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Critical Considerations For High Viscosity/High Volume Drug Delivery Devices

Critical Considerations For High Viscosity/High Volume Drug Delivery Devices

By 2020, biologics are expected to make up more than half of the world’s top 100 selling drugs. To keep pace with these trends, device designers are tasked with overcoming various challenges associated with delivering these drugs. In particular are issues of high viscosity and/or high volume (HV/HV) associated with biologics. Since biologics cannot be taken orally, as the conditions within the stomach denature the molecules, biologics must therefore be delivered via an injection. While the challenges of HV/HV are not unique to biologics alone, per the abovementioned market trend, these drugs demand special attention from device developers.

The produced molecules that make up most biologics are large and complex, especially when compared with synthesized drugs. For example, the molecular weight of synthesized drugs ranges in the few hundred to perhaps a few thousand Daltons (Da). In comparison, molecular weight of biologics ranges around 150,000 Da. Consequently, the larger size of these drugs leads to a higher milligram per milliliter (mg/ml) concentration. As mg/ml increases, so does the drug’s viscosity, or thickness. From a drug delivery device perspective, higher viscosity drugs require more force to push fluid through the narrow orifices used in delivery (e.g., a cannula). This force, or syringeability, is dependent upon a variety of factors including desired flow rate, needle length, and needle diameter, as well as viscosity. The important correlation between these variables is that the needle diameter (D) is a 1/D4  relationship, as indicated in the Hagen-Poiseuille equation, solved for force:

Therefore, any small change in the needle diameter will result in a large change in the plunger force. It is important to note that the above equation applies only to Newtonian fluids and thus any non-Newtonian components within a drug formulation will complicate the relationship between plunger force and viscosity. However, this equation does illustrate the delicate nature of designing a delivery system.

Design Considerations

It would seem to be a simple resolution to increase the needle diameter to accommodate a more viscous drug as a larger diameter needle would lead to reduced plunger force. However, a larger needle would also increase pain at the site of injection and create a negative visual perception by the patient. On the other hand, maintaining a smaller needle will lead to higher forces and higher than “normal” plunger force will lead to user fatigue and poor user experience. Both of these issues can significantly affect patient experience and use compliance.

One common solution, to the abovementioned challenges, is with the use of an assisted delivery device. An example would be auto-injectors used for epinephrine delivery. Auto injectors can be fitted with power sources that drive the plunger at forces higher than could be provided comfortably by the user. This approach enables device designers to maintain a smaller gauge needle and place the burden on the power source to provide the high force needed for delivery. But this approach is not without its issues, which should be considered when designing delivery systems for high viscosity drugs. These include:

  • Size:

A power source capable of providing the force required to push large molecules through a small needle can become large. For example, springs are typically used in such applications; to maintain the force required at the end of a plunger stroke, longer springs might be needed, thus increasing the overall device size. At the other extreme may be electrical devices that use actuators, motors, and such to provide power and likely also increase the size. In either case, the tendency is to increase the size of the device, but the current consumer market trend seems to suggest that users prefer smaller devices.

  • Material:

New high-strength materials are constantly in development and can be used to help alleviate the issue of size by deploying smaller wall sections and structural features in devices and container closures – miniaturizing them. New material technologies can also be used to derive power sources (e.g. springs) that are smaller and yet provide the same forces. However, new materials face the challenge of biocompatibility requirements that may not have been fully tested or satisfied. Furthermore, long-term stability testing of these new materials would be required to ensure safety and performance could be maintained through the life of the product.

  • Safety:

Stored energy devices, such as springs under compression, require robust safety features to prevent injury, device failures, and accidental actuation. In the case of devices capable of delivering viscous drugs, this requirement becomes even more important. An accidental drop, material fatigue, failure of the glass container closure or excessive vibrations can lead to catastrophic failures that could injure users or prevent lifesaving drugs from being administered. But safety is not limited to the user alone. Additionally, device manufacturers need to be aware of the potential for injury during the manufacturing process as well. Improperly secured power sources could derail a high-speed manufacturing process and cause injury to operators as well.

The aforementioned approach focuses on maintaining a smaller needle diameter by accepting a higher plunger force. This approach centers on different ways of executing a high force power source. Another approach could be reducing plunger force (while maintaining a smaller needle) by simply lowering any of the variables in the numerator of the Hagen-Poiseuille equation. One change could be reducing the diameter of the plunger and thus reduce the plunger area (A). However, this has size implications, as the syringe or device would need to become longer to accommodate the same drug volume.

Another option would be to reduce the flow rate, lowering the force but increasing delivery time. Likewise, decreasing viscosity can be achieved through dilution but the increased volume also increases delivery time. Therefore, these solutions require a different delivery approach that cannot be achieved through direct injection methods.

One approach is the use of IV delivery where patients receive an IV solution with the drug mixed into the bag or bottle. This reduces the viscosity of the delivered solution while drastically reducing the flow rate. However, this method prolongs the delivery time. Some drugs have specified delivery through an IV bag or bottle over a certain period of time. While patients may accept this form of delivery for otherwise unavailable therapies, quicker and more convenient delivery methods are always preferred. In response to these limitations, body worn infusion pump devices may be implemented.

Body worn infusion pumps are common in diabetes treatment, in which users wear an insulin pump connected to their body via a cannula. However, for delivering high volume drugs, the device needs to be treated as a prolonged injection device rather than a continual-use pump and, as such, these devices carry a different set of challenges:

  • Size:

Similar to the direct injection devices mentioned above, size is a critical factor to body worn devices. Unlike direct injection devices, the size challenge in body worn devices lies in its necessity to slow down the delivery speed. While the delivered force required to push the drug through a needle may be smaller, it needs to take place over a period of several minutes to a few hours. Thus, any additional necessary components, that can modulate the delivery of power over a long period of time, will require more space and cause the device size to grow.

  • User Interface:

Unlike direct injection devices, where the user maintains constant interaction during its use, users of body worn devices cannot be expected to maintain the same level of interaction over a course of several minutes or hours. Therefore, the ability of the device to provide alerts to errors, indication of progress, and confirmation of delivery becomes critical.

  • Body Fixation Method:

A significant challenge in body worn devices is their ability to be fixed onto the body. The first component of this challenge is where the device should be placed on the body, e.g. torso, upper arm, thigh. Depending on its intended placement location, different fixation methods should be considered.

  • Is the tissue more sensitive?
  • Can an adhesive be used on this part of the body?
  • Is the adhesive aggressive enough to hold the device in place over the required time period?
  • Will it cause allergic reactions?
  • Perhaps a band of some sort should be used instead of an adhesive?
  • Will the device need to survive wet conditions or withstand physical activity?
  • How will the patient feel about wearing a device?Will the skin surface need to be shaved before application?
  • Does the patient feel “tethered” to their device?

Another consideration is departing completely from the conventional needle based designs, and looking at alternate injection platforms. Microneedles and needle-less technologies are potential alternatives that could be explored for delivering high viscosity and/or high volume drugs. With both options, a sound understanding of microfluidics and the associated challenges are important. These challenges might include achieving adequate contact between the drug port and the skin, accommodating varying skin types, and varying use conditions (temperature, humidity, etc.).

Human Factors Considerations

As evidenced by the FDA’s increased attention to human factors considerations in medical devices, a thorough investigation of a user’s interaction is as important as the performance of the device. A well-performing device, that is difficult to use, can detract from patient compliance. Furthermore, a non-intuitive user interface may at best be a source of irritation to the user and at worst cause severe life-threatening consequences due to improper use. Therefore, simple elements such as a location of a button or the presence of an indicator (e.g. lights, sound) require careful human factors considerations. For example, a device with just one LED may seem simple enough. However, if the single LED blinking at different rates indicates different functional feedback, then the device has become significantly more complicated. This approach requires the user to remember numerous potentially non-intuitive device states. Therefore, multiple, labelled LEDs may actually provide a much simpler interface than a single LED. Device developers need to strike a balance of usability and functionality when it comes to safety. A device that requires several sequential user-driven motions to unlock may have a robust safety lockout system, but if it is too cumbersome patient compliance can be compromised.

Device developers will often conduct design and manufacturing process failure mode and effects analyses (FMEAs). Extending these thought processes to include use-FMEA or use error risk analysis (UERA) ought to be an integral component of device development. It is imperative that formative usability studies with representative users be conducted early in the development cycle. Discovering a significant potential use error, once the development or manufacturing phase has begun, can be extremely costly both in terms of time and money.

These and other human centered design consideration (e.g., product form and semantics) play an important role in the potential, overall success of a device. An integrated development process that combines human factors engineering, human centered design, and device performance can go a long way to efficiently producing a product that is useful, usable and desirable to the user. These elements will be key to planning for future product differentiation.

Future Device Trend Considerations

With the saturation of smart devices among the general population, connected devices in all manner of everyday life are also becoming more prevalent. These devices fall under the umbrella of “Internet of Things (IoT)” and represent a source of constant activity in the medical device world as well. The apparent benefits of connected medical devices have typically been around concerns such as monitoring patient compliance, tracking user activity/location to customize care of the individual patient, inclusion of convenience features such as reminders and managing refills. But each of these, and other benefits, need to be weighed against the implications of their deployment.

  • What are the regulatory implications?
    • Will connection technologies, such as Bluetooth and NFC, require FDA oversight?
    • Can third party apps be permitted? How will updates to apps (e.g. bug fixes) be managed?
    • Since the predominant method of app distribution is through only a few entities, how will the distribution of apps be managed for medical devices?
    • How will the manager/holder of user data be regulated?
  • What are the infrastructure implications?
    • Who will manage user data?
    • Will user data need to be anonymized?
    • Which connectivity technologies should be used?
    • How should device recycling/disposal be managed? If the device has a needle, can an electronic device be disposed through a conventional sharps disposal?
    • How can the device/system be protected from hacking?

Overall Device Development Strategy Considerations

Manufacturers of devices will continue to repeat the mantra of “early engagement” with device designers and developers. This stems from the simple premise that it is easier, cheaper, and quicker to make the inevitable change to a design at the beginning of the development cycle than toward the end. Manufacturing issues discovered after a design has been locked can cause severe delays or even derail the entire program. This thought process can extend to the dynamics between the drug developers and device designers, as earlier considerations regarding device strategy can avoid crippling challenges down the road.

For example, due to their nature, some drugs require refrigeration for storage and transportation. For those cases where refrigeration is not possible (e.g. transportation to remote areas without electricity), reconstitution from lyophilized drug powder has been utilized. In addition, some drugs can be rapidly reconstituted via turbulent mixing with the diluent. Other drugs require slow reconstitution with as little agitation as possible. Each of these formulation options carries its own set of consequences in the design and manufacturing of the associated devices. Therefore, as drug manufacturers consider various drug formulation options, early engagement with device designers and device manufacturers is critical to developing the most efficient overall strategy for the drug/device life cycle. This strategy becomes even more important as bio-similars continue to appear on the market.  Drug developers need to be mindful of their device strategy in order to distinguish themselves from the inevitable proliferation of generics and bio-similar drugs.

Not inclusive of what has been described throughout, there are other potentially critical factors, but the most critical and central consideration for device designers should always be the well-being of the patient. High viscosity/high volume drugs are challenging to deliver, but they present a wealth of therapy possibilities for the patient, as these drugs are almost always associated with biologics. Since biologics cannot be administered orally at this time, parenteral administration remains the most viable current option. To those patients for whom biologics can significantly improve their quality of life, a reliable, effective, and easy-to-use delivery device could truly be a lifesaver.