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Guide: Best Practices for Point of Care Product Development

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To develop a successful Point of Care (POC) diagnostic device, product developers face the fundamental challenge of translating the technical workflow of a laboratory assay into an automated workflow performed within a POC diagnostic device.

The POC device (instrument and cartridge) must be miniaturized and the workflow self-contained. It should perform protocols that manipulate temperature, samples, reagents, and other inputs, without human intervention, and always produce accurate results.

The assay may work wonderfully in the lab; however, translating that science into a POC device takes some heavy lifting. Engineers and scientists need to break down the workflow into its components, implicitly understand each piece of the process, and develop creative solutions to emulate the assay workflow steps for the POC environment. This process requires a collaborative and iterative process to result in a robust product – do not underestimate the challenges.

Moving an assay from the lab to a product

There are many elements that make an assay effective in the laboratory, such as fluid volumes and their manipulations, temperature, timing and lighting. When translating that assay from the lab to a product, intensive discovery research is required to determine 1) what are the most critical elements and 2) understanding how those elements and other factors influence results.

Fluid handling is a critical and often challenging example. This process typically needs to be miniaturized to transfer the assay to a POC device, but fluid dynamics differ between a test tube and a cartridge.

For example, moving 50µL of a fluid (the size of a raindrop) with a pipette on a lab bench is a trivial process. On the other hand, manipulating such a small volume of fluid though a channel in a POC cartridge presents a challenge due to dead volumes of the channel.

Mixing may also be an issue when adapting the original bench-side approach (aspirate and dispense, or vortex) to a microfluidic cartridge. It is important to understand how fluids are mixed—rapidly, slowly, vigorously, gently—and develop the instrument and cartridge accordingly.

Methods such as shuttling of fluids back and forth, stir bars, or bubbling are all methods of mixing that are commonly used in a POC cartridge, but they may not be sufficient for the assay. If the method chosen for the cartridge is different from that used on the bench, the assay needs to be re-evaluated using the new method.

Temperature control is another area that can make or break an assay. Some assays require tight thermal controls to ensure a chemical process, such as denaturing DNA or lysing a cell, or even an optimal incubation environment.

When performing these steps on a work bench, equipment dedicated to these tasks are used. They are designed with the optimal geometry and heating components to ensure the steps are completed properly and efficiently.

When performing these steps in a POC cartridge, you encounter competing requirements, such as the need for increasing thermal contact versus the need to keep the cartridge small. Equipment such as PCR, spectrometer and vortex machines may be used when performing a single assay in the lab; however, trying to combine all three into a benchtop system while maintaining their performance poses challenges. During the assay translation process, it is essential to identify the thermal accuracy and precision requirements for the POC device and to understand how making trade-offs in these areas will affect performance.

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Once you understand the discrete workflow steps performed in the lab and their sensitivities, you must test different ways to adapt them to a cartridge—changing the original protocol as little as possible. Using this process to identify potential problems with the workflow fundamentals enables you to begin development on solutions early.

 

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Shifting from research to development

As the original lab protocols are adapted to a cartridge format, designers and engineers need to work collaboratively with the scientists who developed the assay to identify risks and find ways to mitigate them. This multidisciplinary team will conceptualize the types of test beds they must build to ensure the adapted assay continues to function optimally.

Using test beds that represent how the lab protocol will be implemented in the POC system enables the materials, methods and protocol to be evaluated using equivalency studies to the benchtop protocols. New sensitivities and band studies can then be explored on the isolated protocol step with other variables decoupled.

The faster problems are determined and the sooner a fix can be implemented, the cheaper the change implementation and shorter the impact to the timeline. Quick to fail experiments are invaluable during this process. These approaches stress the system design to encourage it to fail sooner, quickly illustrating problems that must be fixed.

For example, if a mixing method of shuttling the fluid is inadequate, then a change to improve the mixing will need to be implemented. The scope of these changes can be as simple as introducing features to induce turbulent flow, or as complex as adding a stir bar to the cartridge which would require a motor and driver on the instrument.

By continuously redesigning and testing the assay protocol steps in the cartridge test beds while the device is being built around it, you can gradually de-risk and mature the product. This is just one more reason why the cartridge design should lead the instrument development.

Making trade-offs

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During the development process, there are always conflicting needs that must be reconciled. It is tempting to want a system that can do everything, but that will increase the scope and complexity of the device exponentially.

For instance, POC cartridges should be as inexpensive as possible; however, when a test is initially converted from a laboratory assay to a commercial POC diagnostic, the cartridge may be too expensive. Developers can engineer those costs down, but that takes time, which can delay a launch. In these cases, understanding the market and competitive landscape is crucial to making trade-offs. For example, if your target market is not price sensitive, you may want to launch as early as possible with a clear plan to reduce those costs over time.

As another example, you may also want to future-proof the instrument to accommodate an evolution of your assay. That would alleviate the need to develop a new device later, but it could also delay market entry.

For companies without an existing revenue steam or looking for a first-to-market advantage, the cost savings may not be worth the delay. In those instances, you could consider moving the instrument to market while simultaneously planning a second-generation device. Integrating the revised device into the development process can help mitigate the increased costs, while going to market with the current device can initiate cash flow.

When sound goals are mutually exclusive, developers need to make strategic trade-offs. The trade-offs should be aligned with the program goals and made early in the design process, to create a clear development pathway for the extended team.

Developing a successful POC device

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Translating an assay into a successful POC product requires a comprehensive understanding of the chemistry, the methods the POC diagnostic device will use to emulate the benchtop protocol, and the users and environment where the product will be used.

Deep collaboration between scientists and engineers to translate the assay into the POC device is essential during development. There may not always be a method to directly emulate the assay workflow performed on the bench to what is performed in the device. In these cases, extensive studies need to be performed to understand how the trade-offs affect the assay performance compared to the benchtop baseline, and if it is acceptable. Understanding the options available in the POC device and how it will impact geometry, proper planning, and diligent testing will all help to ensure a successful assay translation into a POC device.

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