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All IVD assays require chemicals and biochemicals. Choosing and sourcing these components are very important steps in the development and manufacture of any IVD product. The wrong choice of assay buffer, for example, can make all the difference between an assay that performs very well and one that exhibits poor precision or poor sensitivity. Excellent product performance combined with appropriate marketing approaches results in better sales, of course, which is a major objective of most diagnostic kit manufacturers. Obviously, sourcing the right chemicals and biochemicals is not just a routine question for assay developers, but a strategic task for management.

Many aspects of appropriately sourcing biochemicals and chemicals are very similar whether one is manufacturing lateral-flow assays, bead-based assays, microbiology or hematology products, automated immunoassays, clinical chemistry assays, or even molecular diagnostics. The argument in this essay will use as a reference point one of the oldest formats in the industry—the enzyme-linked immunosorbent assay (ELISA) kit.

Sourcing IVD Components

In the early days of the IVD industry, kit manufacturers produced nearly all the components and solutions they required themselves. This is now changing completely. Today, there are specialized suppliers who produce components rather than complete kits. Their specialization enables these suppliers to develop much better components than kit manufacturers ever could.

The main objectives of diagnostics manufacturers are IVD development and production and kit sales. Nowadays, rather than focusing on a development project for a kit component, such as an ELISA plate or a buffer, a successful kit manufacturer focuses on kit development and sales projects. The best return on investment for a diagnostics company is in its diagnostics business rather than in chemical development programs.

But a specialized supplier’s focus on particular IVD components makes possible technological innovations. For several decades, assay buffers were simple solutions that included a buffer substance, bovine serum albumin (BSA), some additives, and, sometimes, human antimouse antibody (HAMA)–blockers. This has now changed. Today, assay buffers are functionalized and highly innovative solutions that can help to regulate assay characteristics and performance. Such an advance could occur only once the work of IVD development had been divided between the diagnostics companies and the high-technology suppliers that serve them.

Such division of effort spells the difference between today’s economically successful industrialized structures and the situation in former times, when companies were self-sufficient but somehow ineffective. A natural development in any growing industry, it enables high-tech suppliers to innovate. As a result, modern IVD kit manufacturers no longer produce assay buffers, blockers, or stabilizers themselves. They instead source new functionalized solutions that outperform the solutions formerly produced in-house. Thus, kits today perform at significantly higher levels than kits developed 5 or 10 years ago.

Managers and development teams at IVD firms should keep in mind that sourcing is a key strategic business factor. Management should enable developers to source the chemical and biochemical components that optimally support the diagnostics company’s product strategy. A company may be satisfied to produce the cheapest possible tests to capture a market that cares little about sensitivity, precision, or test quality; or, it may aspire to be its market’s quality leader and ensure growth by offering cutting-edge products for reliable diagnostics. Both strategies can be successful, but they need to be supported by completely different strategies for sourcing the raw materials of kit production.

Plates, bottles, labels, antibodies, stabilizers, detector enzymes, buffers, chemicals, and substrates are components of modern diagnostics that should be sourced from experienced specialists. An IVD supplier, for its part, should focus on serving the IVD industry. One thing is certain: quality always correlates closely with cost.

An ELISA plate supplies an example. Most producers of injection-molded components would be able to produce a transparent plastic plate with 96 wells very economically. But only a handful of companies worldwide are able to manufacture such a simple product at a level of quality suitable for immunodiagnostic applications. Maybe fewer than five of them are in a position to produce ELISA plates with optimal surfaces in such a way that, lot after lot, year in and year out, they support precise and reproducible assays. Thus, in the IVD context, even a simple piece of plastic filled with holes can be a high-tech component with substantial economic value and a strong quality requirement.

Biochemical and chemical reagents call for similar sourcing considerations. Purchasers should be cognizant of:

• Lot-to-lot consistency of supplies.

• Process controls in place at the supplier’s site.

• Qualification of products for IVD production use.

• Supplier know-how relevant to the IVD market.

• The technical and economical stability of the supplier.

• The independence of the supplier from other business activities than IVD supply.

• Availability of technical support from the supplier (possible only if the supplier has its own team of experienced assay developers).

• Consistency in the raw materials for the components.

• Raw material controls.

• In-process controls and batch controls established by the supplier to meet IVD requirements.

• The possibility of conducting supplier audits.

• The availability, as needed, of any volumes between small quantities and bulk batches.

Regarding the last item in the list, a good supplier is one who is a partner from the very beginning of the product life cycle, when batch sizes are very small, until success is achieved and thousands of kits are produced every month.

Diagnostics manufacturers always have to prepare themselves for challenges the future may bring. One of those challenges is the unknown nature of the future of diagnostics. Manufacturers wishing to be first movers in future IVD markets might well wonder whether making the right sourcing decisions will have something to do with their chances of success. Can biochemical and chemical sourcing be a strategic tool for winning a better market position than competitors?

Future IVD Market Challenges

Successful IVD companies will be those that find answers to most of these questions before they lose market share to other companies who prove to be the first movers. Many kit manufacturers experienced constant growth in sales during the past decade without realizing that their share of the market was meanwhile slowly declining. They need to develop strategies for addressing future market challenges.

Emerging Markets and Their Infrastructure. A huge part of the world’s population does not have access to reliable diagnostics. As the economies of countries with large populations evolve, the need for healthcare delivery, including diagnostic products, will grow enormously. However, in much of the world, this growth in demand will not support highly priced automated diagnostics. Many countries will have diagnostic capabilities based only on easy-to-use lateral-flow assays and similar technologies for many years. This potentially will be followed by laboratory testing based on techniques such as ELISA. Automated testing available nationwide will be characteristic only of high-income industrial nations for a long time to come.

Thus, lateral-flow devices and ELISAs will have to be adapted to the requirements of low-income countries. One of the biggest challenges here is maintaining test stability under potentially harsh conditions. There is no dependable cold chain for products exported to many African, some South American, and some Asian countries. This means that the stabilization method used in producing most kits today is definitely not sufficient for such exports. Stabilizing solutions of the past were very good products when industrialized nations were the only markets for ELISA kit manufacturers. However, when emerging markets are to be served, modern stabilizers will have to be employed in production. This will lead to changes in sourcing approaches, with decisions that were good in the past being bad for the future. The necessary stabilizers based on new technologies have been introduced into global markets just within the past two years.

IVD Ease-of-Use and Clinical Reliability. When, in some countries, only easy-to-use technologies are practical, those technologies have to be altered to accommodate clinical needs under challenging field conditions. Lateral-flow assays, for example, will have to be much more precise and should offer better semiquantitative testing. These devices will have to give more information, either through more lines or by more accurately differentiating between colors or lines representing various concentration ranges. Better lateral-flow device precision necessitates better flow buffer chemistries and better conjugates for signal generation. Conceivably, completely new low-cost technologies allowing mass field use of diagnostics without laboratories will be developed.

New Biomarkers. New biomarkers will gradually be discovered, validated, and brought into clinical use, either as stand-alone markers or as combinations of several biomarkers providing better insight into clinical outcomes than a sole biomarker ever could. The challenge new biomarkers pose for developers of clinical IVD tests is that they do not appear in high concentrations and, in many cases, are not stable for long periods in patient samples. Developing diagnostic products for such analytes, even for markets in industrialized nations, will not be easy.

Companion Diagnostics. Companion diagnostics are coming. That is, some of the new biomarkers will show whether a pharmaceutical drug is effective for a particular patient. Following an initial diagnosis (supported by standard IVD tests for detecting a specific disease) in routine clinical testing, the efficacy of a particular drug therapy for that patient will be determined through a second level of testing. Such first- and second-line testing is known from high-throughput screening and hit verification in drug development.

Where routine clinical diagnostic testing is first-line, companion diagnostics constitute second-line testing. As a consequence, this new kind of diagnostics differs significantly from routine IVD assays. Second-line testing requires much greater reliability, for one thing. Sometimes, test structures are different owing to the very low number of tests of this nature to be performed; there is no call for automation, for example, because patient numbers will not sort with automation requirements and automation economies. On the other hand, the health-economic benefit per patient of a good second-line test is extremely high. Many thousands of dollars per patient can be saved when companion diagnostics prevent the unsuccessful application of useless therapies, or dangerous side effects. Thus, the pricing of such second-line companion diagnostics testing can be much more attractive for kit manufacturers than any kind of routine diagnostics.

The association of extremely high reliability, low sample numbers, and a high health-economic benefit per patient with companion diagnostic technology is something new for the IVD industry—a combination of test characteristics not seen with routine diagnostics. Manufacturers pursuing this development option definitely need other solutions for kit production than those they have used before.

Ensuring Reliability and Stability

All of the future kit production challenges just described have in common the central issues of reliability and stability. Some sourced biochemicals and reagents can have an impact on these. In an ELISA kit, four major groups of components can. Some of them are still produced in-house by some kit manufacturers, but most are now outsourced. These components are antibodies, assay buffers, surface blockers, and antibody-stabilizing solutions.

Antibodies. Most antibodies are tested extensively during assay development; in fact, most development teams have this task in mind when they start working on a new product concept. Even though assays will become more and more challenging to develop, choosing the right antibodies—a function unchanged fundamentally—will still involve questions of specificity, affinity, robustness in coating, and labeling.

Assay Buffers. In the past, assay buffers were mainly produced by kit manufacturers in-house. Some additives, such as HAMA-blockers, came into play, but the general composition of the buffers did not change for 20 or 30 years. However, many problems of interference could not be resolved under this old regime. HAMA interference could be prevented by the HAMA-blockers, but there was no way to avoid cross-reactivities, matrix effects, problems of highly viscous serum from old patients, and similar problems. New assay buffering technology that will overcome all these forms of interference with one approach should lead to better assay sensitivity, specificity, and, thus, clinical reliability. That is exactly what is needed for biomarker assays and for the highly reliable low-cost-format assays emerging markets require.

Surface Blockers. The composition and characteristics of surface blockers did not change for years, but new blockers are exhibiting significantly improved performance. Many, but not all, assays can be enhanced through new chemical protein modification and splitting technologies for blocker production. The problem of blocking layers and their exchange reactions has an enormous impact on assay reliability and sensitivity—for example, in infectious-disease testing. Working with old-fashioned blockers such as fish-based, gelatin-based, or standard BSA-based blockers is probably not a way to improve reliability in future diagnostics.

Antibody Stabilizers. Before an ELISA kit is used, it is subjected to the rigors of the manufacturing process, shipment to the distributor, a wait for customs clearance, storage at the distributor’s site, shipment to the laboratory, and storage there, followed by the measurement. After all these stations, the kit still has to perform very well. Stability of a year or two at 4°C was, for a long time, sufficient. Immunoassay stabilizers were available to ensure this, and there was really no problem with stability. However, the challenges of the coming new IVD markets may occasionally require better antibody and antigen stabilization technologies.

Modern stabilization technologies that outperform earlier solutions have been available for a couple of years and are used in producing ELISA kits. Whereas the older stabilizers form a layer on coated molecules, the new systems create layers of such density that the result could be called a liquid plate seal rather than a coating. Several other stabilizers based on cutting-edge technologies are available—even for antigens and for sample storage. It will be a question for developers of any new assays whether they should stick with established stabilizers or begin to use the modern solutions. A decision to modernize will probably necessitate a change in suppliers.

Conclusion

Successful new product development depends on management having a clear strategic vision for the new product. In forming that vision, diagnostics manufacturers should pay attention to the new challenges discussed here. Sourcing requirements vary significantly with different markets and market-penetration strategies. Companies that want to enter any of the challenging markets of the future face a strategic question to which more-modern chemicals and reagents may provide the answer. Only the correct strategic positioning of a project will lead to an appropriate development and sourcing strategy.