Autoinjectors: Through Thick and Thin

The pharmaceutical market is seeing a rise in new medications that require parenteral delivery to patients – whether through intravenous, intramuscular, or subcutaneous injection. Forecasts indicate that the injectable drug delivery market will grow at a compound annual rate of 12.9 percent to reach US$1,250 billion by the end of 2027 (1). However, rather than administration in hospitals and clinics, there are clear advantages to enabling patients to self-administer injections.

Clearly, parenteral products for self-administration face one challenge in particular: the need for patient-friendly delivery. Auto-injectors have become the go-to delivery device, but many injectable drug products in development have higher viscosities, which often leads to issues when used in conjunction with existing auto-injectors.

Let’s consider the drivers of high viscosity formulations: 

First, biologics contain large, long-chain molecules often at high doses – especially in the case of mAbs, which typically range from >80 mg all the way up to 1000mg (2). Viscosity increases exponentially with protein concentration – but a high concentration is needed to keep the injected volume below ~2 ml (commonly recognized as the maximum volume to be delivered in a single SC dose).

Second, therapeutics designed for sustained or controlled release in the body following administration often contain polymers with high molecular weights, which makes the resulting formulations highly viscous – sometimes more than 1000cP. 

Third, in some formulations the solvent itself is highly viscous; for example, oil-based formulations (used to alter release rates or for poorly water-soluble drugs) often have high viscosity. 

Existing technologies can reduce viscosity levels in some cases; however, not all formulations can be reduced to a viscosity that allows delivery with conventional spring-based auto-injectors. The natural alternative to altering the formulation is to move away from standard auto-injectors towards devices tailored for administration of viscous formulations. In fact, I’d argue that by improving delivery devices we not only overcome the challenges of viscosity, but also optimize the self-administration experience for patients. For example, devices with compact energy sources based on liquefied gas rather than spring power can enable delivery of highly viscous liquids through a fine needle.

Alternate energy sources actually allow for greater flexibility in device design compared with conventional spring-based auto-injectors. By tailoring gas composition, developers can achieve desired performance characteristics, such as delivery time with a particular combination of fill volume and needle gauge, for any given formulation. Additionally, liquefied gas provides a constant pressure profile, lower peak forces, and reduced risks of damaging the primary container through high impact forces.

That said, the risk of damage to the syringe when dealing with the higher forces needed to deliver viscous formulations using an auto-injector should be a key consideration during design. Most autoinjectors on the market use glass syringes, which can break under high pressure. Recent improvements to the design of containers and other materials have significantly reduced the likelihood of such breakages, but the risk persists. One solution is to use polymeric primary containers, such as those based on cyclic olefin copolymer (COC/COP). Such syringes offer a number of advantages over glass syringes, including improved strength, lower frequency of breakages, and tighter tolerance – all of which help to overcome the challenges presented by high-viscosity delivery devices.

Special, thicker-walled versions capable of withstanding forces well above 300N are also being developed by COC/COP syringe manufacturers. However, despite the longstanding availability and numerous advantages of COC/COP syringes, they cannot serve as a straightforward replacement; they still require early consideration in drug development programs in which a high viscosity auto-injector is an option on the table.

In my view, the key to successful development and commercialization of parenteral products is to consider the device requirements right from the start of the project. Merely considering the device in the late stages can lead to complications not only in terms of ensuring the device is fit for purpose, but also in potential interactions between the formulation and the device. It is imperative that the device and formulation teams work closely from the outset to ensure the best outcomes. Their mission must be to not only streamline a product’s journey to market, but also ensure the final product is suitable for the end users.

The technology transfer for BrainStorm's NurOwn^® autologous cell therapy at Catalent’s facility has been finalized. NurOwn will be manufactured at Catalent’s world-class 32,000 square-foot cell therapy manufacturing facility in Houston.

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