Considerations for developing drug delivery devices
Phillips-Medisize examines the critical considerations device manufacturers should bear in mind when producing high viscosity / high volume drug delivery devices.
As the use of biologics continues to increase, early involvement between the drug manufacturers, device designers and device manufacturers is critical to the development of the most efficient overall strategy of drug/device life cycle.
Many biologics are highly concentrated, so a prescribed dose may be very viscous or require large volumes of the medication to be injected slowly over time. This can make it difficult to deliver a consistent dose, potentially impacting patient adherence to a given therapy.
There has been a rise in popularity of wearable self-injection systems for biologics. Instead of scheduling a doctor’s appointment for certain treatments, a wearable device allows patients to self-administer injectable medication. 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. For proteins, issues of viscosity, solubility, and protein aggregation become major obstacles, especially with the smaller-gauge needles that patients prefer. Since biologics cannot be taken orally they must be delivered via an injection.
While the challenges of HV/HV are not unique to biologics, these drugs demand special attention from device developers. From a drug delivery device perspective, higher viscosity drugs require more force to push fluid through the narrow orifices used in delivery (eg. a cannula). This force, or syringeability, is dependent upon factors including desired flow rate, needle length, and needle diameter, as well as viscosity. Any small change in the needle diameter will result in a large change in the plunger force. In order to be truly versatile, the device also needs to be able to deal with the following aspects:
Design considerations
It would seem simple 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. Maintaining a smaller needle will lead to higher forces and higher than ‘normal’ plunger force will lead to user fatigue and poor user experience.
One solution is the use of an assisted delivery device, such as auto-injectors used for epinephrine delivery. These 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 issues. These include:
Size
A power source capable of providing the force required to push large molecules through a small needle often needs to be large. However, the market trend suggests users prefer smaller devices.
Material
New high-strength materials can be used to help alleviate the issue of size by deploying smaller wall sections and structural features in devices and container closures – miniaturising them. New material technologies can also be used to derive power sources (e.g. springs) that are smaller and yet provide the same forces.
Safety
Stored energy devices, such as springs under compression, require robust safety features to prevent injury, device failures, and accidental actuation. Where devices are delivering viscous drugs, this is important. An accidental drop, material fatigue, failure of the glass container closure or excessive vibrations can lead to catastrophes that could injure users or prevent lifesaving drugs from being administered.
The aforementioned approach focuses on maintaining a smaller needle diameter by accepting a higher plunger force. This approach centres 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 reduce the plunger area. 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 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.
These 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. As such, these devices carry a different set of challenges:
Size
The size challenge in body worn devices lies in the 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. Any additional 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. The ability of the device to provide error alerts, indicate progress, and confirm delivery, becomes critical.
Body fixation method
The first challenge with body-worn devices is where they should be placed on the body. Depending on the 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.
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. Device developers will often conduct design and manufacturing process failure mode and effects analyses (FMEAs). Discovering a significant potential use error, once the development or manufacturing phase has begun, can be costly.
Device trend considerations
Connected devices are becoming more prevalent, particularly medical devices. Their benefits include monitoring patient compliance, tracking user activity/location to customise patient care, and managing refills. But these benefits need to be weighed against the implications of their deployment.
• What are the regulatory implications?
• Will connection technologies such as Bluetooth, NFC, etc. require FDA oversight?
• Can third party apps be permitted? How will updates to apps (eg bug fixes) be managed?
• Since the predominant method of app distribution is only through 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 anonymised?
• 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 of through a conventional sharps disposal?
• How can the device/system be protected from hacking?
Overall device development strategy
Manufacturers of devices understand the necessity of ‘early engagement’ with device designers and developers. This stems from the simple fact that it is easier, cheaper, and quicker to make changes to a design at the beginning of the development cycle rather than towards the end, causing delays to the process.
For the drug developer and device designer, early considerations regarding device strategy can avoid crippling challenges down the road. Of course, the most critical and central consideration for device designers should be the well-being of the patient.