Advance Formulation Performance with Rheology Studies

Calliste Scholl | Julienne Regele
March 11, 2024

The progression from formulation development to commercial formulation is dependent on the dose strength, intrinsic stability, and extent of protein self-association in the final drug.1 This is because the drug is reaching the final stage of development. It is critical that the drug is evaluated for effectiveness and stability in real-life conditions. Recently, high concentration antibody products (HCAPs) have become more desirable in the therapeutic sector due to their many unique advantages.

Vaccine needle​ syringe​ hypodermic​ injection single dose

The Advantages of HCAPs

The majority of market available antibody drug solutions are delivered intravenously to patients in a hospital setting. HCAPs would allow opportunities for disease treatment to be done through subcutaneous injections. The maximum volume of products delivered through subcutaneous administration is 2 ml.1 At this volume, HCAPs can deliver larger amounts of protein and allow administration to be performed at a doctor’s clinic or a patient’s home. Overall, subcutaneous administration allows for patient convenience, decreased burden on health-care professionals, ease of use, reduction in hospitalization or in-patient costs, and reduction in treatment costs when compared to the intravenous administration.1

HCAPs allow for self-administration of subcutaneous delivery, which gives more flexibility and freedom to the patient in managing their dosing schedule and living a more normal life while managing a chronic health condition.1 This is especially beneficial for patients who require long-term drug administration to manage their chronic disease, as well as ensures patient compliance during treatment.1

Lastly, HCAPs provides more affordable manufacturing and logistics costs.1 During creation, the drug substance is brought to a high concentration, frozen, and shipped to the drug product fill finish site.1 Since HCAPs have a high protein concentration per unit volume of the drug substance, the cost of shipping, storage, and inventory management is significantly lower compared to lower concentration solutions.

Composition and Stability of HCAPs

HCAPs provide a variety of advantages in advancing the formulation development of a drug. However, to ensure their efficient therapeutic use, the composition and stability of the drug must excel in conditions like that used in treatment. To determine suitability, the aggregation, pH, osmolality, stability, and viscosity can be measured. Typically, lower aggregation is preferred since it limits any reduction in drug efficacy and stability.2 Second, drugs are best absorbed when they are not ionized and can’t permeate freely through cell membranes.3 Therefore, the desired pH mainly depends on the target location of the therapy.3 Third, higher drug osmolality is preferred to allow for larger amounts of delivery to an intended area.4 Fourth, as mentioned above, the antibody itself must be stable enough to survive injection and different bodily conditions, as any impact on the stability of the antibody will reduce its efficiency. Lastly, viscosity can be considered as one of the most important stability measurements. Specifically, in HCAPs where antibodies are formulated as concentrated solutions (> 100 mg/mL), the viscosity of the solutions is expected to increase exponentially beyond what is pharmaceutically acceptable for subcutaneous injections due to the short-range protein-protein interactions.1 These protein-protein interactions can create higher amounts of protein aggregation and severely decrease its overall stability and ability to be delivered to its target location.1 Therefore, it is critical to utilize viscosity measurements to determine and limit protein interactions, when possible, to allow for higher stability and efficacy.

Benefits of Viscosity Measurements in Measuring Protein-Protein Interactions

Measuring rheological properties provides crucial insight into the stability of the specific antibody, and more closely relates to the levels of protein-protein interactions. Recently, a study has evaluated the effect of NaCl on non-specific protein-protein interactions and how that might affect formulation stability and viscosity.5 The nature of net protein-protein interactions changed not only with the concentration of NaCl, but also with the concentration of antibody. As a result, parameters measured from dilute and concentrated antibody samples could lead to different predictions on the stability of antibody formulations.5 Again, this emphasizes the potential benefits of using viscosity measurements to assess antibody stability and performance during the formulation stage of development.

Developing Successful HCAPs

Overall, there are a wide variety of requirements for the progression of a drug from formulation development to commercial formulation. However, HCAPs seem to be the most promising method for efficient progression, mainly due to its ability to deliver high dose concentration, option for subcutaneous delivery by anyone and anywhere, and the lower costs. As these HCAPs are tested, it is massively important to properly evaluate composition and stability to determine success in real-life scenarios. Specifically, it has been shown that viscosity measurements performed with a rheometer are accurate in determining protein-protein interactions. Therefore, it is important for researchers to utilize rheology to facilitate the drug development process and ensure proper stability and behavior of their antibody products.


  1. Ghosh, I., Gutka, H., Krause, M. E., Clemens, R., & Kashi, R. S. (n.d.). A systematic review of commercial high concentration antibody drug products approved in the US: Formulation composition, dosage form design and primary packaging considerations. mAbs, 15(1), 2205540.
  2. Roberts, C. J. (2014). Protein Aggregation and Its Impact on Product Quality. Current Opinion in Biotechnology, 0, 211–217.
  3. Swietach, P., Hulikova, A., Patiar, S., Vaughan-Jones, R. D., & Harris, A. L. (2012). Importance of intracellular pH in determining the uptake and efficacy of the weakly basic chemotherapeutic drug, doxorubicin. PloS One, 7(4), e35949.
  4. Sifniotis, V., Cruz, E., Eroglu, B., & Kayser, V. (2019). Current Advancements in Addressing Key Challenges of Therapeutic Antibody Design, Manufacture, and Formulation. Antibodies, 8(2), 36.
  5. Antibodies | Free Full-Text | Effects of Monovalent Salt on Protein-Protein Interactions of Dilute and Concentrated Monoclonal Antibody Formulations. (n.d.). Retrieved November 8, 2023, from