By Ash Ghadar, Jack Dunkley and Ian Cleathero.
Large molecules and biologics have offered advanced therapies for managing chronic conditions, enabling self-administration. These drug products in their concentrated form can be injected in a relatively low volume, making them suitable candidates for delivery through auto-injectors. The high concentrations mean that typical doses required for the therapy can be in the ~1 ml zone (‘traditional’ auto-injectors) or ~2ml zone and above (‘large volume’ auto-injectors).1
A highly concentrated biologic is often synonymous with a high-viscosity drug product, particularly in low volumes. Delivering a viscous drug within the generally acceptable limit of 10 to 15 seconds, and in a sustained manner introduces significant challenges, most notably dose accuracy.2
With highly concentrated formulations, even a small deviation in delivered volume can meaningfully affect clinical effectiveness. Ensuring that every dose is delivered fully, safely and consistently is therefore critical.
For pharmaceutical and device developers, dose accuracy in high-viscosity drugs is not just a component level issue. It is a systems challenge involving the interactions of the drug product, container and fluid path, device mechanics and human factors.
High viscosity auto-injectors are typically used for delivering large molecule biologics such as monoclonal antibodies, Fc fusion proteins and certain peptide or protein therapeutics where the full therapeutic dose needs to fit into a small volume.3
Many monoclonal antibodies require highly concentrated formulations in the range of 100 lo 200mg/ml, with emerging next-generation biologics, particularly high-dose subcutaneous oncology therapies, requiring even higher concentrations of up to 300mg/ml.4,5
These formulations can result in high viscosity (1ypically above 20cP, in some cases, exceeding 100cP), necessitating specialised delivery devices capable of reliably delivering small volumes under high flow resistance.6 Auto-injectors are often the most suitable delivery mechanism when less frequent injections are required. Patients also naturally prefer as near to a pain-free experience as possible, which makes subcutaneous delivery favourable compared to intramuscular.
However, high-viscosity formulations introduce substantial mechanical challenges for the delivery device. Increased resistance during injection places greater demand on springs, seals and fluid paths, as well as on the overall structure of the device.
Precision and accuracy emerge from the interaction of three fundamental device layers as follows:
Some of the key challenges posed by delivering high viscosity formulations using auto-injectors must also be addressed.
A high-viscosity drug product requires more pressure to deliver than a low-viscosity one, all other parameters being equal. This translates to the need for a high-force drive system using, for example, stiffer springs or mechanical amplification. However, because the force generated by a spring decreases as it expands, the available delivery pressure reduces progressively over the course of the injection. It is important to ensure that a spring will deliver adequate force throughout the entire delivery stroke in order to ensure consistent, accurate delivery.
Higher forces, however, require stiffer and possibly stronger structures in the device to minimise distortion and maintain accuracy and repeatability. It is essential, when designing such a device, to model performance under all usage conditions and tolerance variations in order lo minimise sources of performance variation that would lead to variation in accuracy. With higher forces, the effects of impact during the expansion of the spring can increase dramatically, so the design must ensure that this is minimised or eliminated.
Management of spring energy delivery, for example using a damper, can mitigate the effects of impact with little effect on the available force. Energy sources other than springs, such as compressed gas or electrical drive, may be useful for delivering higher forces more consistently, but the need for thorough performance analysis remains and other characteristics, such as the effect of temperature on gas pressure, would need to be considered.
The needle inside diameter is the dominant factor affecting the pressure needed to deliver the drug product. With high-viscosity drug products,
the need for higher force can be mitigated to some extent by choosing a needle with a larger inside diameter. However, in general, this will also increase the outside diameter of the needle, leading to greater discomfort for the patient. Needles with thin walls are also available in certain gauges, allowing a larger inside diameter for the same outside diameter, but thinner wall needles have a higher likelihood of damage, such as bending. It is important that the selected needle balances delivery force needs with user comfort and needle stability.
Although friction is not directly affected by viscosity, higher forces and pressures increase axial stress on the stopper, which in turn raises radial force against the barrel. It is therefore important to minimise the stopper-barrel coefficient of friction and account for the effect of increased radial force in theoretical modelling.
The dimensional characteristics of the container will affect the delivery accuracy in two main ways. Firstly, the inside diameter will affect the crosssectional area, which, in turn, affects the volume per unit length of stopper movement. Secondly, the axial location of the container within the auto-injector housing affects the stopper’s starting position, which can influence the delivered volume for both complete and partial evacuations. It is therefore essential to account for tolerances in these dimensions when analysing performance to ensure accurate, consistent delivery.
Aside from factors that should be taken into account in any auto-injector development – such as typical characteristics of the target population, intuitive usage steps, clear and obvious feedback from the device, and foreseeable misuse scenarios – the effects related to high-viscosity drug products must be considered.
High forces can introduce additional human factor challenges, including a jolt from the drive mechanism that may startle the patient and lead to premature device removal, resulting in an incomplete dose. Other effects, such as increased recoil, audible mechanical noise, greater perceived injection time, and the need for firmer grip stability, can also influence user confidence and behaviour during administration. Such effects must be analysed using formative studies where appropriate and mitigated in the design as necessary.
When developing an auto-injector for high-viscosity drug products, it is paramount to follow a structured design process. Maintaining delivery accuracy under high operating forces introduces additional challenges that must be addressed through rigorous analysis across the full range of operational and manufacturing parameters.
Design space analysis enables critical interactions to be identified and supports a clearer understanding of which features and dimensions must be tightly controlled. Advanced tolerance analysis methods, such as Monte Carlo simulation, can then be used to predict device behaviour at the extremes of tolerance bands as well as under statistically likely component arrangements.
Mathematical modelling of device performance, combined with finite element analysis (FEA) of the device both in storage and during use, allows performance to be assessed across the applicable storage and operational conditions, building confidence in the reliability and accuracy of the design.
Combining tolerance analysis with FEA also provides assurance of how devices will perform through the production process, including the impact of variability introduced by manufacturing.
This analytical approach must, of course, be underpinned by practical testing to validate and refine theoretical assumptions and models. Physical testing of individual parts or specific features – using tensile or torque test machines for example – enables accurate, geometry-specific data to be fed back into FEA models. This improves the fidelity of the analysis and allows design changes to be better understood and assessed before additional physical parts are manufactured.
Where possible, analysis beyond specified parameters can also be valuable in establishing safety margins and informing reliability estimates. By following such a process, design verification and validation can be approached with high confidence. A well-structured combination of physical testing, design space analysis, tolerance analysis and FEA should
be used alongside the device design and development process, enabling performance to be assessed and understood not only under nominal conditions but also at the extremes or the operating envelope.
Achieving accurate and precise dose delivery for high-viscosity biologics requires a multilayer approach, with a focus on the characteristics of the drive system, now path and container. By applying a systems-level mindset and leveraging advanced analytical and engineering methods, developers can create devices that not only meet the technical demands of high-viscosity delivery but also support better patient outcomes and more accessible care.
Human factors and the specific requirements of a highly viscous drug – particularly in circumstances involving home-based patients managing chronic diseases – add another critical dimension to these considerations. Equally essential is the analytical discipline that must underpin development. Rigorous design space exploration, tolerance analysis and FEA are indispensable tools for predicting performance and accommodating potential variations across the full scope of use scenarios, storage conditions and manufacturing processes. When combined with targeted physical testing, these methods enable developers to build confidence early, reduce risk and ensure that devices perform reliably under extreme circumstances and at edge cases.
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