A perspective on high-concentration spray-dried monoclonal antibody suspensions for subcutaneous delivery

Abstract

There is a growing demand in the subcutaneous delivery of monoclonal antibodies (mAbs) to reduce treatment burden for both patients and healthcare systems when compared to intravenous administration. However, it poses significant challenges in formulation development primarily due to high viscosities in highly concentrated solutions of mAbs for subcutaneous injection, which impacts injectability and effective dosing. Advances in protein spray drying have enabled the production of solid protein powders with enhanced stability. When suspended in non-aqueous media, these spray-dried powders facilitate the achievement of protein concentrations far exceeding 200 mg/mL to overcome challenges associated with high-concentration formulations for biologics such as solubility, viscosity, and aggregation. This perspective aims to discuss recent studies showcasing the successful application of spray-dried proteins to achieve high protein concentrations; key formulation aspects of protein spray drying with respect to subvisible particles; formulation considerations for spray-dried protein suspensions in non-aqueous media; technical and regulatory challenges for subcutaneous delivery of non-aqueous suspensions for mAbs; their knowledge gaps in clinical translation; and the need for patient-centric studies to enhance patient experience, providing insights into how future research can better balance quality and compliance. Finally, with the growing exploration of drying technologies, this article discusses the future outlook for high-concentration suspensions of therapeutic proteins.

Introduction

Monoclonal antibodies (mAbs), since the approval of the first therapeutic mAb in 1986, muromonab-CD3 (OKT3), have revolutionized the pharmaceutical industry over the past decades by offering a more effective, safer, and targeted therapeutic option for multiple disease areas (Chan et al. 2025). The landscape of therapeutic mAbs is advancing rapidly beyond the standard immunoglobulin G (IgG) format, with alternative antibody formats such as antibody–drug conjugates (ADCs) and bispecific antibodies (Chan et al. 2025). This progress has led to the approval of over 212 antibody therapeutics and the treatment of millions of patients to date (Chan et al. 2025). An economic analysis has revealed that the global market revenue of mAbs is projected to reach half a trillion dollars in 2030 (Stone et al. 2024). Traditionally, proteins are formulated as liquid aqueous formulations to facilitate intravenous infusion and directly deliver the drug into systemic circulation, but it can pose heavy burdens from patients’ perspectives: A qualitative study found that hospital patients had decreased feelings of quality and safety due to issues upon receiving intravenous infusions, including the nuisance of infusion pump alarms, the lack of mobility, and associated discomfort due to pain and irritation relating to cannulation (Wheeler et al. 2020). These challenges can negatively impact patient compliance and adherence to prescribed mAbs, ultimately impacting health outcomes. Therefore, the development of alternative delivery methods for mAbs from a patient-centric perspective is critical to enhancing the patient experience and broadening accessibility to life-saving treatments.

Subcutaneous delivery of mAbs offers several advantages over traditional intravenous infusion, including improved patient convenience, reduced healthcare costs, and the potential for self-administration. The growing demand for subcutaneous administration is mainly driven by the patient and healthcare provider preference to reduce treatment burden (Ghosh et al. 2025). According to a recent survey, patients reported greater satisfaction, increased convenience, and less impact on daily activities with subcutaneous administration of oncology therapies compared to intravenous administration (George et al. 2025). For subcutaneous delivery of mAbs with high doses, it typically requires formulations with high protein concentrations because of small injection volumes (e.g. < 2 mL injection volume) (Shire et al. 2004; Davis et al. 2024). This has motivated the development of high-concentration protein formulations to predominantly enable this route of administration. A recent report highlights that 76% of the total approved numbers from 1998–2021 for therapeutic antibodies with high-concentration formulations (≥ 100 mg/mL) are developed for subcutaneous administration (Wang et al. 2021a). However, at elevated concentrations, mAbs are more prone to self-association, which can cause several issues, including increased solution viscosity and a higher risk of protein aggregation (Zarzar et al. 2023). These challenges are problematic in compromising the drug product quality of mAbs, leading to reduced therapeutic efficacy and potential safety issues. One key focus area in the development of high-concentration liquid formulations is managing viscosity. A number of different formulation approaches such as viscosity-reducing excipients, formulation pH optimization, and ionic strength modulation are effective strategies for viscosity mitigation (Banik et al. 2022; Cruz et al. 2025; Prašnikar et al. 2025). Another promising approach is to leverage hyaluronidase by breaking down hyaluronic acid in the extracellular matrix, thus enabling the administration of higher drug doses and increasing dose volume in subcutaneous tissues (Guo et al. 2025). While these strategies have proven effective to some extent, achieving protein concentrations far exceeding 200 mg/mL with sufficiently low viscosity remains a considerable challenge. A recent survey from a group of formulation experts reported that challenges in the development of high-concentration formulations for biologics such as solubility, viscosity, and aggregation could result in delays in clinical trials or product launches (Desai et al. 2025). High viscosity formulations can lead to practical issues in manufacturing and dose administration, such as reduced syringeability and increased injection force, which can negatively impact patient compliance and acceptance (Wang et al. 2025). On the other hand, suspending spray-dried powders of mAbs in non-aqueous media emerged as a potential alternative in achieving high protein concentrations (Bowen et al. 2012; Ren 2025). However, the clinical use of spray-dried proteins remains limited, critical gaps still exist in bridging preclinical data on spray-dried protein suspensions and human clinical applications.

With the increasing demand for mAbs to be formulated in high concentrations that enable patient-friendly subcutaneous injections, this perspective focuses on the broad challenge and addressing gaps for clinical translations of spray-dried protein suspensions. The following sections will first examine the specific formulation challenges with respect to subvisible particles associated with spray-dried proteins and highlight emerging trends in utilizing spray-dried proteins to facilitate subcutaneous delivery of mAbs, supported by examples from the development of high-concentration spray-dried protein suspensions (Fig. 1). Specifically, this article aims to pose the following questions: What is our current understanding of subvisible particles for spray-dried proteins? What are the key considerations and knowledge gaps for formulation development of spray-dried protein suspensions for mAbs? Furthermore, how do pharmaceutical scientists work collaboratively with regulatory agencies to bridge the use of spray-dried protein suspensions from preclinical to clinical settings?

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Tam, Y.T. A perspective on high-concentration spray-dried monoclonal antibody suspensions for subcutaneous delivery. AAPS Open 12, 22 (2026). https://doi.org/10.1186/s41120-026-00160-8

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