SomaLogic Inc. (Boulder, CO)
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The PSD/4 syringe pump by Hamilton Co. (Reno, NV)
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Supply-chain management at any company occupies a link between the engineers designing a new system and the vendors of the sourced components. Managers will find that a close working relationship with both vendors and the engineering staff optimizes supply-chain processes and pays great dividends during the transition from development to manufacturing. Organizations are constantly looking to improve margins through lean-flow manufacturing, kanban management, and product synchronization, not to mention the selection of cost-effective components. These techniques often involve maintaining good vendor relationships.
The engineer’s perspective is different, and involves a different challenge. The technologies associated with microfluidics, DNA/RNA, microarrays, and the POC device drive critical part selection during the product design stage. Component selection and the system integration associated with that component are the engineer’s chief concerns.
System integration involves all engineering disciplines, including the validation and verification effort and the manufacturing process. All too often, designers lose sight of these two project areas. More important, V&V and manufacturing are not even acknowledged in early discussions with vendors during establishment of the supply-chain management plan.
Technology Trends
The IVD market has seen many changes over the years. Twenty years ago, there was little discussion about DNA’s use in an IVD. Today that is not the case, and its application is expanding.
Significant development efforts are under way in this area, involving FISH, cytology, various forms of mass spectroscopy, and microarrays. The microarray technology has even captured the eye of FDA, which published a special controls guidance document for instrumentation for clinical multiplex test systems in March 2005. This technology is largely focused on the biotechnology and drug-discovery markets, but there is a strong underlying motivation to bring these technologies to the IVD marketplace as quickly as possible, and as a result FDA has created this guidance document.
Another area of heightened activity in the IVD market, although somewhat underreported, is associated with homeland security and bioterrorism. Significant government funding has occurred in the past years to support this effort. The technologies involved here are now beyond the concept phase and well into demonstrating their viability. Companies working on these technologies use all of the scientific techniques named above, and more, in developing systems hoped to be able to identify biological agents quickly, with great sensitivity and specificity. In the coming year it is expected that some of these systems will begin field evaluation. It has been said what NASA did for the semiconductor industry, biodefense will do for the diagnostics market.
The upshot of these trends is that “smaller, faster, cheaper” and “multiplex testing” are themes that will be prominent in the future. Integration of mechanical, electronic, and software components in creating devices to address the coming technology challenges is crucial. Microarrays will require finer-resolution mechanical systems and optics, as will FISH and cytology. Additional technology is under development to reduce not only the size of IVD systems, but also the complexity and cost, for both system and reagent. All of these technologies militate toward a microfluidics-based technology to reduce cost and system complexity.
The Integration Challenge
Most instrument development projects begin with the establishment of the general system architecture. Here, the engineering staff divides the system into subsystems that address specific areas of functionality. During this process, the system engineer considers what general hardware, software, optics, and electronics can address a particular need. Additional considerations include serviceability once the system reaches production. This architectural process is very fluid and dynamic. When the general structural plan has been settled, the engineers begin to look at alternative hardware solutions and to balance their pros and cons.
Orders of components used in forward-looking diagnostic instrumentation increasingly are placed with vendors who are able to customize their offerings. Customization requires frequent and timely communications between manufacturers and vendors. The challenge for the instrument developer is to select the component that minimizes the integration demand.
There are trade-offs that need to be considered. For example, when implementing a stepper motor driver, a motor controller could either be purchased from a different company and integrated, or be developed internally. Alternatively, a stepper motor with a built-in motor controller could be purchased in order to reduce project risk and accelerate the schedule. However, this would entail costs 15–50% higher. In another case, developers might identify an input/output (I/O) board or PLC that includes features similar to those needed for the instrument and compare this option with designing a custom I/O board to interface with peripheral devices within the instrument. The cost of the former option may be higher because the board has features not required for the application and the margin to the organization supplying the board. The lower-cost latter option will require more development time but provide a more custom and application-specific solution. In considering choices like these, sales projections for the instrument should be measured against the costs of in-house development versus purchasing off the shelf.
As mentioned, microfluidics technology is now central to many diagnostic instruments as the industry matures and miniaturizes. The capability of an instrument to move fluid in nanoliter volumes grows increasingly desirable. Subsequently, focus is directed toward pumps, improved precision and accuracy, and more-sensitive liquid-level-sensing circuitry. The technology for dispensing microliter to nanoliter volumes requires different components than the traditional syringe and stepper motor. The demands on motor controllers and encoders are much greater.
The integration challenge here is the mix of technology—the right hardware and the right electronics with the right software—that will ensure that project requirements are fulfilled in a timely manner for all involved, including the validation and verification team.
Incorporating Other Technologies
A fully functional system including transport mechanisms for samples and cuvettes, temperature regulation for assay reactions, reagent cooling, and, depending on the technology involved, even thermal control to 80°–95°C. Many other subsystems besides microfluidics require some form of active temperature control. Improvements in flex circuitry and thick-film technology have provided advances in this area in recent years—advances that address both price points and the design of the heaters, coolers, and temperature-monitoring technology employed in applications like thermal cyclers for DNA and RNA.
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The Quadrus Mini imager (left) by Microscan Systems Inc. (Renton, WA) offers true autofocus capabilities. The MS-4 imager (right) by Microscan Systems was designed specifically for embedded bar code and 2D symbol applications.
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Industry miniaturization efforts have been accompanied by a need for greater motion control precision in applications like microarrays and FISH. Thus, encoders with nanometer resolution are now part of many systems, especially those that require imaging in pixels as small as 0.1–50 µm. The introduction of such encoders has increased processing demands and information management overhead, which require more processing power at the controller level. Whenever there is significant motion control involving an encoder with nanometer precision, the best solution may be, from the standpoint of cost and development schedule, to purchase a dedicated controller as one of the system components.
Not to be overlooked are larger subsystems that integrate components into subassemblies. Examples of these are fluidic pipettors, microtiter plate stackers, and electro-optical imaging subassemblies. Again, the balance between cost and schedule should be considered. While these larger subassembly components are costly to purchase, the alternative, an in-house development effort, also requires a substantive investment. It may be less expensive to purchase the component and integrate it than to design, refine, validate, document, and produce a large subassembly internally. The deciding factor will probably be the anticipated instrument production volume.
System Control. The evaluation of controllers should be performed with care to ensure that the processing power and interface options necessary to support the project are all present. Without proper planning, such evaluation may not be sufficient, which could lead to significant delays in the project schedule if problems should arise. It is once again important to take a system view to ensure that all disciplines are supported, including testing and manufacturing. Today’s embedded micro markets provide for full-featured processors with built in digital I/O, A/D, D/A, and memory, all for < $10 in large quantities. Suppliers provide the development tools at no or low cost to accelerate development. When implementing the design, test points can very easily be included on a circuit board if the need is considered in the design phase. The time involved in adding them later and returning the board through the fabrication process during the manufacturing stage can hold up the schedule by weeks. Such test points also facilitate the software development effort when used in conjunction with the rich feature set that the development tools provide.
A similar line of thinking should apply in dealing with component vendors. A vendor is not going to rework its production line to accommodate a manufacturer without foresight. Ensuring at an early project stage that the electrical components have the necessary test points can save a lot of time, preserve good relations with the vendor, and result in a successful product launch on schedule.
The Right Integration Mix. The cost of development, the cost of production, and time to market are considerations always in tension and in balance. Similarly, design and development is an iterative process, involving periodic reference to time to market, system production cost, a possibly shifting sales forecast, the dedication of effort to system integration, and the availability of mechanical, electronic, and software components that suit the system architecture.
With every component selection, the entire IVD system and its development project should be taken into account. A component that may be the best choice from an electromechanical standpoint could cost months in software development. It is of little value to select a processor that has a 6-month lead time. Every instrument development effort is different, but each involves a mix of electronic, mechanical, and software elements. The challenge is to find the mix best suited to the system design that will demand the least complicated and laborious integration effort during the design phase, prototype verification, and transfer of the design to manufacturing.
While the architecture of the system may make writing custom software seem highly desirable, customization may necessitate substantial validation and verification. Off-the-shelf software also requires validation and verification when it is integrated into a product, but the likelihood of bugs should be significantly lower as long as the product is fully developed and reputable. Not to be overlooked, consideration should also be given to the regulatory submission process. Systems that include software require more validation and backup data for PMA or 510(k) submissions. IVD manufacturers should ensure the regulatory pathway is not a significant gating item due to design decisions that should be taken.
As the design effort iterates, the selection of components will change. A component that had been eliminated as a candidate may come back into favor. Here is an area where regular communication with knowledgeable vendors can enhance the development effort.
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NMP miniature air and gas diaphragm pumps by KNF Neuberger Inc. (Trenton, NJ) have 316 stainless or aluminum heads to provide threaded ports.
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User Interface. From the operator’s perspective, the IVD system is often a product developed on top of a Microsoft Windows–based platform. In addition to the typical Microsoft tools for development such as Visual Studio, numerous libraries exist to support all aspects of the development process. These include cross-platform development tools, medical connectivity tools for HL7, libraries for specific I/O boards, and dynamic link libraries for bar code readers. In recent years, there has been increased utilization of Linux in IVD systems. There are a growing number of libraries and development environments that support this platform. While the platforms should meet the product requirements, it may provide a very cost-effective solution.
Bar code readers today are generally of the 1-D or 2-D type. The 2-D reader is gaining in popularity because it can store significantly more information. Unfortunately, information cannot be written back to a bar code. Alternatives involve radio-frequency identification (RFID), which allows writing back to the disposable identifier. The volume of information that can be stored ranges from bytes to kilobytes, significantly more than a bar code holds. Such a feature provides great flexibility, but with a price penalty—one that may be worth paying, depending on the application.
Bar code readers and RFID readers have a similar look and feel. The read range of RFID technology is typically a bit longer. RFID readers are often significantly less expensive as well. Such technology is not the best solution for all applications, but may answer a specific need.
Working with Vendors
Time to market can be vital to a project’s success. Certainly, delays in delivery of any component do not help. The component selection process calls for attention to more than just the technical features and capabilities of a subsystem; it is also important to ascertain vendors’ logistical capabilities to supply prototype and production components when and in the quantities needed. Paying visits to key vendors to get a first-hand view of their operations is well worth the up-front cost. Ultimately, the regulatory process requires some form of vendor qualification. But knowing the vendors’ capabilities during development may save significant time and cost down the road. Also important is knowing the vendor’s track record of on-time delivery. That history may not need to be exemplary to ensure that the vendor-customer relationship is successful. Knowledge and communication and the best component are the cornerstones of a good relationship; a spotty delivery schedule may be something for which the IVD manufacturer can plan accordingly. Asking the vendor for on-time delivery history, out-of-box failures, shipment linearity, and other similar metrics is a key indicator of the commitment that a supplier is making to ensure customer satisfaction. They demonstrate a vendor’s desire to track key indicators of customer satisfaction and not simply revenue generated.
Keeping current with technology is a major challenge for every company. Many organizations focus on a core technology and outsource that which they see as not central to their business. For example, a company whose core technology is microarrays, FISH, or biochips may find instrument design to be beyond its core competency. To fully comprehend the disciplines of instrument design, development, QSR compliance, lean-flow manufacturing, microfluidics manufacturing, flex-circuit assembly, ESD compliance, CE marking, and industrial design—let alone maintaining a balance among their demands and requirements—can be too much for many companies to expect of themselves. Since managing all these resources is at times overwhelming, outsourcing enterprises that perform these services as their primary business can be a great help to an IVD manufacturer. (See the introduction to Section 8, “Contract Manufacturing,” for a discussion of these organizations.)
Both contract engineering firms and IVD manufacturers with their own engineering resources should find this year’s IVD Technology buyers guide of great assistance in selecting components for their systems. Both supply chain managers and engineers can identify and distinguish key vendors in relevant technology areas. The guide is intended to save them time in their search for essential IVD system components, and to make it easier for them to locate the right vendors.
