From IV to SC: Why Reformulation is Reshaping BiologicDrug Development
For decades, intravenous (IV) administration has been the preferred route for delivering biologic therapies. Many of today's blockbuster monoclonal antibodies (mAbs),peptides, and other complex biologics were originally developed as IV infusions because they enabled large doses to be delivered directly into systemic circulation with complete bioavailability.
However, the industry is increasingly shifting its focus toward subcutaneous (SC) delivery. Across oncology, immunology, and metabolic diseases, companies are investing heavily in reformulating existing IV therapies into SC products. This trend is driven by a combination of patient preference, healthcare economics, and advances in formulation science. As a result, converting an IV drug into an SC formulation has become one of the most active areas of pharmaceutical development.
Why the Shift from IV to SC?
The advantages of subcutaneous administration are clear. SC therapies can often be self-administered at home, reducing the burden on healthcare systems and eliminating lengthy infusion appointments. For patients managing chronic diseases, this can significantly improve convenience, treatment adherence, and quality of life. Healthcare providers also benefit through reduced infusion center utilization and lower administration costs.
Historically, many biologics required IV administration because the required dose could only be delivered in large volumes. While IV infusions can accommodate virtually unlimited volumes, subcutaneous injections are constrained by the limited capacity of the subcutaneous space, traditionally around 1 – 2 mL.
However, advances in formulation technologies, device engineering, and absorption enhancers such as recombinant hyaluronidase have made it increasingly feasible to deliver larger doses subcutaneously. As a result, many companies are revisiting established IV products to determine whether they can be successfully converted into more patient-friendly SC therapies., making IV-to-SC conversion one of the fastest-growing areas of biologic drug development.
Reformulation Is More Than Simply Increasing Concentration
Although the concept may sound straightforward, converting an IV product into an SC formulation presents significant scientific challenges.
An IV formulation enters directly into circulation, bypassing many of the barriers encountered in the subcutaneous space. In contrast, SC formulations must navigate a complex extracellular matrix before reaching lymphatic and vascular uptake pathways.
To achieve equivalent exposure, developers frequently need to create high-concentration formulations capable of delivering the required dose in a much smaller volume. However, increasing protein concentration often introduces a range of formulation challenges, including:
- Increased viscosity
- Protein aggregation
- Reduced stability
- Manufacturing difficulties
- Injection force limitations
- Altered bioavailability and absorption kinetics
These factors are particularly important for monoclonal antibodies, where concentrations exceeding 100 mg/mL are now common for SC products.
As a result, reformulation programs often involve extensive excipient screening, concentration optimization, device compatibility studies, and evaluation of injection site behavior.
Understanding What Happens After Injection
One of the greatest challenges in SC development is that many critical events occur immediately after injection and are difficult to observe directly.
Once injected, a formulation may:
- Disperse rapidly through the extracellular matrix
- Form a depot at the injection site
- Aggregate or precipitate
- Interact with formulation excipients
- Undergo lymphatic uptake
- Release API at varying rates
These events can have a profound impact on bioavailability, pharmacokinetics, and ultimately clinical performance.
Traditionally, developers have relied heavily on animal studies to understand these behaviors. However, animal models often provide limited (if any) predictive value for human subcutaneous absorption, particularly for biologics such as monoclonal antibodies. At the same time, regulators are increasingly encouraging the adoption of New Approach Methodologies (NAMs), including in vitro and insilico approaches, to improve human relevance while reducing animal use. This shift is creating demand for tools capable of generating mechanistic insights earlier in development.
Accelerating IV-to-SC Development with Human-Relevant In Vitro Models
As reformulation efforts continue to grow, developers need ways to rapidly screen candidate formulations before advancing into expensive preclinical or clinical studies.
The SCISSOR N3TM platform from Pion was specifically developed to address this challenge.
SCISSOR simulates key aspects of the human subcutaneous environment using a biomimetic extracellular matrix (ECM), allowing researchers to inject formulations into a controlled in vitro system and monitor their behavior in real time.
By measuring formulation release, depot formation, dispersion, turbidity changes, and visual injection-site behavior, SCISSOR provides insights that are difficult to obtain through conventional dissolution methods or animal studies alone.
For teams converting IV therapies into SC products, this means the ability to:
- Compare multiple formulation candidates rapidly
- Evaluate excipient effects on release behavior
- Understand depot formation and diffusion
- Assess formulation stability post-injection
- Rank-order candidates before in vivo studies
Rather than waiting months for animal studies to identify formulation differences that may not even translate to the clinic, developers can obtain mechanistic data early in development and make more informed decisions about which candidates warrant further investment.
The Future of Biologic Drug Development Is Subcutaneous
The trend toward subcutaneous delivery shows no signs of slowing. As healthcare systems continue to prioritize patient-centric therapies and regulators increasingly support human-relevant testing approaches, the ability to efficiently convert IV products into successful SC therapies will become a critical competitive advantage.
Success will depend not only on creating high-concentration formulations but also on understanding what happens after injection. By combining advanced formulation science with predictive in vitro tools such as SCISSOR, developers can reduce risk, accelerate development timelines, and improve confidence in formulation selection.
The future of biologic drug development is increasingly subcutaneous, and the companies that can predict injection-site behavior early will be best positioned to succeed.
