High-concentration therapeutic antibodies are becoming increasingly essential in the biopharmaceutical market, driving demand for formulations that balance stability, manufacturability, and patient convenience. However, achieving robust, high-concentration protein formulations presents unique challenges, including viscosity and stability challenges, such as aggregation, phase separation, and pH variability. Samsung Biologics has addressed these complexities with the S-HiCon™ platform, a systematic, science-driven approach designed to optimize high-concentration formulations through advanced analytical techniques, strategic risk mitigation, and stepwise process development.
Overcoming Challenges in High-Concentration Formulations
The COVID-19 pandemic and a growing emphasis on proactive health management have intensified interest in self-administered drug therapies, including parenteral formulations. At the same time, the biopharmaceutical industry has increasingly prioritized incorporating the patient perspective into drug development to enhance medication adherence. This shift has driven a renewed focus on innovative formulation and delivery solutions that facilitate at-home administration of injectable, oral, and liquid-dosage medications. The self-administered drug market was estimated to be valued at $22.79 billion in 2024 and is projected to grow at a CAGR of 10.3% from 2025 to 2030 (Figure 1), reflecting increasing demand for patient-friendly treatment options.1
Figure 1. Self-Injection Devices Market. Size by Product 2020–2030 (USD million)1
Patient convenience and ease of use are now central objectives for drug manufacturers across new and existing products. Traditionally, biologics have been administered intravenously in clinical or hospital settings. However, industry efforts have pivoted toward developing formulations that can be self-administered through subcutaneous injection, minimizing reliance on healthcare facilities and improving patient autonomy.
A significant challenge, however, is that subcutaneous injections are limited to 1–3 mL per dose, whereas on-body delivery devices, although capable of administering larger volumes over extended periods, still present constraints on patient tolerance. In contrast, intravenous infusions impose no such restrictions, allowing for lower-concentration formulations. To overcome these limitations, high-concentration, higher dosage formulations are increasingly required to facilitate subcutaneous delivery while reducing injection volumes and frequency. These solutions also offer logistical advantages, such as lower storage and shipping costs due to decreased volume and weight.
Despite these benefits, formulating high-concentration (>150 mg/mL) protein and monoclonal antibody (mAb) therapies presents major hurdles related to viscosity, manufacturability, and stability. Increased viscosity can impair syringeability and require specialized devices for injection, while stability concerns — such as aggregation, opalescence, and phase separation — can compromise drug efficacy and shelf life. Addressing these challenges requires expertise in protein formulation and a structured, science-driven approach that systematically mitigates risk and ensures robust, scalable solutions.
Complexities of High-Concentration Formulations
Proteins and antibodies in solution exist in a delicate equilibrium between their native folded, partially unfolded, and fully unfolded states.2 Partially unfolded proteins can misfold into prefibrils, which may further aggregate into fibrillar or partially folded aggregates. Fully unfolded peptide chains, however, often form amorphous aggregates.
At high concentrations, protein and antibody molecules are packed densely, increasing the likelihood of unintended molecular interactions that would be negligible at lower concentrations. This heightened molecular crowding exacerbates chemical, physical, colloidal, and conformational stability challenges, particularly by enhancing the propensity for aggregation, which in turn increases viscosity.3
These stability concerns significantly affect the processing and delivery of the product. The Donnan and volume-exclusion effects can alter pH and excipient levels during ultrafiltration/diafiltration (UF/DF), leading to unexpected formulation behavior. Elevated viscosity levels complicate filtration and filling operations, while the presence of aggregates raises potential safety and efficacy risks. Additionally, high-viscosity solutions present syringeability challenges, as reduced flowability can hinder accurate and pain-free administration.
Critical Factors in High-Concentration Formulation
The high-concentration formulations pose significant stability challenges that impact manufacturing efficiency and injection feasibility. Addressing these challenges requires careful consideration of the molecular complexity of proteins and antibodies, balancing stability, manufacturability, and patient convenience to ensure adherence and therapeutic success.
The first step in formulation development is determining whether a target process/product concentration is feasible. For proteins and antibodies that can support high-concentration formulation, establishing the optimal pH and excipients is crucial to maintaining chemical, physical, and colloidal stability while ensuring solubility under storage and shipping conditions.
A robust formulation strategy relies on long-term stability studies to monitor changes in pH, viscosity, and visual appearance over time. Advanced analytical tools, such as physicochemical stability monitoring and predictive simulation techniques, enhance formulation precision. For instance, cation-exchange (CEX) and size-exclusion (SE) high-performance liquid chromatography (HPLC) are instrumental in evaluating chemical and stability properties, while SE chromatography-based dissociation constant measurements provide insights into high-molecular-weight species formation and aggregation risks at various pH levels.
Figure 2 provides a more detailed example of how different analytical methods contribute to understanding protein stability. CEX-HPLC analysis helps assess chemical stability by tracking changes in the main peak at 40°C under different pH conditions, revealing a clear degradation trend at lower pH values. SE-HPLC evaluates physical stability, demonstrating how protein integrity declines over time depending on the pH environment. Additionally, colloidal solubility studies indicate how buffer conditions impact repulsion and aggregation potential, which is crucial for mitigating viscosity issues. Finally, polyethylene glycol (PEG) solubility experiments provide insights into relative solubility at varying PEG concentrations and pH levels, helping optimize formulation parameters to reduce aggregation risk.
Figure 2. Examples of formulation pH and buffer system impact on chemical, physical, colloidal, and solubility behaviors
Strategic Approach to High-Concentration Formulation at Samsung Biologics
Samsung Biologics employs a structured, stepwise approach to high-concentration formulation development, starting with a ‘Concentration Gate Check’ and leveraging the S-HiCon™ platform. This process ensures the early identification of potential formulation bottlenecks — such as manufacturability, storage, shipping, and final administration — thereby mitigating risk and preventing costly delays.
The S-HiCon™ platform enables comprehensive feasibility studies of the target concentration, including evaluation of all stability aspects and drug-delivery needs. The platform also helps optimize high-concentration formulations and the manufacturing processes required to produce them, with customized workflows established for different modalities. This integrated approach systematically addresses the crucial aspects of formulation development.
A critical facet of the process is addressing unintended pH shifts, aggregation risk, and viscosity challenges. The S-HiCon™ platform proactively identifies expected pH changes caused by the Gibbs-Donnan and volume-exclusion effects, and screens for stabilizing and viscosity-reducing excipients.
The high-concentration formulation development process begins with the Concentration Gate Check (Figure 3), where tangential flow filtration (TFF) is used to determine whether the target concentration is achievable. If it is not, alternative strategies — such as incorporating stabilizing or viscosity-reducing agents — must be explored early in development to avoid costly adjustments later.
Figure 3. The high-concentration formulation development process
Once it is determined that formulation at the target high concentration is possible, the actual formulation process is pursued using the S-HiCon™ platform. Surfactant screening is conducted, followed by the evaluation of established buffers and excipients to explore different pH conditions and determine the appropriate excipient types. A UF/DF feasibility assessment is then performed using the most promising formulations. The impacts of a wider range of excipients on the behavior of top candidates are further evaluated to identify the optimal final formulation. These steps ensure that the concentrated material maintains sufficient short-term stability at room temperature, allowing for further processing.
During UF/DF processing, non-diffusible charged molecules, such as mAbs, can disrupt electrolyte distribution across membranes, leading to unexpected shifts in pH and concentration. Therefore, UF/DF feasibility studies are essential to fine-tune diafiltration buffer conditions and maintain formulation integrity. Once the top candidates are selected, additional excipient screening is performed to optimize stability, solubility, and viscosity. The final formulation undergoes further testing, during which its ability to maintain structural and chemical properties under real-world storage and processing conditions (e.g., ambient temperature over a four-week period) is confirmed.
Beyond pH and buffer selection, optimizing the excipient is critical for balancing stability and injectability. Excipients play a crucial role in maintaining chemical stability by minimizing oxidation and metal-catalyzed degradation. They also enhance physical stability by improving conformational, colloidal, and frozen stability. Furthermore, excipients influence solubility and viscosity, preventing unwanted protein interactions that lead to aggregation or formulation failure.
However, excipients can also introduce challenges, such as protein precipitation or increased opalescence, particularly at concentrations exceeding 200 mg/mL. Formulation viscosity must be carefully evaluated, as high viscosities can negatively impact filling operations and syringeability. Extensive high-throughput screening and analytical testing are therefore essential for selecting the optimal excipient combinations that support manufacturability, stability, and patient-friendly administration.
By following this rigorous, stepwise methodology, Samsung Biologics ensures the development of high-concentration formulations that are robust, scalable, and aligned with industry needs.
Backed by Proven Expertise and Comprehensive Capabilities
Since 2018, Samsung Biologics has been a trusted provider of formulation development services, successfully completing over 60 projects, with more than 35 garnering regulatory approval in the United States, Europe, and/or other jurisdictions. High-concentration mAbs constitute a significant portion of these projects, alongside multispecific antibodies, fusion proteins, synthetic peptides, nanobodies, and other recombinant molecules.
Whether a product is standard- or high-concentration, Samsung Biologics’ formulation development services include surfactant, pH/buffer, and excipient screening; UF/DF and stability studies; and recommendations on the optimal final formulation. The company’s high-throughput screening systems significantly enhance efficiency, helping optimize formulation conditions for standard mAbs at concentrations below 100 mg/mL within 3.5 months and high-concentration mAbs and complex proteins within four months. For formulations with concentrations exceeding 150 mg/mL, the S-HiCon™ platform follows an extended five-month timeline, incorporating the Concentration Gate Check to ensure feasibility before finalizing the optimal formulation.
In addition to its formulation expertise, Samsung Biologics possesses capabilities in upstream and downstream process development and analytical method optimization. These combined strengths support high-titer processes and high-purity products, ensuring a seamless supply of materials while reducing the risk of process and formulation challenges in later development phases. This comprehensive approach provides clients with robust, scalable, and regulatory-compliant services tailored to meet the evolving demands of biopharmaceutical development.
Science-Driven Innovation for High-Concentration Success
High-concentration therapeutic antibodies represent a rapidly expanding segment of the biopharmaceutical market. However, developing high-concentration formulations of complex proteins presents unique challenges in achieving the desired manufacturing efficiency and product performance. Recognizing the need for innovative services, Samsung Biologics has introduced the S-HiCon™ platform, designed to deliver robust and stable high-concentration formulations.
The S-HiCon™ platform enables a systematic and rational approach to formulation development, evaluating each molecule’s behavior through a structured, step-by-step process. The process begins by assessing the feasibility of the target concentration while ensuring stability and manufacturability. Once feasibility is established, the optimal surfactant and pH/buffer system are identified to provide physical, colloidal, and chemical stability. Determination of the appropriate system is followed by extensive excipient screening, to evaluate various types and combinations to minimize degradation and viscosity.
Leveraging advanced technologies, strategic gate checks, and a data-driven formulation strategy, Samsung Biologics mitigates risk and enhances outcomes for high-concentration protein and mAb formulations. This comprehensive, science-backed methodology ensures that clients receive effective, scalable, and high-performing services tailored to the evolving demands of biologic drug development.
References
1. Self-injection Devices Market Size, Share & Trends Analysis By Product (Auto Injectors, Pen Injectors), By Usability (Disposable, Reusable), By Application (Cancer, Autoimmune Disorders, Hormonal Disorders), By Region, And Segment Forecasts, 2025 – 2030. Grand View Research. Accessed 11 Feb. 2025.
2. Murphy RM, et al. “Protein Misfolding and Aggregation.” Biotechnol. Prog. 23: 548-552 (2007).
3. Apgar JR, et al. “Modeling and mitigation of high-concentration antibody viscosity through structure-based computer-aided protein design.” PLoS ONE. 15: e0232713 (2020).