On-Chip Blister Packs for Liquid Reagent Integration

Benefits of Blister Packs for On-Board Reagent Storage

So-called “Lab on a Chip” cartridges can perform functions that were once impossible outside of central labs. By integrating reagents on the chip itself, some of the workflows that were typically done in a lab environment can be automated. For example, in central lab environments, many assays use multiple reagents and those would typically be administered by pipetting robots. By incorporating the reagents onto the cartridge using blister pouches, much of the workflow can be automated.

The obvious benefit is that tests that could once only be performed in a lab can now be performed on POC or benchtop devices, greatly increasing their accessibility in other healthcare settings, such as urgent care clinics.

By combining microfluidic and on-board reagent integration, along with micropumps and valves, it is possible to create a self-contained test with only mechanical or electrical connections between the cartridge and the instrument. This approach significantly simplifies the instrument cost and negates the need for washing steps between patient tests.

Liquid Reagent Blister Pack Design Basics

Blister packs can come in a variety of sizes depending on the design of the chip and space constraints. Dome blisters are the most common configuration because they're economical, easy to mold and have proven, reliable actuation mechanisms. Other geometries and asymmetrical blister shapes can be designed to maximize card space, but it is important to validate performance of custom designs and to make sure that they will scale economically. We have seen well-intentioned engineers make the mistake of trying to design a unique blister geometry that maximizes the space on the cartridge platform but causes problems later when the blisters need to be scaled or ends up using more reagent because the chosen geometry does not dispense as much reagent as expected…requiring a large blister!

Another common mistake is underestimating the amount of reagent that will be needed in the test site. In this regard, it is vital to account that some of the reagent will remain in the channels and within the blister itself even after actuation. As a general rule, the dispensed volume will be 70-85% of blister capacity, which can vary. Larger blisters (100 μl or more) will dispense a higher percentage of the stored reagent, while smaller ones will dispense a lower percentage. Why? As the blisters collapse during compression, folds are created that can retain reagent even when the actuator remains compressed. Obviously, you don't want to make a blister larger than necessary to be “on the safe side” because you would be wasting reagent, but you also don’t want to underdeliver reagent to the test site. Actual delivery volume needs to be tested and validated. 

Determining Compatible Materials

Reagent blisters are typically made of two different materials: the well (typically a dome configuration) and the flat bottom that attaches to the cartridge substrate. The well is comprised of a heavier foil gauge that allows it to be molded more easily. The tricky part here is thermoforming a well that is thick enough to retain its shape and meet its burst maximum but soft enough to compress well so that all of the reagent is emptied. The bottom is typically an aluminum film with a frangible seal or surface that can easily be pierced. The opening force required typically ranges from 20-50 N.

It is also important to fully understand how each of your chosen reagents will
interact with the chosen polymer substrate to avoid bonding and leakage problems later. Reagents react differently to specific polymers and their chemical resistance needs to be carefully evaluated. Barrier performance characteristics should also be examined to meet shelf-life requirements.

Every year new assays are developed and new reagents are introduced into these concepts. More complex reagents, such as alcohol, are being integrated into the assay of point of care devices, greatly simplifying the workflow in ways not possible a few years ago. To get this process right, it's important that you work with experienced IVD design and material science experts who can find a good match between your proposed reagents, blister materials and cartridge substrate. 

Manufacturing Considerations for the Blister

As mentioned earlier, despite their deceptively simple appearance, blister pack manufacturing and their attachment to cartridge substrates is a highly complex manufacturing process most often performed in a clean room production suite.

Blister domes are often constructed with several layers. Generally, there is an aluminum layer that is sandwiched between two polypropylene layers. All blisters include a flange which must be heat sealed to the cartridge substrate. This flange needs to be wide enough to create a strong bond to the foil on the blister and the substrate of the chip. Adequate space must be allotted in the design phase so that it does not cause manufacturing problems later.

One additional thing to consider. If your test is highly sensitive to fungal spores and particulates (example: DNA, RNA or RNase applications), consider where your blisters will be manufactured. While most blisters are made in clean room environments, some areas of the world have excessive humidity and higher airborne fungal spore counts that can complicate blister manufacturing and
storage. 

The Importance of Validation and Verification

Along the way you will perform many tests to see how your blisters perform. You'll test how they adhere to the cartridge substrate, the amount of reagent they deliver, the reliability of the actuation mechanism and many other things. We could write an entire book on how this is done but suffice it to say that you validate that your design and manufacturing process is capable of consistently meeting your performance specifications and then you verify that it did. All this validation work will become a vital component of your regulatory submission to FDA or European Notified Body. For more information on how validation works consult FDA 21 CFR Part 820.75 and ISO 13485:2016. Talk to your proposed partner about this as well.

As you work through the process of evaluating potential blister manufacturers for your application ask potential suppliers if they are using the same equipment for prototyping as they use for manufacturing. Often the answer will be no, which is a red flag, because it will be more difficult for you to validate the performance of your blisters if you're doing so with prototypes made on different equipment than the final product.

Engage an IVD Blister Design Expert Early On

COVID taught us many things including the precarious balance of the supply chain and the ongoing risk it poses to business. Since blister packs are considered a critical component in your cartridge design, and because it is not quick and easy to switch critical suppliers, it is imperative to work with a partner that understands IVD blister design and manufacturing and can provide a clear transition through various production phases from prototype to scale. Discovering design mistakes later in the preclinical stages can be very costly and delay your time to market. Working with a contract manufacturer that has design, clinical and manufacturing capabilities under one roof is advantageous.