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Biochemistry Instruments and Reagents

Automation, the mainstay of biochemistry

Recognizing the impending challenges on the horizon, IVD manufacturers have begun rolling out automated solutions, with varying capabilities to support laboratories and their growing operations.

Automation has strongly contributed to revolutionizing many human activities, thus providing unquestionable benefits on system performance. The abundant and multifaceted advancements of automation technologies have also generated a profound impact on the organization of clinical laboratories, where many manual tasks have now been partially or completely replaced by automated and labor-saving instrumentation.

In recent years, multiple vendors, who traditionally have focused on analytics, released second-generation automation systems that provide new options for the clinical laboratory to automate front-end processing with core laboratory testing, including chemistry, hematology, and coagulation. Many of these systems make total laboratory automation (TLA) more accessible to the mid- to high-volume clinical laboratory. These automation options improve workflow, quality, and efficiency, and reduce errors. However, developing a model of TLA presents some potential problems, mainly represented by higher costs in the short term, enhanced expenditure for supplies, space requirement and infrastructure constraints, lab professionals overcrowding, increased generation of noise and heat, higher risk of downtime, psychological dependence, critical issues for biospecimen management, disruption of lab professionals trained in specific technologies, along with the risk of transition toward a manufacturer’s-guided laboratory.

Technological advancements
Automation has strongly contributed to revolutionizing many human activities, thus providing unquestionable benefits on system performance. The abundant and multifaceted advancements of automation technologies have also generated a profound impact on the organization of clinical laboratories, where many manual tasks have now been partially or completely replaced by automated and labor-saving instrumentation.

New chemistry assays. When it comes to test menus for clinical chemistry and related areas, several new assays and new biomarkers are in development. Certainly, there are new tests that are always innovating in terms of the core laboratory.

For example, high-sensitivity troponin assays for diagnosing myocardial infarction are now becoming available to laboratories in the United States. New biomarkers may soon be available for diagnosing and monitoring traumatic brain injury, and encouraging research is emerging for tests for Alzheimer’s disease.

Developments in multi-analyte markers to screen for cancer, and the use of artificial intelligence and machine learning to find combinations of physiological markers that correlate with disease states. For example, multi-analyte markers related to immune response to infection, perhaps in conjunction with molecular techniques, could help diagnose and predict the severity of infectious diseases, such as the outcome of a patient presenting with the early signs of sepsis.

Promising research also is underway involving biomarkers for ischemic stroke and for kidney disease.

In addition to new assays, innovations are leading to improved performance of existing assays and in core laboratory instruments. Automated platforms are being designed to handle a wider variety of sample types and smaller sample volumes.

Radioactive and toxic components of many assays are being replaced with safer materials, and there are innovations in electrical technologies and biosensors.

The era of automation. Beyond new and improved assays, innovation is underway in how clinical chemistry connects through automation to other areas of clinical laboratories. This is a continuation of a trend that has been happening over the past few decades, as core laboratories have grown to encompass disciplines spanning chemistry, immunoassay, hematology, and hemostasis, among other categories.

With today’s clinical advancements, current technologies include a vast variety of colorimetry/spectrophotometry, nephelometry, turbidimetry, photometry, ion-specific electrode testing (ISE), and a range of chromatographic and ligand assay methodologies such as chemiluminescence techniques.

Going forward, more novel technologies, once reserved for specialized settings, such as molecular/virology, may increasingly migrate into the core laboratory.

Efforts are underway to connect both mass spectrometry and molecular diagnostics instruments to clinical chemistry systems. If mass spectrometry could be connected to chemistry and immunoassay analyzers on the same platform, drugs-of-abuse testing could be done in real time, with samples moving directly from immunoassay screening to confirmatory testing.

An example of today’s advancements in technology and science can be identified with ELISA-based techniques, which are notoriously inefficient and are particularly draining on time and personnel owing to the manual intervention required. The manual nature of the method also means there is greater potential for human error, ultimately resulting in lack of sensitivity and potential for cross-reactivity.

In the laboratory, the transition from traditional ELISA techniques to an automated method for the detection of the same analyte will significantly improve both cost and time. However, despite the abundant advancements in automation, many clinical laboratories continue to utilize manual methods like ELISA for some specialized chemistries. The move to laboratory automation is still a premise of development, particularly in developing countries where the use of manual techniques is still in use and the availability of resources and high-quality diagnostics are reduced due to detrimental socio-economic factors.

Likewise, if molecular diagnostics instruments were to connect to core laboratories, chemistry and immunoassay testing could be combined for diagnosing and monitoring infectious diseases, with follow-up molecular confirmation using the same sample on the same track.

The risk of contamination for molecular diagnostics tests has been a barrier in the past, but companies are coming up with new ways to manage this risk.

Continuous flow analysis. Based on meeting the specific needs of the biochemistry laboratory, significant innovations involve manufacturers focusing heavily on developments on the introduction of multichannel systems, non-selective batch analyzers, and continuous-flow analysis. The rise in continuous-flow analysis enticed the movements in production and research on the use of discrete analysis with cuvettes and automatic mixing and pipetting of both samples and reagent, ultimately reducing the workflow of clinicians and increasing the accuracy, precision, and reliability of patient results. It was not until the 1980s that truly sparked the move to laboratory automation where the introduction of simultaneous detection of multiple analytes at different wavelengths came into play, ultimately bestowing a new era for in vitro diagnostics.

Complementing labs and automated instrumentation. In the early 1950s, to accompany laboratory automation and scientific innovation, ready-to-use reagent kits with instructions for use introduced a very significant innovation to the field of automation, eliminating the process of manually preparing the reagent. Scientific research and development over the past few decades have increased laboratory testing capabilities and allowed for laboratories to significantly reduce time and cost, consolidating routine and specialized tests onto one single platform.

An example of how this has advanced clinical chemistry testing is the two main methods for the detection of proteins in patient samples, nephelometry and immunoturbidimetry. Nephelometry, although traditionally thought to be more sensitive, can be expensive due to higher consumable costs. In addition, nephelometers can be inefficient and are limited by their test menu. Immunoturbidimetry presents labs with the added advantage of consolidating a variety of chemistries on one system, lowering laboratory costs as nephelometry requires the use of dedicated equipment, and are much slower and require highly trained personnel.

Selecting an analyzer. Choosing a chemical analyzer will depend on the types of tests the laboratory wishes to run, and the throughput required. Many other factors include sample handling, degree of automation, footprint, operational costs, turnaround time (TAT), STAT capabilities, service dependency, and whether the analyzer can handle micro-volume samples.

With both semi-automated and fully automated analyzers, laboratory informatics and process management software has increased heavily over the last two decades. Significant implementation of quality control and interfacing automatically and reliably transmit data to and from various systems. This improves both quality and productivity, creating straightforward operations, requiring users to have minimal training requirement for use.

Today, the advancements in quality-control software are designed to allow laboratories to meet industry and international standard requirements, while ultimately ensuring accurate and reliable instrument performance.

Indian scenario
In India, the emerging trend of corporate players, establishing diagnostic centers in small towns and rural areas, provides opportunities for import of automated systems and reagents. One emerging trend is centered on miniaturized, fully automated, and network-enabled cell phone-based PoCT technologies, integrated with paper-based and/or lab-on-a-chip platform. The option of PoCT is currently a popular trend since it provides faster results and supports patient-centered approaches to health delivery.

Automation, combined with cloud-based technology, has helped laboratories streamline daily operations, and better manage patient information. Clinical chemistry has evolved greatly over time, driven by numerous factors, not the least being technological advancements in the world at large. Computers, microprocessors, and robotics have paved the way for automation and cloud-based technology.

Biochemistry analyzers have now become completely automatic, making almost negligible manual involvement. Complete automation of pre-analytical, analytical, and post-analytical tasks enables laboratories to perform more work, using less labor and fewer resources. Consolidation of stand-alone modules and integration of multiple units into a single system has led to the evolution of highly efficient workstations that perform a number of tests, and are capable of running a number of assays simultaneously. However, only 5 percent of laboratories in India are fully automated. This is because they are often faced with the challenge of balancing cost with quality and patient safety. However, with increasing emphasis on evidence-based medicine, quality and technical strengths are gaining importance. Depending on the workload, a laboratory can opt for either a semi- or fully automated analyzer, based on various operational criteria like test throughput, method, continuous/batch or random-access mode, and reagent stability.

With innovations taking place rapidly, the manufacturing industry had to innovate better methods of testing and instrumentation and highly stable reagents. Gone are the days of radio immune assays (RIA), using a gamma counter; the industry now has the CLIA technology with better sensitivity, specificity, and reproducibility. Even the enzyme-linked immune sorbent assays (ELISA) are now available on fully automated platforms. The reagents now have a better stability and a longer expiry period. The need to perform frequent calibrations has also reduced, thereby becoming more cost-effective.

Since most instruments are closed systems, the industry has become more competitive, and even global players had to offer the reagent rental schemes. The advantage of the rental system is that the onus of keeping the instruments in perfect working condition is also shared by the manufacturer. Preventive maintenance and routine maintenance have taken center stage, thereby ensuring the quality of reporting.

The present scenario seems nice, but there is a major lacuna in the Indian context. Barring a few, there are no Indian players in reagent or equipment manufacturing business. There are, however, global companies who make their reagents in facilities located in India. This increases the cost of purchase of instruments and reagents and the fluctuating Indian currency adds to the woes of pricing in terms of cost per reporting test.

The major players are entering the diagnostic field but only a handful want to venture into manufacturing.

There has been a long debate regarding human psychological dependence on automation. Basically, replacement of manual activities with automation has some major consequences, i.e., locus-of-control in the staff, rapid deterioration of skills, and inefficient resuming of manual functioning when automation should fail. These last two aspects are especially important in clinical laboratories, as the transfer of technical skills to the operational environment would then make it challenging, both technically and psychologically, to resume manual abilities.

It may even seem paradoxical but replacing many manual activities with automation would make the staff feel like being sent into the middle of nowhere when facing automation failures. The human response to automation failure was shown to often be dramatic, and this might be attributable to – at least – two major causes. The first is the almost irreversible loss of confidence in manual skills, whilst the second, even more challenging, is the lack of manual power (consequent to staff reduction) needed for resuming all those activities that have been conveyed to automation (e.g., sorting, centrifugation, decapping, aliquoting or recapping, sample loading and unloading, and so forth).

This challenge is magnified for young or new staff, who may have little experience with manual laboratory work, thus paralyzing the laboratory, being unable to provide data to the clinicians, and ultimately jeopardizing the patients’ health.

There is no easy way to come out of this situation other than by implementing an expensive back-up system or delivering samples to another neighboring laboratory. Additional staff-related problems can then be highlighted, including anxiety, uncertainty, and even resistance to the changes.

Hence, the laboratory management should be engaged in emphasizing the exciting aspects of the changes, highlighting the many possible favorable consequences and opportunities that may be generated by the new organization.

Another major challenge is risk of transition toward a manufacturer-driven laboratory.

A highly automated clinical laboratory strongly depends on efficient software programs (including the LIS) and constructive partnership with manufacturers. The establishment of a strategic relationship with suppliers is thus essential for achieving the goal of an efficient automation. Importantly, the manufacturers of some laboratory automation systems can integrate analyzers from many different companies, whilst this option is still under development for other companies. This implies that tenders should be more accurately defined according to the expected laboratory layout.

Full commitment to a single vendor may be an additional risk, as this may pave the way to a manufacturer-driven laboratory. Hence, this may substantially limit, or even avert (in the worst scenario), laboratory professionals from organizing and managing their own laboratories.

Way forward
The history of automation in the clinical laboratory is long and varied. Manual testing is clearly of the past century for a modern laboratory except for a few very specialized tests. Even if a laboratory’s workload is of such a low volume and TAT is not a concern, the inherent variability of manual procedures makes them nonviable in comparison to modern automated methods, and it is a given that laboratories will inevitably adopt automation.

The dilemma for clinical chemists is to decide what kind of automation and what extent of automation is suitable for a given facility. The advantages of automation are undeniable. The challenge is for laboratories to embrace the right kind of automation to best meet their specific patient testing needs. This starts with a careful analysis of a laboratory’s current process and optimizing it before making any automation decisions. It can be tempting to make the jump to some level of automation without first performing a process analysis, but it is a risky move. It is better to fully understand what kind of automation is needed, and adapt the right kind of automation to meet the need.

There are myriad options available, from stand-alone integrated systems, to pre- and post-analytical modules that can be mixed and matched with analytical units, to total laboratory automation. This is definitely a situation in which one size does not fit all. Automated systems must match the specific work volumes and needs of each laboratory. Blindly copying the automation solution that is acceptable for another laboratory is discouraged. At the same time, standardization of automation throughout a network of laboratories is highly desirable. TLA is the ultimate automation development, but not necessarily the right solution for a laboratory. A facility may find specific, targeted automation to be a better option.

Not to be overlooked is the availability of middleware, the sophisticated software that links analyzers and the LIS and offers the ability to take test results, combine them with patient demographic data and principles of evidence-based laboratory medicine, and offer value-added clinically useful information to healthcare providers. Middleware is applicable to every level of automation.

Second Opinion

Biochemistry market growth continues

Dr Bhaskar Bhattacharya
Laboratory Director,
Genu Path Labs Limited

Trends in usage of biochemistry analyzers are expected to grow exponentially, which focuses on estimation of various analytes ranging from routine to special to point-of-care in biological samples. A typical biochemistry analyzer is designed to measure various chemicals and characteristics in an individual’s samples consisting of blood, body fluids, urine, and metabolites as materials of testing. The principle of a biochemistry analyzer is based on Beer-Lambert’s law of photochemistry, and the usage span from high-throughput clinical labs to point-of-care clinics, to test enzymes, electrolytes, and proteins; diagnosing diseases such as diabetes, endocrinological disorders, renal functions, drugs-of-abuse testing, etc.

The technological modernizations, with enabled artificial intelligence in clinical chemistry analyzers, have led to early disease detection and specialized diagnosis in the areas of diabetes, cardiology, cancer diagnostics, and endocrinology-enabled testing on a larger scale. The advancements comprise advanced modelling and parameter estimation, better resolution, improved pattern recognition, computer-assisted interpretation, and artificial intelligence. In the global biochemistry analyzer market, Persistence Research forecasts that the current estimated account of USD 3716.8 million in terms of value in 2020 is expected to reach USD 5429.5 million by the end of 2027.

The global biochemistry analyzer market is anticipated to show significant growth, which can be attributed to the rising prevalence of diseases and rapidly growing demand for diagnostic tests. Owing to increase in disposable income, the number of people with insurance coverage has also increased, giving them accessibility to private labs that have high-end diagnostic instruments. These devices bring precise results at the shortest possible time, because technologically, they are highly advanced and are made for such purpose.

The supportive government initiatives with high implementation of practice guidelines, released by healthcare organizations present across this region, are some of the key factors responsible for the high share registered by the South-East Asian region, in particular India. Fully automated biochemistry analyzers held a principal place in the global biochemistry analyzer market in 2019, accounting for 85.6 percent share in terms of value. High R&D investment by the global players and presence of unexplored opportunities in this region serve as high growth-rendering drivers.

Major players operating in the global biochemistry analyzers market include Roche Diagnostics GmbH, Siemens AG, Beckman Coulter Inc., Abbott Diagnostics Inc., Shenzhen Mindray Bio-Medical Electronics Co. Ltd., Randox Laboratories Ltd., Awareness Technology, Inc., Transasia Biomedicals Ltd., and Nova Biomedical Corp. These companies have been expansively undertaking novel and innovative product development activities, collaborative strategies, and mergers and acquisitions, leading to significant progress in this sector.

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