High-dose subcutaneous Administration of Biologics: Overcoming barriers through formulation and device innovation

Abstract

The therapeutic landscape for biologics is rapidly transitioning from intravenous (IV) to subcutaneous (SC) administration, offering significant benefits in cost reduction and patient convenience through enabling treatment in flexible care settings. This shift necessitates patient-centric SC administration solutions. To address this, two primary innovative strategies are emerging: higher concentration formulations and large-volume SC (LVSC) injection/infusion. Ultra-high concentration biologic (UHCB) formulations, defined here as ≥250 g/L, are actively being pursued as suspensions. These UHCB suspension approaches rely on processing methods to entrap biologics within microparticles of a defined particle size (e.g., spray drying, electrospraying, solvent evaporation and dehydration, alginate, crystals). These UHCB suspension formulations are shear-thinning injectable drug product solutions. For LVSC administration, delivery is aided by co-formulating with hyaluronidase and/or utilizing on-body injectors (OBIs), high-volume autoinjectors (HVAI), or other administration equipment that reduces the treatment burden for healthcare professionals, caregivers, and patients. Despite promising preclinical data, the commercial translation of these platforms faces substantial hurdles, including establishing robust aseptic manufacturing processes for suspensions, developing specialized analytical control strategies, ensuring device compatibility (e.g., avoiding needle clogging), and navigating complex regulatory pathways requiring clinical bridging and comparability assessments. Continued collaborative efforts among industry and regulators will be essential to streamline development and realize patient-centric high-dose SC options.

Introduction

From 2000 to 2019, the majority of monoclonal antibody (mAb) approvals were based on intravenous (IV) administration [1]. However, a significant and accelerating shift towards subcutaneous (SC) options emerged around 2016 without indication restrictions [1], [2]. This transition has been driven by the inherent advantages of SC delivery, which include lower costs to healthcare system, reduced treatment burden, faster administration times, and the potential for enabling self-injection or administration by a caregiver [3], [4], [5]. Unfortunately, the SC route of administration comes with decreased bioavailability compared to IV for biologics, resulting in the need for higher doses.

Due to SC tissue space limitations, high, or ultra-high, concentration biologics formulations are necessary for reducing injection volumes to achieve high-dose patient-centric administration. This approach can facilitate at-home or other flexible care setting administration outside the hospital, often coupled with a commonly available 1- or 2-mL prefilled syringe (PFS) or autoinjector (AI) device to enhance patient convenience and adherence. However, higher concentration antibody formulations face considerable technical challenges, such as aggregation and increased viscosity, which can lead to difficulties in manufacturing, stability, and delivery [6].

To navigate these delivery challenges, formulation scientists require clear viscosity limits to guide development; however, true rheological boundaries can only be established when dose volume, injection force, and injection time are concurrently defined. These parameters are highly dependent on the clinical indication and chosen technology. Currently, PFS and AI platforms supporting up to 2 mL nominal volumes are commercially robust and widely available. Notably, PFS needles are typically longer than AI needles to accommodate angled insertion, whereas AIs utilize perpendicular insertion to reach the same subcutaneous depth. According to the Hagen-Poiseuille law, needle geometry—both length and inner diameter—critically dictates the relationship between injection force and flow rate; however, larger diameters may increase patient pain and the risk of leak-back. While historical injection benchmarks range from 10 to 15 s, longer durations may be justified through human factors studies. A persisting challenge in streamlining platform SC biologics development is that the commercial dose and SC bioavailability information often emerge late in development. Furthermore, detailed mappings of technical factors (e.g., dose volume, injection time) relating to human factors and human tolerability limits are not yet available.

Given these intersecting device and clinical constraints, early mitigation of viscosity-related challenges commonly involves the use of viscosity-lowering excipients and optimized formulation conditions [10], [11]. These may include arginine, salts, and other excipients that may disrupt protein-protein interactions. However, studies indicate that for high and ultra-high protein concentrations, certain excipient-API interactions may prove to be destabilizing [12], [13], [14]. Moreover, the inclusion of viscosity-lowering excipients may not be sufficient for reaching ultra-high protein concentrations [11]. Novel technologies such as protein microparticles suspended in a non-aqueous vehicle may enable commercialization of ultra-high protein concentration medicinal products [6], and have been explored for concentrations up to 500 g/L [15]. For the purposes of this manuscript, an ultra-high concentration biologics (UHCB) formulation is defined as ≥250 g/L. The concentration limit was based on a desire to move focus beyond standard biologics formulations using viscosity-reducing excipients, and to discuss emerging innovative formulation trends of interest to the industry pushing concentrations closer to theoretical physical packing limits [16].

As an alternative to pushing concentration limits, achieving high doses can also be realized through large-volume SC administration (LVSC), defined here as greater than 2 mL [17], [18], [19]. LVSC doses expand therapeutic applications and improve patient-centric dosing regimens [8]. A growing market of devices and equipment supports LVSC administration, including on-body injectors, high-volume autoinjectors, and syringe pumps. Additionally, co-formulating biologics with permeation enhancers such as hyaluronidase can make LVSC administration a more suitable fit for Target Product Profiles (TPPs) by facilitating more rapid SC delivery at a larger volume.

Whether utilizing UHCB or LVSC, enabling high-dose subcutaneous administration presents a myriad of challenges. These include formulation design (e.g., viscosity, aggregation, hypertonic solutions, excipient selection), bioprocess optimization to address polysorbate degradation stemming from host cell proteins, unit operations process performance (e.g., sterile filtration, needle clogging), and patient centricity (e.g., usability, treatment adherence, portability, refrigerated storage space) [6], [17], [18], [19], [20]. Patient-centric, attribute-focused product design is a proven strategy to approach the above-mentioned challenges with SC products. Beyond the benefits to the patients, flexible care setting SC products enable moving treatments out of the hospital and into patients’ homes or nearby infusions centers/capable pharmacies. SC flexible care products enable a higher number of patients to be treated within a given time and fixed amount of resources, bringing overall healthcare costs down [21], [22], [23], [24]. Despite growing demand for higher SC doses, limited commercial biologic products have been approved that enable high SC doses, except for several plasma-derived subcutaneous immunoglobulin medicinal products and a limited number of mAbs discussed later. Emerging technologies offer promise but also present significant challenges and risks. This manuscript explores the various considerations, approaches, and challenges associated with the development of biologics requiring high SC doses.

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Tarik A. Khan, Deep Bhattacharya, Twinkle R. Christian, Melissa Holstein, Xiaoqing Hua, Roshan James, Bowen Jiang, Alexander Josowitz, Danielle Laiaconaf, Shrenik Mehta, Apurva More, Edel Mullen, Matthew Myers, Brendon Ricart, Timon Rickenbacher, Yongchao Su, Naveen Kumar Reddy Yaragudi, High-dose subcutaneous Administration of Biologics: Overcoming barriers through formulation and device innovation, Advanced Drug Delivery Reviews, 2026, 115885, ISSN 0169-409X, https://doi.org/10.1016/j.addr.2026.115885.

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