.3 case.

Clinical Chemistry is a polyglot discipline combining Early Automated Analysis


chemistry, biochemistry, immunochemistry, endocrinology, In the 1956, Leonard Skeggs developed the first practical and
toxicology (abused and therapeutic drug testing), analytical completely automated system for measuring urea, glucose,
chemistry, engineering, informatics and doubtless other and calcium, the AutoAnalyzer, an instrument designed to
specialties, to provide the necessary support to physicians meet the specific needs of the clinical chemistry laboratory.4,7,8
and other healthcare providers to improve the diagnosis and It performed blood analysis from start to finish without manual
treatment of patients.4 Modern technology includes colorimetry/ intervention by a technologist. Skeggs developed several
spectrophotometry, nephelometry/immunonephelometry, modules to automate the various steps and his models were
turbidimetry/immunoturbidimetry, atomic absorption, flame manufactured by the Technicon Corporation, Tarrytown, NY,
emission photometry, potentiometry (ion specific electrodes USA. In that year, Skeggs and the Technicon Company fielded
or ISE), and a variety of chromatographic techniques, commercially-available Technicon single and multichannel
including gas chromatography (GC), high performance continuous flow autoanalysers, the initial AutoAnalyzer
liquid chromatography (HPLC), gas chromatography-mass model selling for $3,500.9 It consisted of a dialysis membrane

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Laboratory Automation

for protein-free filtrate, tygon tubing, air bubbles to separate compartments into a reaction chamber. Several manufacturers
patient samples and ‘scrub’ tubing, mixing coils, a flow- introduced centrifugal analysers and these models proved
through cuvette with photometric monitoring and a strip-chart successful for about 20 years in clinical laboratories.
recorder. Later designs offered simultaneous analysis of over
20 analytes at 150 samples per hour. The multichannel systems Just as important as the development of automated analytical
were non-selective batch analysers, that is, they performed an systems was the introduction in the 1950s by the Sigma
array of tests on every sample whether all tests were requested Chemical Company in St. Louis of clinical chemistry ‘kit’
or not. Continuous flow analysis changed the character of methodology- prepackaged, ready-to-use assay reagents, with
clinical chemistry testing so that only minutes instead of instructions for use.7 This was a very significant innovation
hours (or even days) were needed to complete an analysis, and in the field. Automated analysers were a tremendous boon to
personnel were free to develop tests for subspecialties such clinical chemistry but it must be recognised that automation
as toxicology, endocrinology and molecular diagnostics.2 would be only partially successful if reagent kits were not
The autoanalyser reached its highwater mark with the SMAC readily available to ‘feed’ them. Clinical chemists ‘of a certain
(Sequential Multiple Analyzer with Computer) in 1974, which age’ can remember when reagents were prepared manually in
had a built-in computer. clinical laboratories, a practice that is now essentially defunct.

The AutoAnalyzer led to the widespread use of batch The era of automation blossomed after the introduction of
analysers, many of which only measured one analyte but the AutoAnalyzer. Doumas observed that the 1976 edition of
could test up to 100 samples in continuous mode. In the Tietz (Fundamentals of Clinical Chemistry) included a chapter
early 1980s, the photodiode array for spectrophotometers on automation, covering 13 automated analytical systems,
with grating monochromators allowed a sample to be tested one of them the DuPont ACA, an unique and revolutionary
simultaneously for multiple analytes, each test detecting an analyser that enjoyed a long life.1 The next edition of Tietz in
analytical signal at different wavelengths.4 The advantages 1986 (titled “Textbook of Clinical Chemistry”) had a chapter
of the AutoAnalyzer meant less labour, fast analysis, and the on instrumentation that included HPLC, mass spectrometry,
use of screening panels. The disadvantage was the pursuit and guidelines for the selection of instrumentation. The
of the ‘defensive medicine’ concept in response to the threat second edition of the Tietz textbook (1993) deleted from the
of malpractice suits, and this unnecessarily increased the automation chapter the Technicon SMA and another one-time
laboratory workload.10 standard system, the Beckman Astra, but included point-of-
care testing (POCT) and specialised immunoassay analysers,
Not long after the introduction of the AutoAnalyzer and reflecting the then current situation. Spectrophotometry,
the ascendency of continuous flow analysis in clinical previously known as colorimetry, was now being used in
chemistry, a different approach appeared in 1959 with the a wide variety of photometric techniques: fluorescence,
production of the Robot Chemist by the Research Specialties fluorescence polarisation, nephelometry, chemiluminescence,
Company.2,7 The Robot Chemist used discrete analysis with and electrochemiluminescence.2 Discrete analysers, otherwise
conventional cuvettes and automatic pipetting and mixing, known as random access analysers, are selective and perform
essentially automating all of the manual steps performed by only those assays ordered on each sample, and these systems
medical technologists. The Robot Chemist was not ultimately came to the fore. By the 1990s, batch analysers, such as
successful because it was too mechanically complex to be autoanalysers and centrifugal analysers that performed the
practical. It went out of production in 1969, but ironically same assay simultaneously on all samples, were on the wane.
the Robot Chemist proved to be the automation direction Batch analysis still has a role to play, but discrete analysers
manufacturers would take and the discrete analysis model can be used in this mode in addition to performing any number
ultimately replaced the AutoAnalyzer and continuous flow of tests in the random access mode.
analysis.
It is instructive to review some terms to appreciate the various
Another approach to automation was introduced with approaches to automation. Batch analysis means that multiple
centrifugal analysis in 1968, developed by Norman Anderson.2 samples are tested in a ‘run’. In contrast, sequential analysis
Centrifugal analysers are single-test at a time batch analysers means samples are tested one after the other and results are
in which analysis is sequential, discrete, and parallel.11 reported in the same order.11 Continuous-flow analysis is a
Centrifugal analysis uses the motion of a spinning rotor for form of sequential analysis through a continuous stream at a
mixing, thermal equilibration, transport, and measurement. constant rate, e.g. the AutoAnalyzer. With discrete analysis,
Sample and reagents are pipetted into rotor compartments and each sample is tested in a separate cuvette or other reaction
mixed when the rotor spins and they flow over the walls of the chamber with reagents added to each individual sample

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container. Single-channel analysis uses an analytical ‘line’ or analysers that use a unique slide technology. The reagents
channel dedicated to a single test. Multiple-channel parallel are dispersed in emulsions on the slides and the reaction is
analysis uses two or more ‘lines’ or channels, each dedicated activated as the sample diffuses through the layers on the slide.
to a single test, and analysis occurs simultaneously. With The spectrophotometric reading is taken using reflectance
random access analysis, specimens are tested in or out of technology. The slides for the electrolytes contain miniature
sequence with each other, as reaction vessels are available ion-selective electrodes. The slides are conveniently stored
and without regard to accessioning order, although testing of in refrigerators or freezers and are recognised for their
designated specimens, such as stats, may be given priority. convenience. However, it is difficult to develop slides for the
Assays are either end-point tests (reaction is complete after wide variety of analytes and specimen matrices now tested
a fixed time) or continuous monitoring tests (multiple data and slide systems have of necessity been supplemented by
points recorded over a specified time interval).11 The specimen adding conventional open liquid channel options.11
throughput rate depends on the ‘cycle time’ of the analyser
for a fixed sequence of events and the optical measurement Automated Stand-alone and Integrated Analysers
cycle.11 Regardless of the type of analyser, laboratories must A central laboratory may contain a variety of analysers using
consider workload, manpower needs and costs, preventive a mixture of analytical techniques, including electrophoresis,
maintenance, down-time, reagent and disposables cost, service LC-MS/MS, colorimetry/spectrophotometry, potentiometry,
costs, and the instrument cost, when choosing a system. and immunoassay (using various methodologies).8 Some
traditional methodologies such as radioimmunoassay,
The AutoAnalyzer continuous flow, batch analysis atomic absorption, and flame photometry, may still be
paradigm was displaced by discrete systems using positive- retained for reference purposes but are now essentially
displacement pipettes, with various volumes possible, or fixed historical techniques. Typical modern clinical chemistry
volume, for sample processing and reagent dispensing, with analysers use automated discrete systems, as opposed to
some kind of washing step in between sample dispensing batch analysis instrumentation, which allows for an almost
to avoid carryover contamination. Mixing is performed by unlimited mix of analyses on a single instrument, combining
forceful dispensing, magnetic stirring, or mechanical stirring routine clinical chemistry and immunoassay tests and fewer
(rods or piezo-electric mixers). Temperature is controlled by analysers requiring less floor space and greatly improving
waterbaths, heating blocks, or heated air compartments (air operational efficiency.8 Manual procedures, and even semi-
bath). Cuvettes are glass or plastic; the glass cuvettes intended automated procedures, are now relatively rare. Benefits
to be permanent and the plastic cuvettes made to be disposable of replacing manual procedures with automation include:
after a single use or after extended use with replacement after eliminating potentially dangerous, error-prone manual
a set number of tests.11 Most discrete analysers use individual procedures with automated processes requiring minimal
cuvettes, although some may use a type of flow cell. Various technician involvement, increasing productivity, decreasing
types of detectors are used, with a variety of lamp types TAT, improving safety, minimising error, improving sample
(tungsten, quartz halogen, mercury, xenon, and lasers). The handling, and allowing practical reallocation of laboratory
monochromators use interference filters, prisms, or diffraction staff who are freed from manual tasks. As emphasised by
gratings.11 The analytical signal is typically detected using Melanson et al., “Selecting clinical chemistry laboratory
photodiode arrays, allowing a wide variety of wavelengths to automation is a complex, time-consuming process” and
be monitored. “Automation is a customised process that may range from
automating only a few steps of the analytical process to total
The majority of analysers use liquid reagents, either received laboratory automation, depending on the needs and resources
as liquid, ready to use, or reconstituted by the laboratory of each laboratory”.12
after receipt. However, there have been some very successful
analysers that employ ‘dry’ or ‘damp’ reagents. Some of Fully automated low, medium, and high volume analysers are
these systems used a tablet form of reagent, for example, the available as independent units and it is with these systems that
DuPont ACA and the Paramax. Reagents were reconstituted a clinical laboratory typically begins the automation process.
with diluent and mixed with the specimen during analysis. These analysers are designed for a wide range of sample
This was a ‘unit dose’ concept that offered advantages such workloads, and range from small or modest sized benchtop
as avoiding carryover. The disadvantage was that the dry units or large to very large floor models. They routinely
reagents were more expensive than liquid reagents, although employ spectrophotometry for a wide variety of colorimetric
they were more stable and minimised reagent wastage.11 and/or immunoassay tests. They often include an ion specific
The most successful analysers of this type are those from electrode (ISE) module for electrolyte analysis (Na, K, Cl).
Ortho (originally Kodak). Ortho has offered generations of They can offer a large menu of assays or, if used for high

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volume work in reference laboratories, may be dedicated analytical signal. Automated systems now use variations of
to a relatively small number of assays, such as test profiles. both techniques.13 Fluorescent immunoassay (FIA) is perhaps
Typically, the manufacturer of the analyser also provides the best recognised as the automated technique of Fluorescence
reagents for them. If only the proprietary reagents from the Polarisation Immunoassay (FPIA) methodology from Abbott,
instrument manufacturer are suitable for use on the analyser, it long used on the TDx analyser. Automated immunoassay is
is designated a ‘closed system’. If reagents from many vendors also available on the Elecsys, Modular, Hitachi, and Cobas
may be adapted to an analyser, it is designated an ‘open analysers (Roche), Immulite, Vista, Dimension, and Advia
system’. Assay applications for closed systems are optimised analysers (Siemens), Access (Beckman-Coulter), AIA
for them and verified by the manufacturer. Laboratories need (Tosoh), AU analysers (Olympus), and Architect systems
to perform method validation for every assay they adapt to an (Abbott). Some analysers may even employ more than one
open system. It is usually considered desirable for an analyser immunoassay methodology, such as the Siemens Vista.
to have open system capability.
Immunoassay moved away from dedicated special chemistry
During the development and proliferation of fully laboratories to the general core laboratory as fully automated
automated, stand-alone analysers, a dichotomy emerged: systems were made available that allow both homogeneous
mainstream clinical chemistry systems using colorimetry/ and heterogeneous immunoassays to be performed on
spectrophotometry and immunoassay systems that used a general purpose chemistry analysers.13 However some
variety of other analytical techniques. Radioimmunoassay immunoassays use methodologies such as nephelometry
(RIA) was developed by Yalow and Berson in 1959 and and immunoturbidimetry that stand in contrast to routine
resulted in the award of the Nobel Prize in Medicine in 1977. techniques.14 A variety of stand-alone immunoassay analysers
They did not patent RIA, making it easier for others to further were introduced and operated side by side with clinical
develop the technique. Monoclonal antibodies developed chemistry instruments, nicely complementing each other,
by Millstein and Kohler (Nobel Prize in 1984), improved but at the cost of maintaining multiple independent systems.
specificity of antibodies. Fusion mouse myeloma cell Examples included the Abbott TDx, a successful automated
lines (‘immortal’ lines) and B-cell lymphocytes producing batch FPIA analyser, later replaced by the IMx which could
antibodies, resulted after screening, in cell lines producing perform multiple immunoassay tests in a single analytical
specific monoclonal antibodies indefinitely.13 Variations of run, both now retired. Batch immunoassay was replaced
immunoassay appeared, such as IRMA (immunoradiometric by random access immunoassay, such as the Ciba Corning
assay with lower limits of detection than RIA and analyte ACS:180 and the Abbott AxSYM, and now systems such as
concentrations directly proportional to increasing signal), the Abbott Architect and the Siemens Vista.
and EIA (enzyme immunoassay), including EMIT (enzyme
multiplied immunoassay technique, patented by the Syva Multiplex, or multivariate, analysis through various techniques
Company), ELISA (enzyme labelled immunosorbent assay), allows two or more analytes to be measured simultaneously.
cloned enzyme donor immunoassay (CEDIA), microparticle Multiplexing offers an obvious advantage in speed of analysis
enzyme immunoassay (MEIA), and fluorescence polarisation however a potential disadvantage is reimbursement for clinical
(FPIA).14 Enzyme tag immunoassays are still used effectively laboratory testing may not allow for payment of analyte test
on general purpose clinical chemistry analysers, such as with results that are not specifically ordered.13
EMIT and CEDIA assays. Fluorescent and chemiluminescent
tag assays are also available, allowing quantification at lower Inevitably, clinical chemistry and immunoassay analysers
analyte concentrations, but they require specialised detection were merged as ‘integrated’ systems, combining immunoassay
systems and typically separate analysers. with spectrophotometric and potentiometric assays.15
Clinical chemistry analysers already offered immunoassays
RIA was automated by Becton-Dickinson with the ARIA such as EMIT tests, reading the analytical signal using a
and ARIA-II instruments but these analysers were short- spectrophotometer. Adding an immunoassay unit with a
lived. EMIT, using non-isotopic labels, allowed for practical different methodology dramatically increased the spectrum
automation of immunoassay. Homogeneous assays such as of assays that could be offered. Of course a laboratory could
EMIT do not separate bound from unbound constituents, maintain separate clinical chemistry and immunoassay
but heterogeneous (sandwich) assays use a separation analysers if it desired instead of using integrated systems.
step to improve selectivity and sensitivity by separating Large integrated systems provide advantages over multiple
the antibody bound analyte from the other constituents of smaller systems but, if they are disabled for any reason, a
the assay mixture. Sandwich immunoassays use a capture laboratory may lose the ability to perform testing unless it has
antibody first and a second labeled antibody to generate the back-up systems (although some can continue to operate either

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the clinical chemistry or immunoassay module if the other is provides most of the major benefits of TLA without the cost of
inoperable). Thus laboratories must carefully consider their a track. With stand-alone automation, sample transport is still
options if they rely almost totally on a single integrated system. performed manually by the laboratory staff, sometimes called
Multiple smaller systems provide for redundancy, but require the ‘sneaker network’. The stand-alone options offer a smaller
more maintenance and cross-analyser method comparisons to footprint (some components are even bench top modules) and
establish and maintain equivalency of test results. The ability lower cost, and thus may be good choices for laboratories
to load new reagents during analyser operation (‘on-the-fly’ with limited floor space.
loading) instead of pausing an analyser to replenish reagents,
is an advantage. Open channels for assays not available from Beginning in the 1970s, the clinical laboratory saw the
the instrument manufacturer are also desirable.12 introduction of robotics and informatics allowing for great
leaps forward in automation, leading to the development of
Sample throughput and turn-around-time (TAT) of automated TLA.8 TLA is generally defined as laboratory automation
systems vary with the size and capability of analysers that includes pre-analytical, analytical, and post-analytical
and the complexity of the assay mix and test volume. operations.16 Automated systems that lack one of these
Marketed throughput and TAT values are dependent on the components are subtotal. In the early 1980s, Dr. Masahide
actual test orders and sample volume and represent only a Sasaki at the Kochi Medical School, Kochi, Japan, developed
‘ballpark estimate’ under manufacturer defined conditions. conveyor belt systems, robots to load and unload analysers,
Manufacturer suggested throughput/TAT are not disingenuous and process control software, and is credited with the first
numbers touted by vendors to lure customers but usually a attempt at TLA.10 By the 1990s a few companies began
good faith, rough estimate, best guess under likely real-world offering automation but these systems were expensive and
testing scenarios. The oft reported caveat for automobiles had limited functionality, and generally fell somewhat short
is “Your actual mileage may vary,” and paraphrased for of TLA. Some clinical chemists fielded their home-made,
automated analysers becomes “Your actual throughput/TAT in-house TLA systems, but they were limited to the facility
may vary.” in which they were created and their sustainability was
questionable without the key personnel who developed and
Integrated systems offer the advantage of consolidation. It is supported them.
preferable to place as many assays on a single analyser than
to maintain two or more analysers because each instrument TLA combines a wide variety of processes, including
will require separate QC, preventive maintenance, record accessioning and sorting specimens, decapping tubes,
keeping, etc. For a laboratory large enough to need multiple centrifugation, aliquoting, delivery to analysers, recapping
analysers or for an integrated delivery system (a medical care tubes, and storage and archiving of samples.8 TLA’s advantages
network) consisting of two or more laboratories, it is highly include the standardisation of testing to improve patient care,
desirable to use a family of analysers. This might consist of eliminating the always present potential of human error in
duplicate instruments or a mixture of analysers from the same the handling and testing of samples. TLA also allows for the
manufacturer but designed for different sized workloads. reduction of sample handling steps, decreasing the likelihood
Analysers belonging to the same family, use common of handling errors and improving patient safety. In addition,
calibrators, controls, reagents, cuvettes or reaction vessels, TLA increases productivity, decreases and standardises turn-
disposables, methodology, and software, which is distinct around time (TAT), improves safety, and allows manpower to
advantage. Most important, the commonality of analysers be reallocated for optimisation of those tasks that cannot be
belonging to the same family should guarantee equivalent automated. Laboratories adapt TLA to handle ever-increasing
test results so that it makes no difference which instrument workloads and demands for quicker TATs and standardisation of
is used to test a patient sample. The reference intervals and laboratory operations. Highly efficient TLA can even eliminate
medical decision levels are equally suitable for all analysers. the need for separate STAT laboratories, depending in part
Automated analysers may be supplemented with stand-alone on the ability to get STAT samples to the central laboratory.
pre-analytical and/or post-analytical systems, which can be TLA is ideally suited to core laboratories that conduct a wide
described as partial or task-targeted automation. spectrum of testing using highly automated systems coupled
with sophisticated laboratory information systems (LIS).
Laboratory Automation and Total Laboratory Automation
There are two approaches to automation: stand-alone or task- The challenge for laboratory directors is to balance cost with
targeted automation and total laboratory automation. TLA is the goals of analytical quality, patient safety and clinical service
distinguished by the presence of some sort of track system that needs. TLA offers a potential solution and has been adapted
connects the various components. Stand-alone automation in various forms by clinical laboratories world-wide.12 Given

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that all modern analysers are fully automated, ‘automation’ to process a wide variety of sample tubes; centrifugation
here refers to the pre-analytical and post-analytical manual capability as part of the track; stat handling capability;
procedures of testing. The important considerations to be repeat testing and dilutions functions; refrigerated storage
examined when considering TLA include: methods (provide and retrieval unit; decapping/re-capping of primary tubes;
for the existing assays and also allow for open channel TAT; throughput; service availability; assay quality; potential
applications); TAT (aim for achieving desired TAT about 90% for sample carryover; clot detection; detection of sample
of the time); specimen handling (allow for stats, decrease integrity or HIL; ability to handle small sample volumes (e.g.
manual procedures, check for haemolysis/icterus/lipemia paediatrics),18 open system option;19 hands on technologist
(HIL)); ability to locate, retrieve, and test a sample for time (e.g. preventive maintenance, reagent preparation, QC
dilution, repeat, or add-on testing; throughput (accommodate and calibration); environment, space, heat, noise, and water
fluctuating loads through the day); cost (be affordable and consumption considerations; informatics (e.g. interface with
even decrease operating costs over time); ability to operate existing LIS/HIS, middleware to bridge the analysers and
with a laboratory information system (LIS; communicate with LIS).12
the LIS and provide middleware); environment and safety
(decrease health hazards); downtime and service (require A track system is integral to TLA. ‘Laboratory streets’ or
minimal preventive maintenance and downtime and service ‘laboratory assembly lines’ have sometimes been used as
will be readily available).12 alternative descriptions for the track.4 The track may either
be a dual lane circular, or ‘loop’, layout or a linear, or
The first step towards TLA is to conduct a thorough, detailed ‘unidirectional’, design.8 Circular tracks allow samples to
analysis of the current laboratory processes, i.e. a workflow return to various analysers attached to the track but can require
analysis. It will demonstrate the strengths and weaknesses of more floor space. Specimen carriers should be standardised
the current system, whether it be manual, semi-automated, or and racks, typically with capacity for five samples, are
automated, and identify the steps that can be eliminated or routine. The sample handling module must provide error
improved by TLA. The old saw is true: applying automation free specimen identification using barcodes or RFID labels.
to the current, suboptimal process only serves to automate a Software must allow the sample ID to be read and to obtain
poor process.12 Moving from multiple automated systems to associated patient information, including the tests requested,
TLA is a big, complicated, and expensive step for a laboratory. from the LIS.8 Such process control software is often called
Hawker very appropriately notes that failure to properly the laboratory automation system (LAS). The LAS should
analyse the needs of the laboratory and understand the current determine the number of aliquots and sample volume for
state and processes in the laboratory are the primary reasons each specimen, route the samples to the analysers, recap the
why automation projects are not successful, or at least do samples and store them for future testing or until disposal,
not live up to the initial expectations of the adapters.16 The and also control sample level detection, and HIL/integrity
workflow analysis completely maps the current processes evaluation. LAS or middleware includes autoverification and
from specimen receipt, testing, reporting, and storage/disposal autoretrieval capability for repeat or reflex testing and dilution
of specimens. Hawker lists ten reasons why automation can testing. The racks and the track must be able to handle a wide
fail to deliver on its promise: incomplete understanding of the variety of primary collection tube sizes and types and also
current non-automated process; lack of flexibility due to fixed sample cups placed in tube adapters. The major instrument
processes and limited throughput; unrealistic expectations; manufacturers provide track systems and tracks and they
poorly executed workarounds to interface automated are also available from independent automation vendors as
and manual processes; unclear expectations of system well. Laboratoriess must confirm that a track is compatible
functionality; unnecessarily complicated designs; inadequate with analysers other than those from the track manufacturer.
technical support; failure to conduct realistic impact analysis; The theoretical throughput claimed by a manufacturer may
hidden costs (labour, supplies, maintenance); and failure to not match reality. This is not necessarily a false claim by the
optimise the current processes prior to automation (never manufacturer as throughput and TAT will logically be affected
automate a poor process). As a rule-of-thumb, a good TLA by the actual sample volume and the exact number and type
system should handle at least 80% of the workload. of tests requested for each sample. Very efficient integrated
analysers combining clinical chemistry and immunoassay
TLA involves some kind of track system that connects the systems are attached separately to tracks and some advantages
pre-analytical, analytical, and post-analytical components. of the stand-alone integrated clinical chemistry/IA systems
Melanson et al. have carefully described the key criteria: may be lost when this happens.12 Although not considered
track design and analyser connection; unambiguous sample here, haematology, coagulation, urinalysis, and microbiology
identification; aliquoting of primary sample tubes; ability analysers may also be part of a track system.

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Expert rules based software allows for automatic release of discussed. These methodologies are widely used but often in
test results without issues and flags results that require human more specialised laboratories and LC-MS/MS is the analytical
attention and review.17 The goal is hands-off, walk-away technique that has gained most attention in recent years. As
operation, but technologists are still required for analyser explained by Greaves, “The relatively new implementation
maintenance and operation, replenishing reagents and of liquid chromatography coupled with tandem mass
disposables, responding to analyser messages, and loading spectrometry (LC-MSMS) techniques as routine assays in
specimens onto the initial sample processing module. diagnostic laboratories provides the unique opportunity to
harmonise, and in many cases standardise, methods from an
Laboratories must be realistic and recognise that TLA is not early stage”.19
a panacea. They should use only as much automation as is
necessary and appropriate. Stand-alone sample processing LC has been used in clinical laboratories in the form of HPLC
units seem to make sense for laboratoires with daily workloads since about the 1980s and was then coupled with MS.20 LC
of 500–2,000 samples/day. Laboratories with larger workloads allows for separation of analytes and MS breaks down analytes,
can expand automation to include a track to interface with identifies the resulting ion fragments, and quantitates them.
analysers and provide specimen storage/retrieval capability. A Currently, LC-MS/MS represents the analytical state of the
laboratory can mix and match modules to achieve the desired art because the dual MS technique provides better selectivity
configuration. If TLA appears to be the answer, it is important and resolution of analytes than a single MS unit. LC-MS/
to know if a system is ‘closed’, that is, only compatible with MS is now routine in many large, sophisticated laboratories,
analysers from the same vendor as the processing units, or providing significant analytical improvements and potential
‘open’, meaning analysers from other manufacturers can be cost savings.20 It offers advantages specifically for drugs
attached to it. of abuse testing, therapeutic drug monitoring (TDM), and
endocrinology.
Does TLA deliver on its promise or is it overkill? That is a
question each laboratory must answer, and the conclusion Immunoassays made it possible to measure dozens of
should be based on hard data. Sarkozi et al. presented a individual proteins and other analytes, but sometimes the
compelling argument in favor of TLA at their facility.10 They results are misleading due to a lack of concordance across
calculated, when expressed in constant 1965 dollars, the multiple methods/platforms, and due to autoantibodies,
total cost per test decreased from $0.79 to $0.15 between anti-reagent antibodies (heterophile antibodies), anti-animal
1965-2000 and the TAT decreased so that stat samples antibodies (human anti-mouse antibodies, HAMAs), and the
requiring a TAT of < 1 hour did not need to be prioritised high-dose hook effect. In addition IA suffers from the high
and tested separately. The introduction of a robotics system cost of antibodies, lot-to-lot differences, calibration bias, and
for perianalytical automation brought large improvements in crossreactivity.21 These issues can be avoided with tandem LC-
productivity together with decreased operational costs, even MS/MS.22 The strengths of LC-MS/MS include: wide range
though the workload increased significantly and the number of analytes that can be measured, high sensitivity (exceptional
of personnel decreased. In fact, despite a dramatic increase limit of detection), specificity, precision, accuracy, and the
in productivity, the staff was reduced by 24% over time. In capability of multiplexed analysis.21 Automated IA using
their analysis, productivity increased by 58.2% as measured chemiluminescence provide low LoD (e.g. 10–100 pg/mL)
by tests/employee, and 82% as measured by specimens per but LC-MS/MS tests can detect substances down to about
employee. A dramatic reduction in total cost per test was due 1 pg/mL and are suitable for drugs and hormones such
almost entirely to the reduction of labour due to increased as testosterone and estradiol.5 IA antibodies can measure
productivity and spare capacity in the system allowed for a multiple analytes, such as the members of a large drug family,
significant increase in volume without any increase or minimal but may also bind to many unwanted, interfering substances
increase of personnel. This is the kind of hard data required to and lack the specificity of LC-MS/MS.
objectively evaluate the return on investment of TLA.
Of course LC-MS/MS has its drawbacks. The initial cost
LC-MS/MS of equipment is high, but the cost of reagents for extraction
A review of current developments in laboratory automation and analysis are typically lower than that of IA.5 The lack of
would not be complete without inclusion of liquid universal, routine, standardised LC-MS/MS methods means
chromatography-mass spectrometry/mass spectrometry individual laboratories must develop their own methods,
(LC-MS/MS), or LC tandem mass spectrometry.18 Related which is difficult and time-consuming. Ready to use methods
chromatographic methods, such as gas chromatography from vendors are not yet widely available. LC-MS/MS
(GC), high performance liquid chromatography (HPLC), and suffers from interference caused by ‘ion suppression’ by
gas chromatography-mass spectrometry (GC-MS) will not be which interfering compounds in the sample matrix decrease

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the signal of the target analyte(s). IA offers 24 hour testing Partnering of immunoassays with LC-MS/MS has proven
capability while LC-MS/MS is not always available round the a happy marriage in drugs of abuse testing.20 Screening
clock due to its complexity. Tandem MS cannot distinguish immunoassays reveal specimens that contain a wide variety
compounds of the same mass and may require adjustment of drugs, producing putative positives, and confirmation and
to the chromatographic settings to separate compounds quantitation of the screen positive samples is performed using
prior to entering the mass spectrometer. The usual clinical LC-MS/MS. In specialised TDM for immunosuppressant
laboratory workforce is not universally well-trained to operate drugs, LC-MS/MS offers the ability to reliably quantitate
sophisticated mass spectrometry systems and it typically very low drug concentrations. LC-MS/MS is also used for
requires highly trained operators, although newer systems may analysis of steroid and thyroid hormones, and vitamins such
allow general medical technologists to operate them. Other as Vitamin D, a common application.20 The method also has
potential pitfalls include the complexity of serum and plasma the unique ability to perform ‘multiplex testing’, that is, it
samples, post-translation modifications of analytes, molecular can measure a variety of different analytes simultaneously.
polymorphisms, and multiple isoforms of many proteins.22 In LC-MS/MS’s exquisite specificity allows it to be used as the
short, detecting a portion of a protein in a sample does not accepted reference method (the ‘gold standard’) for many
mean that the intact protein is measured. Another limitation analytes, but because such a variety of LC-MS/MS assays are
of LC-MS/MS is that parent compounds can be fragmented available for the same analyte, there can be multiple putative
by MS in such a way as to produce different fragments that reference methods.
have the same molecular weight, thus producing inaccurate
results for the intended analyte.20 Other disadvantages include It is currently a challenge to successfully integrate MS with
the lack of standardisation, and the lack of assay ‘kits’ similar TLA. However, as noted at the beginning of this paper, there
to those for routine automated procedures.5 was a time when completely automated analysis of patient
specimens was only a speculative dream. That is now a reality
LC-MS/MS procedures are typically ‘laboratory developed and there is reason to believe that LC-MS/MS units can be
tests’ (LDTs).5 They are not approved by a regulatory agencies attached to track systems and/or other automated modules.
such as the FDA but are validated by individual laboratories
for clinical use. Validation requires determination of analytical Informatics
sensitivity and specificity and clinical performance, parameters Hawker emphasises that information technology is a critical
not required by regulatory approved assays. MS procedures element of any automation solution.16 Solid metrics should
are intended for use only by the laboratory that developed be used to assess pre- and post-automation performance to
them and are not to be used to test samples from other clinical objectively prove automation effectiveness. Such metrics
laboratories. MS assays are unique to each facility’s needs include: stat and routine TAT, number of process failures [lost,
and lack lab-to-lab standardisation/harmonisation.20 LC-MS/ mishandled, mislabeled, mis-delivered specimens; aliquoting
MS faces the same challenges as routine clinical chemistry and pour-off errors, client complaints per billed units, and
tests and immunoassays, namely metrological traceability to productivity parameters (billed units reported per employee)].
reference materials and/or methods that allow for equivalent Process control software should read specimen ID and access
patient test results regardless of the laboratory that performs from the LIS the specimen type and orders for each sample.16
the analysis. It is now recognised that comparability of It then determines the necessary processes for each sample,
patient test results is a key desideratum. Some LC/MS assays e.g. centrifugation, decapping, aliquoting, and the exact
demonstrate a large degree of variability, as observed for analytical route the sample will take through the automated
LC-MS/MS methods for a major immunosuppressant drug system. Additionally, it should monitor analysers for in-
such as tacrolimus, in contrast to the relative consistency control production status and make decisions to accept or
of analysis in terms of accuracy and precision observed for reject test results using rules based algorithms. This includes
standard automated immunoassays.23 evaluation of sample integrity (HIL) and autoverification.
Process control software should also determine the need for
Although progress may occur rapidly, at present there is still repeats and dilutions, apply QC rules, and provide custom
a need to make LC-MS/MS a routine methodology in clinical comments.12 All of these activities and processes fall under
laboratories.21 Industry support is still in its infancy and IVD the heading of informatics.
companies must invest in LC-MS/MS to produce analysers fit
for routine use in the clinical laboratory. LC-MS/MS currently Over the last two decades, laboratory process management
appears to be a complementary methodology, although there software (middleware) has evolved significantly. Initially
are many fervent supporters who may disagree. middleware was a simple interface engine but today it
is a process control and management tool. It allows the
laboratorian, to be the expert orchestrator of the process,

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focused on supervising and managing the execution of the also possible to automate work order optimisation protocols,
laboratory operations and resolving exceptions beyond the e.g. hold a test requested if it is not appropriate given current
capabilities of the automated system. Middleware enables the patient status, history, or demographics. The ease of use makes
laboratorian by integrating available relevant data and tools middleware accessible to a broad spectrum of laboratories.
to access, visualise and act on information and by automating For example, the automation of routine protocols enables
data handling tasks. This allows efficiency gains by lowering laboratories to handle escalating demand for services while
unit (test result) costs and providing greater productivity. meeting access, productivity and cost targets. Furthermore,
Quality improvements include less process variability, more the automation of routine protocols allows laboratorians
attention to detail, and improved levels of service with less to focus their limited time on tasks requiring their special
human induced delays for results and better TAT. Some knowledge and experience, such as advising physicians and
specific advantages include: robust, high bandwidth interfaces; patients and resolving complex exceptions.
comprehensive data schemas and flexible data integration,
filtering and visualisation; work order and test results review Quality Control is an area in which middleware information,
rules (autoverification); and Average-of-Normals tracking integration and process automation can yield important
and QC data manager integration. improvements to quality and productivity. The integration
of QC data managers enables automated transcription of QC
Informatics allows robust, comprehensive interfaces that test results. Consequently, manual transcription of non-value
automatically and reliably transmit data to and from various added work and associated delays and errors can be avoided.
systems. Interfaces with laboratory and hospital information The bi-directional integration with QC data managers enables
systems go well beyond medical work orders and include real-time communication and integration of QC status. A
full patient and ordering physician demographics, diagnosis laboratorian can see test results in a single screen along with
codes, order priority, and more. Interfaces with instruments relevant QC events, such as Westgard rule violations, in a
include graphs and images, and instruments exception and way that improves the ability to take appropriate corrective
error reports. This allows middleware to speed the reliable action. Middleware also provides Average-of-Normals
transcription of all relevant information the laboratory scientist (AoN) modules that continuously evaluate the analytical
needs and presents it in one place, avoiding information loss, performance of an instrument providing a near real-time
printouts and handwritten notes, manual transcription, delay detection of performance degradation. Through automated
and errors, and related rework. responses to QC events via a middleware rules engine (e.g.
automatically holding results release and routing specimens
Flexible data integration, filtering and visualisation provided for testing on a different analyser), laboratories can develop
by middleware helps the laboratory scientist make sense of novel best practices in QC.
and take action on the analytical information. Middleware
can collate and present in a single screen all the information Conclusion
related to a patient and related work orders, physicians, and The history of automation in the clinical laboratory is long and
results, integrated with tools to obtain additional information, varied. The Latin aphorism at the beginning of this review,
make annotations, order reprocessing or new tests and much loosely translated as “Victory loves careful preparation,” is
more. Filters, context-sensitive colouring, and adaptable apt for laboratories picking and choosing among the various
screen/field layouts enable the laboratory scientist to focus on automation options available in the 21st century. Manual
relevant information while minimising information overload. testing is clearly of the past century for a modern laboratory
Interactive real-time dashboards with graphical information except for a few very specialised tests. Even if a laboratory’s
displays are available to enable process status awareness and workload is of such a low volume and TAT is not a concern,
management engagement. Middleware allows laboratorians the inherent variability of manual procedures makes them
to manage orders and results for any instruments and any nonviable in comparison to modern automated methods and it
workstation in the lab, not only those closest to the instrument. is a given that laboratories will inevitably adopt automation.

Most middleware can automate routine tasks normally The dilemma for clinical chemists is to decide what kind of
performed by a laboratorian using Rule Engines that are flexible automation and what extent of automation is suitable for a
(capable of sophisticated logic and decisions); powerful (can given facility. The advantages of automation are undeniable.
consult patient health status, history and demographics and The challenge is for laboratories to embrace the right kind of
initiate a wide range of actions, such as computations, adding/ automation to best meet their specific patient testing needs.
cancelling tests or routing specimens) and relatively easy to This starts with a careful analysis of a laboratory’s current
use (can be programmed using visual drag and drop tools). It is process and optimising it before making any automation

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Laboratory Automation

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