Originally Published IVD Technology April 2005
Anniversary Essays
2. Instrumentation and automation
IVD manufacturers have not only improved lab instruments but also adapted them for emerging technologies.
Warren Hancock and Andrew Evans
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| Warren Hancock is a director, and Andrew Evans is business development manager at Invetech (Melbourne, Victoria, Australia). The authors can be reached at wjh@invetech.com.au and are@invetech.com.au, respectively. |
During the past decade, the IVD instrument market has undergone sweeping changes. Such changes have been driven by several independent factors, from the ever-growing graying population in developed nations to increased consumer expectations for improved and safer healthcare. Dramatic changes in the marketplace are also being driven by major scientific breakthroughs, new technologies aimed at earlier detection and prevention of disease, and the development of point-of-care (POC) or near-patient testing processes and systems.
While such developments continue to emerge, IVD manufacturers are constantly searching for new and more-efficient ways to reduce turnaround times and lower costs. Manufacturers must also deal with ever-higher regulatory compliance requirements and charges.
This article discusses how such developments have changed the landscape of the IVD instrument field during the past 10 years, as well as provide insight into emerging industry trends.
Automation Takes Center Stage
Few IVD industry analysts would argue with automation’s critical role in the day-to-day performance of clinical diagnostic laboratories. Automation has helped labs keep up with ever-increasing demands for efficient, speedy, inexpensive, and reliable test results.
An article in IVD Technology noted that, “Automation will increasingly become a crucial mechanism for clinical laboratories to achieve higher productivity and cost-efficiency. Automation helps streamline the work flow and results in a more reproducible process with less hands-on interaction, which can significantly reduce costs and decrease the need for skilled labor.”1
Another industry trend among diagnostic companies is to offer more-integrated systems by combining immunoassay and clinical chemistry analyzers. Some systems are moving toward incorporating other processes, such as hematology, in the future.
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| Figure 1. The Architect ci8200 integrated system by Abbott Laboratories (Abbott Park, IL). |
An example of instrument integration is the Architect series by Abbott Laboratories (Abbott Park, IL). Abbott developed its ci8200 by integrating the i2000SR immunoassay module and the c8000 clinical chemistry module with a shared sample handler, user interface, and information system (see Figure 1). While the current instrument has a throughput of 1200 clinical chemistry and 200 immunoassay tests per hour, the earlier stand-alone AxSym instrument has a throughput of only 80–120 immunoassay tests per hour.
The lack of skilled medical technologists has also influenced the growth in lab automation. Shortages of skilled laboratory personnel were not as prevalent 10 years ago since the list of analytes was relatively short and not expanding rapidly.
However, the increasing number and range of diagnostic tests being requested from labs today has placed a greater strain on IVD systems and the supply of skilled technicians. In turn, increasing instrument complexity emphasizes the need to develop instruments that can effectively be used by a progressively less-skilled workforce.
Greater Safety and Certainty of Results
Through a disciplined and staged process, the development of IVD instruments must ensure that patient safety requirements are comprehensively captured and verified before clinical trials and validation are conducted. A central theme of today’s instrument development practices is the use of risk management techniques that minimize the possibility of functional defects, design flaws, and vulnerabilities.
The accuracy of test results from IVD instruments is also receiving greater attention. In a recent interview, Cass Grandone, vice president of systems development at Abbott, said that a major focus for Abbott is to ensure the accuracy of test results while a sample is in a system’s chain of custody, from the sample prep stage to the release of results.2
Most laboratories rely on laboratory information management systems to manage and control the increasing complexity of sample and data flow. IVD instrument manufacturers have addressed this need by improving user and electronic interfaces, platform interconnectivity, and data management systems.
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| Figure 2. The UniCel DxC 600 Synchron clinical system by Beckman Coulter Inc. (Fullerton, CA). |
An example of the emphasis on connectivity is the UniCel DxC 600 Synchron clinical system by Beckman Coulter (Fullerton, CA) (see Figure 2). This system has a throughput of up to 990 tests per hour compared with the earlier CX3’s 675 tests per hour. However, the focus of this system is multiplatform configuration, management, and connectivity through unidirectional and bidirectional communications. Such features allow labs to consolidate workstations, optimize work load and labor resources, and reduce costs.
Many IVD instrument systems also have additional fail-safe features with built-in reporting triggers coming from individual instruments. Other features include software embedded in each instrument system which is capable of performing quality control functions. With such added features, confidence in the produced and released test results has improved dramatically.
The end result of such information system improvements is the linking together of all lab instruments, which expedites work flow and productivity checks. Another result is the ability to communicate with a lab’s reporting system so that staff can create a single patient report from different laboratory input systems.
Some IVD instrument manufacturers have indicated that another key technological trend during the past decade has been the significant developments in smart information systems. In addition to data flow and exchange, some decision-making or interpretive functions are being performed by the automation system.
One example is the software of the Vitek 2 microbiological detection and susceptibility instrument by bioMérieux Inc. (Marcy l’Etoile, France). In this instrument, an expert system integrates artificial-intelligence technologies and interprets the results of the antibiotic susceptibility test by using a highly developed knowledge database.
Such new systems have created major improvements in a lab’s efforts not only to make single reports but also to track patients’ treatments over time. Such systems have also improved patient management decisions.
Speed, Accuracy, and Sensitivity
The IVD instrument field will encounter a continuing need for greater productivity levels, which is driven by an increasing demand for testing and other commercial factors. When compared with instrument systems from a decade ago, many improvements have been made, including higher throughput and reliability, greater accuracy in fluidics, and better sensor performance. While many of these changes may be considered incremental, they also have been important to IVD manufacturers’ attempts to keep up with or stay ahead of the competition.
User-Friendly User Interfaces
Many mistakes caused during medical device operation result from human error. Until recently, a prime target for such errors stemmed from an IVD instrument’s user interface, with such problems as complex word usage, poor legibility due to low color contrasts, small symbols, faulty labeling, and inadequate training.
An article in Medical Device & Diagnostic Industry pointed out that “A lot of medical devices, particularly those employing relatively large displays with high resolution…are presenting functional options—actions such as calibrating a device, setting alarms, or reading the user guide—in the form of icons. This shift within the medical industry to an iconographic user-interface style matches trends in the consumer and business software arenas.”3
The drive to make IVD instrument user interfaces more user-friendly comes at a time when they are being developed to provide more-complex functions and undertake tasks such as quality control, device relationship manager, and rules-based reflex/rerun, while maintaining a simple, intuitive appeal (see Figure 3).
An article in IVD Technology noted: “Effective user-interface design is critical to instrument performance. It minimizes the risk of error and the need for dedicated operator training. Ergonomic interface layout speeds up routine activities and helps eliminate annoyances. Smooth user interactions correlate with attractive and ergonomic industrial design. Careful study of both physical and data interaction work flows by the instrument developer will result in an analyzer design that maximizes efficiency.”4
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| Figure 3. A modern menu-based multiple-screen interface on a touch screen LCD panel. |
Contemporary user interfaces focus on intuitive work flows that minimize potential operator errors and offer other user-friendly features. Such features include context sensitive help, real-time instrument status (including information such as real-time reporting of reagent levels, which could be linked back to reagent management systems for reordering purposes), multimedia training tools, and integration into other networked applications (e.g., LIMS and ERP) (see Figure 3).
Instrument software and user interfaces in particular have benefited from a number of trends during the past decade within the software engineering industry. Such trends include user interface form-design tools (for the layout of user interfaces), modelling and notation with the industry-standard unified modelling language, and integrated software development life cycle tools (e.g., for requirements engineering and change management).
In addition, evolving and newly emerging technologies have given rise to benefits such as sophisticated scheduling systems (through greater CPU power), highly interoperable network capabilities (through the ubiquitous Web and Web services protocols such as SOAP), and improved data archiving mechanisms (e.g., DVD and terabyte RAID facilities).
New Molecular Diagnostic Technologies
While the IVD device market is not short of promising new technologies, molecular diagnostics has attracted perhaps the most attention in recent years. Fueled by the sequencing of the human genome, molecular diagnostics offers many advantages over conventional testing technologies. One example is the ability to discover fundamental markers of disease and identify a person’s predisposition to illness.
From an IVD manufacturer’s point of view, molecular diagnostics offers plenty of opportunities for developing new and unfamiliar instrument technologies, such as chip-based DNA biosensors, tandem mass spectrometers, microfluidics, nucleic acid probe-based tests, and nucleic acid amplification techniques.
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| Figure 4. The Tigris DTS System by Gen-Probe Inc. (San Diego). |
An example of an IVD instrument based on molecular diagnostics is the Tigris DTS system by Gen-Probe Inc. (San Diego) (see Figure 4). This system automates all phases of molecular diagnostics testing from sample preparation, amplification, and detection, to reporting results. FDA has granted marketing clearance to the Tigris system for sexually transmitted disease testing, with further clinical diagnostic and blood screening tests to follow.
A decade ago, some larger research labs contained early generations of DNA sequencing systems and PCR amplification systems. However, the molecular diagnostics field has grown rapidly, particularly as such devices have become more integrated in clinical laboratories. For example, there has been a movement toward taking a more holistic approach in which assays involving genetic, cellular, tissue, and environmental samples will be tested concurrently.
An anomaly in the regulations for genetic testing has recently been discussed. New genetic tests developed by IVD companies are subject to rigorous regulatory compliance standards, even when the tests are not necessarily diagnostic in nature. At the same time, reference laboratories offering home-brew testing are not so rigorously regulated. Even though the discovery rate is high, the rate of introducing new nondiagnostic molecular tests is slower than might be expected.
To address this issue, certain industry groups have proposed the creation of a new regulatory category. This proposed category would regulate tests that do not make any clinical utility claims and would undergo a less-rigorous fast-track FDA approval process.5 However, molecular diagnostics researchers believe IVD manufacturers must still overcome several hurdles, including reimbursement, lack of clinicians who feel confident enough to prescribe genetic tests, and better data analysis methods.6
Although molecular diagnostics is still several years away from providing major healthcare benefits to patients, the IVD industry’s understanding of the human genome has given laboratorians new information with which to interrogate for diseases and new tools to assay the whole gene faster and more cheaply.
Other Notable Technologies
IVD instrument manufacturers have rapidly developed several other technologies during the past decade with the prime aim of delivering more results in less time.
Magnetic-bead-based assays, used to separate proteins, nucleic acids, hormones, disease markers, cells, and bacteria, is a growing area. Some IVD instrument manufacturers are combining the benefits of bead-based assays with multiplexing. Such assays provide a significant throughput enhancement by generating the assay results required in one single vessel.
Further refinement of such technologies is expected since such tests can also compete on a cost-per-run basis. Magnetic-bead assays require lower sample and reagent volumes than more-traditional testing methods.
Multiplexing technology, in which multiple results are generated in a single tube or array, has been developed to meet customer demands for selectable multianalyte testing. Although all analytes are processed, only those tests ordered are reported. The obvious benefits of multiplex technology include significant labor reduction and increased throughput, as well as reduced calibration, quality control time, and calibration reagent storage requirements.
POC Convenience
During the past 10 years, the promise of diagnostics moving from research laboratories to centralized labs to POC or near-patient environments has started to occur, mostly through such tests as diabetes, thyroid, fertility, cardiac markers, and drugs-of-abuse monitoring. However, POC testing is not ubiquitous although it makes the best economic sense in cases that require frequent testing, such as diabetes, or for tests that need to be done quickly, as in emergency rooms.
While POC instruments have advanced in recent times due to new developments in miniaturization, there is still concern about accuracy, versatility, difficulties in linking POC test results to other clinical processes and information systems, and reimbursement restrictions by third-party payers.
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| Figure 5. The Afinion AS100 Analyzer by Axis-Shield (Dundee, UK). |
The Afinion instrument was developed by Axis-Shield (Dundee, UK), one of the pioneers in POC testing (see Figure 5). Using fingerstick whole blood, the Afinion AS 100 analyzer provides laboratory-quality results for a number of tests within 3 to 5 minutes. The planned test menu includes several markers that are not available on other POC systems. In 1992, Axis-Shield upgraded its earlier NycoCard Reader system to provide quantitative results. The following four tests are available on the NycoCard system: CRP, D-Dimer, HbA1c, and U-albumin. The installed base of the NycoCard Reader is more than 14,000.
Conclusion
The IVD device market is changing rapidly for various reasons. One is the move toward miniaturization and nanotechnology. Another is the vast quantities of new information unleashed by the completion of the sequencing of the human genome.
However, new developments in the IVD industry will focus on such genetically dynamic areas as proteomics and metabolomics. Proteomics represents the full complement of proteins produced by the human genome at any one time. Metabolomics is a new discipline and technique that looks at the number of metabolites produced by the human body. Since there are relatively few metabolites, particularly when compared with molecular methods, some evidence suggests that by watching a patient’s metabolism, a disease could be predicted before it becomes clinical.
For IVD instrument developers, such new applications will demand new processing technologies, such as mass spectrometers moving out of the research environment into clinical use. However, the overriding concerns, driven by improved patient outcomes, are still likely to be traceability, safety, and an acceptable cost per test.
References
1. J Zakowski and D Powell, “The Future of Automation in Clinical Laboratories,” IVD Technology 5, no. 4 (1999): 48–57.
2. R Park, “Overcoming Challenges in Instrumentation Development,” IVD Technology 11, no. 1 (2005): 26–30.
3. ME Wiklund, “Making Medical Device Interfaces More User-Friendly,” Medical Device & Diagnostic Industry, no. 5 (1998): 177–182.
4. F Davis, J Palander, and J Bussell, “Automated Laboratory Analyzers Analyzed,” IVD Technology 8, no. 6 (2002): 37–48.
5. R Park, “Clearing a Market Roadblock,” IVD Technology 10, no. 9 (2004): 8.
6. S Beard and R Mondesire, “Tools for Molecular Diagnostics,” IVD Technology 8, no. 8 (2002): 70–72.
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