Joel Pike, senior global product manager, Avantor looks at the role of excipients in enabling the shift from intravenous to subcutaneous drug delivery.
Avantor
The successful conversion of IV-administered biologics, including blockbuster cancer immunotherapies, into subcutaneous (SC) formulations reflects the significant benefits of this route of administration for both patients and healthcare providers. However, this change requires more than simply switching the delivery process. Reformulating biologics into high-concentration, injectable products introduces new challenges related to viscosity, stability, device compatibility, and manufacturability, areas where excipients play a critical enabling role. Such inactive ingredients help ensure the drug product remains stable, effective, and manufacturable throughout development and commercialisation.
Why the industry is moving toward subcutaneous delivery
The growing interest in SC delivery is being driven by multiple stakeholders across the healthcare ecosystem. For patients, subcutaneous administration offers greater convenience and flexibility. Rather than spending hours in an infusion center receiving an IV treatment, patients can often self-administer therapies at home using prefilled syringes or autoinjector devices. This can significantly reduce treatment burden and improve quality of life.
Healthcare providers and systems also benefit. SC therapies reduce the demand on infusion facilities, clinical staff, and healthcare resources, helping to alleviate operational pressures while improving patient access to treatment.
For biopharmaceutical manufacturers, subcutaneous formulations can provide product differentiation and potentially extend the commercial value of existing therapies. As a result, many companies are actively investigating ways to convert established IV products into SC formulations while simultaneously designing new pipeline molecules with SC administration in mind.
The formulation challenge: High-concentration biologics
One of the most significant differences between IV and SC delivery is volume. IV infusions can be administered over extended periods, allowing large volumes of drug product to enter the bloodstream gradually. SC injections, by contrast, must deliver the same therapeutic dose in a much smaller volume and within a matter of seconds or minutes.
To achieve this, drug developers often need to create highly concentrated formulations. However, increasing protein concentration introduces a new set of formulation challenges. Concentrated proteins are often more susceptible to aggregation, which can compromise stability, shelf life, and product performance. Viscosity can increase as protein-protein interactions become more significant, particularly when attractive colloidal interactions promote reversible self-association or transient clustering of antibody molecules.
High viscosity can limit opportunities for dose escalation and volume reduction. High viscosity can make injections difficult to administer, create challenges for device compatibility, and cause injection site pain for the patient. If the required force or injection duration exceeds the capability of the user or device, the risk of incomplete injection, user error, or variability in delivered dose may increase.
The challenge for formulators is to balance concentration, stability, injectability, and manufacturability while maintaining the therapeutic performance of the biologic.
How excipients help solve viscosity and stability challenges
Excipients play a central role in overcoming many of the challenges associated with high-concentration biologic formulations. One important class of excipients used to address viscosity includes amino acids such as L-arginine and L-arginine hydrochloride. These materials can help reduce unfavorable protein-protein interactions that contribute to viscosity increases and protein aggregation.
By minimising these interactions, formulators can improve both injectability and protein stability. This is particularly important because elevated viscosity in concentrated biologic formulations can arise from reversible protein-protein interactions, self-association, and, in some cases, aggregation, each of which can also affect stability and product performance.
Other excipients can also contribute to formulation performance. Salts help maintain appropriate tonicity and osmolarity, while sugars such as trehalose and sucrose provide protein stabilisation during storage, handling, freezing, lyophilisation, and thermal stress. These excipients help preserve protein integrity without introducing unnecessary complexity into the formulation.
The optimal excipient strategy varies depending on the specific protein and formulation requirements. As a result, developers typically evaluate multiple excipient combinations during early formulation development to identify the most effective approach for their molecule.
Beyond formulation: Process-wide impacts
The move to SC delivery can affect more than just the final drug product formulation. Changes made to address viscosity or stability may influence upstream and downstream manufacturing operations as well. For example, developers may need to consider additional processing aids, protein recovery strategies, or purification approaches to maintain product quality and yield throughout manufacturing.
In practice, converting an IV formulation to SC administration can require a holistic assessment of the development process. While there may be substantial overlap between IV and SC formulations, the higher protein concentrations associated with SC delivery can create unexpected processing and scale-up challenges.
Device compatibility adds another layer of complexity
SC therapies also introduce device-related considerations that are less prominent in traditional IV administration. Instead of infusion bags and tubing, subcutaneous products are often delivered through prefilled syringes, autoinjectors, or pen devices. Formulations must therefore be compatible not only with the biologic itself but also with the materials and mechanics of the delivery device.
Device compatibility is not only a materials-of-construction issue. High-viscosity formulations may exceed the practical limits of prefilled syringes, autoinjectors, or pen devices by requiring excessive actuation force, longer injection duration, larger needle diameter, or extended device hold time. These constraints can affect usability, patient acceptance, and the ability to reliably deliver the intended dose.
Surfactants such as polysorbate 20 and polysorbate 80 play an important role in protecting biologics from aggregation and interfacial stress during manufacturing, storage, and administration. These excipients help prevent proteins from adhering to device surfaces and maintain product quality throughout the supply chain.
For multidose applications such as certain GLP-1 therapies, antimicrobial excipients may also be required. Benzyl alcohol, for example, can help preserve sterility in products designed for repeated use over time.
Building on existing formulations
Importantly, transitioning from IV to subcutaneous delivery does not necessarily require developers to start from scratch. Existing IV formulations often provide valuable information about protein behavior, stability, and excipient compatibility. In many cases, developers can retain portions of the original formulation and make targeted adjustments to address the demands of high-concentration SC delivery.
This approach can reduce development risk by minimising unnecessary formulation changes while leveraging established knowledge of the molecule. Because introducing new excipients can create unintended consequences, many developers prefer to optimise existing formulations before pursuing more extensive reformulation strategies.
The growing importance of excipient innovation
As the industry continues to embrace subcutaneous administration, excipients are becoming increasingly important enablers of biologic drug development. Future therapies are expected to feature even higher concentrations, improved injectability, and enhanced patient experiences. Achieving these goals will require continued innovation in excipient technologies, including novel materials specifically designed to address viscosity, stability, and device compatibility challenges.
For drug developers, success will depend not only on selecting the right excipients but also on partnering with suppliers that offer deep technical expertise, high quality products and robust quality systems, reliable supply chains, and regulatory support.
Ultimately, excipients are no longer simply supporting ingredients. As biologics become more concentrated and delivery methods evolve, they are emerging as critical tools for enabling the next generation of patient-centric therapies.