465© 2013 David G. Wild. Published by Elsevier Ltd. All rights reserved.
466 The Immunoassay Handbook
Finally, exhibitions are an obvious source of information
at national and international meeti...
467CHAPTER 6.4 Choosing an Automated Immunoassay System
departments or specialized laboratories such as those sup-
468 The Immunoassay Handbook
Direct computer connections to the manufacturer as well
as video cameras for real-time analys...
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The immuassay handbook parte48

  1. 1. 465© 2013 David G. Wild. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/B978-0-08-097037-0.00032-4 Choosing an automated immunoassay system, like choosing any new instrumentation, is not an easy task. There are cur- rently over 70 immunoassay systems on the market, many of which are described in later chapters in this book. Although immunoassay analyzers have come a long way, with many systems now incorporating features that were previously found exclusively in high-throughput chemistry systems, there is no one perfect system. Furthermore, all laborato- ries—whether hospital, commercial, physician’s office, satel- lite, etc.—are different, each with unique requirements. The choice of an immunoassay analyzer therefore depends on the goals to be achieved with analyzer acquisition. This chapter will discuss automation goals, sources of system information, considerations and criteria, and briefly, system evaluation. Defining Automation Goals The first and most important step in choosing an automated immunoassay system, or any automated system, is to define the goals and objectives to be accomplished with the sys- tem. It is then possible to survey systems to determine which systems can meet those goals. The advantages of automation are many. One of the most beneficial aspects of automation is the ability to consolidate testing and worksta- tions, including manual testing, batch, selective, or random- access analyzers. Consolidation can include integration with other analyzers such as those performing general chemistry tests. Automation can therefore reduce labor requirements and hence testing costs. With shorter incuba- tion and assay times and the ability to increase testing fre- quency, such as with random-access capabilities, turnaround times can be improved. Quality of testing can be achieved with immunoassay automation, with improved assay perfor- mance resulting from improved precision, limit of detection and wide dynamic ranges. Errors due to sample handling and processing can be reduced by using primary tubes, avoiding the need for sample splitting. The use of barcod- ing and bidirectional interfaces can eliminate manual data entry errors. Automation also allows for increased capacity for growth and productivity. In summary, the overall goal of automation, in this case immunoassay automation, should be to improve overall testing efficiency with the previous issues discussed all contributing to that goal. Sources of Information There are numerous sources of information and resources that can aid in gathering information about the attributes of the immunoassay analyzers currently available in the marketplace as well as those in development and soon to be released. Information can be found on the web as well as in printed materials. This book is of course an excel- lent resource with in-depth discussions of individual sys- tems. Considering the number of systems available, summarized information can be very useful. Several pub- lications, including CAP (College of American Patholo- gists) Today and ADVANCE, publish annual surveys of current instrumentation in tabulated format allowing for ease of comparison among systems. Websites from indi- vidual manufacturers are excellent starting points for general overviews and test menus. The most up-to-date information and specific details may need to be obtained directly from the companies themselves. Manufacturers should be able to provide performance data on all of the analytes of interest including precision, linearity, correla- tions with other instruments, reference ranges, etc. Infor- mation to be obtained from the manufacturer also includes space, power, water, waste, laboratory informa- tion system (LIS) interface, and other specifications and requirements. Another invaluable source of information is other users. Contacting colleagues at laboratories with similar test volumes and test mixes to learn which analyzers they are using and their experiences can be insightful. Email mailing list services, e.g. using LISTSERV®, can also be beneficial. Manufacturers will also provide names of cus- tomers using their systems, although most likely their most satisfied users, as well as arrange visits to see their instruments in use out in the field. Current instrument users, including laboratory directors in addition to the end users, can provide their experiences with instrument performance and operation. Users may also share certain documentation from their laboratory such as quality con- trol records. Knowledge about systems from outside sources can also be obtained by employing industry consultants. Firsthand knowledge is unquestionably useful in select- ing an instrument. Most manufacturers are now willing to bring a system into an institution for a demonstration as well as leave the system for an extended period to allow a partial or full evaluation. If the opportunity arises, partici- pation in alpha and beta site testing as well as other research and development projects can also provide in-depth expo- sure to systems in development or to systems already avail- able. It must be kept in mind however that early hardware and software versions may bear little resemblance to final production models. System evaluations allow the technol- ogists running the analyzers to become closely involved in the selection procedure. Laboratory supervisors and administrators, as well as LIS administrators, should also play a role in the selection and evaluation process. Choosing an Automated Immunoassay System Lori J. Sokoll (lsokoll@jhmi.edu) Daniel W. Chan (dchan@jhmi.edu) C H A P T E R 6.4
  2. 2. 466 The Immunoassay Handbook Finally, exhibitions are an obvious source of information at national and international meetings of organizations such as the American Association for Clinical Chemistry (AACC) and the Clinical Laboratory Management Asso- ciation (CLMA) in the US, the Association of Clinical Bio- chemists (ACB) in the UK, and the International Federation of Clinical Chemistry (IFCC). Time and the number of systems being exhibited may limit the number of instruments that can be viewed and investigated but these forums do allow the opportunity to have a first look at new systems with launch dates in the near future. Considerations and Criteria Once automation goals have been determined for an individual laboratory, the next step is to identify systems that meet those goals. The previous section described sources of information on immunoassay analyzers, while this section will discuss considerations and criteria for choosing a system. Laboratory environment, test menu, technical, clinical, financial, and operational issues will be covered. LABORATORY ENVIRONMENT CONSIDERATIONS The type of laboratory and the goals and plans for the organization of the laboratory are important consider- ations. The size and test volume of the lab in addition to the type of lab will dictate priorities. In a large hospital laboratory, random-access analyzers with short times to first result, stat capabilities, and breadth of menu may be critical factors to consider, while commercial reference laboratories may consider throughput the most significant consideration. Laboratories with smaller volumes may be limited to smaller analyzers that may not have high- throughput or walkaway capabilities. The goal of the laboratory with respect to consolidation is another defining feature. It is now possible to combine testing from previously segregated disciplines by focusing on methodology as opposed to clinical pathology specialty. The standard immunoassay or special chemistry labora- tory can now be combined with the drug assay area as well as testing from microbiology and diagnostic immunology. It is now possible to perform homogeneous and heteroge- neous assays on the same instrument allowing chemistry and drug testing to be combined with standard immunoas- says such as thyroid and cardiac markers. Immunoassays, encompassing all testing or high-volume stat tests, may also join other types of highly automated testing in a core laboratory. The ability to consolidate will therefore depend on the type of automation as well as specific tests available on the system. Space is an important consideration. Where are the ana- lyzers to be placed in the laboratory and what is the func- tion of the laboratory? Are floor models appropriate or is a smaller benchtop unit a better fit? In a satellite or emer- gency room setting, space is at a premium. Satellite labora- tories associated with the main laboratory or laboratories that are part of a network may choose to use the same instrumentation throughout the system. Therefore, choice of an instrument line with several models, such a smaller benchtop version, may be beneficial. It may also be benefi- cial to choose the same vendor used for chemistry or hematology testing. Using one vendor will allow for better pricing and decreased training due to possible common user interfaces. Vendor choice may be limited by buying groups associated with the institution. Variability in future testing volumes is also a consider- ation for the laboratory. Will the system acquired now be adequate in the near future? One possible solution is inte- grated or modular systems. In these systems, multiple ana- lytical components can be linked together with a common specimen transport system and specimen and data man- agement unit allowing for increased or decreased testing depending upon demand. Modular systems can also include modules for other types of testing such as high or mid-volume chemistry testing as well as pre-analytical processing units. Modular systems are one type of automation to take into consideration. Other types of automation currently present in the laboratory or planned for the future should also be kept in mind if the immunoassay system is to be incorporated. Automation may be a total, partial, or mod- ular laboratory system, either closed or open to instru- ments from a number of specific manufacturers. A number of immunoassay analyzers are designed for use with spe- cific systems while others are designed to be flexible in nature allowing the instrument to sample directly from any track system. Individual systems that allow stat speci- mens to be added at an additional entry point and those that can operate independently from the automation sys- tem are advantageous compared to those with inclusive track systems that are unusable when transport systems are inoperable. TEST MENU CONSIDERATIONS Test menu may in many cases be the most influential fac- tor in choosing an immunoassay system. Again, the goal of the system will dictate the required menu. If the goal is consolidation, assays in a large number of categories are available although no analyzer has a complete menu and the depth in each category may also be an issue. Cat- egories currently include thyroid, fertility, cardiac, ane- mia, tumor markers, therapeutic drugs, drugs of abuse, adrenal/pituitary, reproductive, allergy, infectious dis- ease, transplant, bone metabolism, cytokines, and other special proteins. Assays available worldwide typically outnumber those available in the United States due to regulatory requirements by the FDA for assays such as tumor markers and infectious disease tests. If a large number of platforms are consolidated resulting in an expanded menu, the number of tests onboard and the quantity of reagents onboard for each test should be examined carefully. Menu is also of utmost importance if the function of the analyzer is to provide specific types of testing such as spe- cialty endocrinology testing, hepatitis testing, tumor marker testing, etc. Specific testing can also be related to location such as those analyzers located in emergency
  3. 3. 467CHAPTER 6.4 Choosing an Automated Immunoassay System departments or specialized laboratories such as those sup- porting in vitro fertilization (IVF) programs. There are also certain tests only available on one platform thereby limiting analyzer selection. TECHNICAL AND CLINICAL CONSIDERATIONS Technical issues such as precision, accuracy, limit of detection, and dynamic range should be considered when choosing an immunoassay analyzer. Automation has allowed for greatly improved precision of steps such as pipetting, washing, separating, and measuring such that specimens can be analyzed in singlicate as opposed to manual assays requiring duplicate analyses. Intra- and inter-assay precision, particularly at important medical decision points, and other technical parameters should be evaluated carefully when considering a system. Examin- ing results from proficiency surveys can be useful to determine intra- and inter-method precision as well as compare absolute values to determine whether labora- tory reference ranges may be affected and need adjust- ment. A contributing factor to inter-assay precision, which should be minimized, is lot-to-lot variability in reagents. The limit of detection and linear range can be affected by the type of label and detection method as well as by assay design, with improvements observed with chemiluminescent signals compared to older colorimet- ric and fluorometric detection methods. Accuracy of results has also improved with automation due to built-in quality checks such as sensors for malfunctions. There should be checks associated with pipetting of specimens and reagents and with timing of incubation and reading steps. Appropriate reagent addition as well as positive sample identification, including controls and calibrators, can be assured with barcoding. Specimen carryover is a concern with many immunoassays that have results span- ning a wide range. Therefore, many systems have taken the approach of using disposable tips for specimen pipet- ting. Other system features include clot and short sample detection, and autodilution and autorepeat capabilities. Immunoassay analyzers integrated with chemistry ana- lyzers may also allow the detection of hemolysis and other potential interferents. In order to be useful clinically, assay results need to be accurate and precise and be provided in a timely manner. Turnaround time is dependent upon how often the test is performed and how long it takes to complete the test. Random access allows tests to be performed upon receipt at the analyzer with testing time dependent upon incuba- tion time, method of separation for heterogeneous immunoassays, and type of detection. Instrument throughput depends upon time to first result, time between results, number of assays onboard the instru- ment as well as incubation time. Incubation times are fixed in some systems while variable in others. Specific test mix will greatly influence throughput for systems with varying incubation times; and therefore, the optimal throughput may not be attainable. Other system features such as wide dynamic ranges (reducing dilutions required), use of primary and secondary tubes of differ- ent sizes, reflex testing capabilities, and barcoding can also increase testing efficiency. A final clinical consider- ation is specimen volume. Required assay volumes and dead volumes should be as small as possible. Analyzers are now available that can multiplex a panel of analytes, minimizing sample volumes and increasing efficiency. FINANCIAL CONSIDERATIONS There are a number of financial aspects to assess when considering the choice of an immunoassay analyzer. It must be determined if implementation of a specific ana- lyzer will be cost-effective. The total cost of testing should be considered. The following costs should be compared among systems: instrument, reagents, calibrators, controls, disposables, labor, service contract, maintenance and over- head, renovations required, and LIS-associated tasks such as interfacing. Features affecting cost-effectiveness include long calibration stability (30–60 days or greater), decreased maintenance requirements and training from instrument consolidation, decreased specimen processing, such as sample splitting or aliquotting, etc. Although difficult to quantify, cost savings resulting from the impact on patient care, such as reduced length of stay, and improvements in communication and reporting of results should be included. Instrument acquisition may be accomplished through direct instrument purchase, leasing, reagent rental contract, or on a cost per reportable basis. OPERATIONAL CONSIDERATIONS Operational issues associated with immunoassay analyzers encompass a number of aspects including instrument, human, and manufacturer issues. The instrument itself should have features that allow for continued reliable operation. This includes a system that is easy to operate and requires minimal maintenance and service. Mainte- nance that is performed automatically by the system, including automatic start-up and shutdown as well as auto- matic calibration, and the ability to add specimens and reagents and dispose of waste without interruption are desirable features. Efficiency of operation is gained with automatic inventory of reagents, multiple stored calibra- tions, auto-calibration and QC, long-term calibration and reagent stability, and liquid reagents or lyophilized reagents reconstituted onboard. Walkaway ability is real- ized with adequate onboard test availability and reagent capacity, onboard refrigeration or room temperature sta- ble reagents, and a large reserve of disposables such as tips and reaction vessels. Other operational issues related to the instrument include compatibility of the system with the laboratory LIS system and ability to easily interface the instrument. Barcoding in combination with a bidirectional interface operating in host query mode is a key feature for large laboratories. Another aspect of the reliable operation of the analyzer is the inclusion of mechanisms to deal with system mal- functions. The system should alert the operator with audi- ble prompts when there is a system failure and provide error messages and troubleshooting assistance. The trend is for more operator involvement in system repair with help manuals and video clips on the analyzer’s computer.
  4. 4. 468 The Immunoassay Handbook Direct computer connections to the manufacturer as well as video cameras for real-time analysis can aid in trouble- shooting. Error and system logs as well as instrument set- tings can be sent to the manufacturer via modem or secure internet connections while messages and software upgrades can be automatically downloaded to the system. Help from the manufacturer should also be provided through a tele- phone hotline accessible 24h a day as well as through on- site service. The response time for on-site technical service is a fundamental question to be asked when selecting a sys- tem. The availability of local technical service personnel may be a critical deciding factor for laboratories located in rural or remote areas. Even in locations with a local service representative, territories covered may be very large pre- cluding a prompt response. Acceptable downtime, if any, must be determined. A backup instrument may be required. Human issues should also be considered when choosing an automated instrument. The system should be designed with the safety of the operator in mind with respect to mechanical aspects such as moving parts and exposure to infectious materials from both sampling and waste. The system should be easy and intuitive to operate with ease of training. Software should be user-friendly with a graphical user interface and online help and system manuals. A final operational issue relates to instrument manufac- turers and instrument placements. A consideration for sys- tems on the market is the number of systems placed and track record of those systems. For systems on the market for several years, inquiries should be made as to the new sys- tems being developed and time until launch. If a new system is imminent it may make sense to consider the new system or include trade-ins or upgrades in contracts if acquiring current systems. Another factor to consider is the number of immunoassay systems offered by a particular vendor. Mergers and acquisitions have resulted in companies with several product lines; long-term support is critical. Summary This chapter has discussed the criteria for selecting an auto- mated immunoassay system. It must be emphasized that choosing an immunoassay system is dependent upon the needs and requirements of the individual laboratory. Therefore, it is necessary to first define the goals of the sys- tem and how those goals fit into the overall laboratory plans and then to determine which instrument features will help to achieve those goals. It is then possible to choose a system(s) with the required features. Once a system has been short-listed, a thorough evaluation should be carried out to ensure that the system meets the specifications claimed by the manufacturer as well as the expectations of the laboratory. System evaluation should include technical, clinical, operational, and economic elements. Briefly, a technical evaluation would assess within- and between-run preci- sion, limit of detection linearity, accuracy (including evaluation of recovery), dilutions, interferences, carry- over, calibration stability, lot-to-lot variability, and method comparisons. A clinical evaluation would assess the diagnostic accuracy of the methods with an emphasis on reference values and disease management issues. An operational evaluation would assess system operation including data management and interface capabilities, technical service issues, and an assessment of throughput capabilities from simulation studies with the expected test mix. Finally, an economic evaluation should be per- formed to determine the system cost as well as the total cost of testing including pre- and post-analytical steps to determine the effects on labor requirements and productivity. Immunoassay testing has come a long way, and auto- mated systems continue to evolve. Improvements in fea- tures and the move towards integrated systems and analyzers with multiplexing capabilities will improve effi- ciency for the clinical laboratory. The growing number of systems speaks to the bright future for automated immu- noassay systems. Further Reading Assessing the Quality of Immunoassay Systems: Radioimmunoassays and Enzyme, Fluorescence, and Luminescence Immunoassays; Approved Guideline. I/LA23-A. (Clinical and Laboratory Standards Institute, Wayne, Philadelphia, USA, 2004). Auxter, S. What you should know before buying a lab instrument. Clin. Lab. News 24, 16–47 (1998). Blick, K.E. Specifications for the selection of automated immunoassay (IA) systems. J. Clin. Ligand Assay 19, 220–228 (1996). Blick, K.E. Current trends in automation of immunoassays. J. Clin. Ligand Assay 22, 6–12 (1999). Blick, K.E. Automated immunoassay selection. Advance/Laboratory 10, 41–46 (2001). Blick, K.E. Refinements in AIA technology. Advance/Laboratory 12, 84–90 (2003). Bock, J.L. The new era of automated immunoassay. Am. J. Clin. Path. 113, 628–646 (2000). Cook, T.M. Defining “best fit” features. Advance/Laboratory 7, 24–28 (1998). Chan, D.W. (ed), Immunoassay Automation: A Practical Guide (Academic Press, San Diego, 1992). Chan, D.W. (ed), Immunoassay Automation: An Updated Guide to Systems (Academic Press, San Diego, 1996). Felder, R.A. Immunoassay automation. J. Clin. Ligand Assay 22, 13–24 (1999). Li, D.J., Sokoll, L.J. and Chan, D.W. Automated chemiluminescent analyzers. J. Clin. Ligand Assay 21, 377–385 (1999). Melanson, S.E.F., Lindeman, N.I. and Jarolim, P. Selecting automation for the clinical chemistry laboratory. Arch. Path. Lab. Med. 131, 1063–1069 (2007). Pearlman, E.S., Swiss, S., Stauffer, J. and Bilello, L. Selection factors in the choice of immunoassay technology: implementing technology in the new era. Clin. Lab. Man. Rev. 12, 27–30 (1998). Phillips, J.E. Emerging trends in immunodiagnostics. Advance/Laboratory 12, 46–50 (2003). Sokoll, L.J. and Chan, D.W. Clinical instrumentation (immunoassay analyzers). Anal. Chem. 71, 356–362 (1999). Wheeler, M.J. Automated immunoassay analysers. Ann. Clin. Biochem. 38, 217–229 (2001).