(M1530-02-10) Highly Concentrated mAb SubQ Formulations Using Nanoformed Particles: Trastuzumab Case Study

Purpose: Subcutaneous (SubQ) delivery has emerged as an attractive alternative to intravenous infusion (IV), providing the opportunity for self-administration and reducing the frequency of hospital visits, thus improving overall patient experience. Indeed, across 33 studies analyzed, both patients and healthcare professionals strongly prefer SubQ over IV route. For example, when comparing the time in oncology unit for trastuzumab (Herceptin®) administration, SubQ patients spend less than one third of the time compared to patients receiving IV. [1-6] However, SubQ delivery is challenging, especially where a high dose is needed, due to issues such as protein stability and viscosity, and there are currently no marketed products containing more than 200 mg/ml proteins. For trastuzumab, the current SubQ dose (Herceptin HYLECTA^TM) of 600 mg is administered over 2 to 5 minutes in a 5 ml volume injection of 120 mg/ml solution with hyaluronidase. Therefore, innovative approaches are still required to produce the next generation of patient centric SubQ products.  To this end, Nanoform has developed a highly concentrated SubQ formulation of a model IgG1 compound (trastuzumab) as a non-aqueous suspension over 400 mg/ml.

Methods: The key methodology for this work is Nanoform’s novel biological nanoparticle technology, which is a particle production method for biological APIs that can control the particle size of the resultant dry powder from 50 nm through to 5 mm. Trastuzumab was the chosen therapeutic due to the proven time reduction for the IV to SubQ switch, the relatively high dose, making it an ideal candidate for a single high concentration SubQ injection, and the availability of biosimilar products.

Results: The properties of the particles produced from Nanoform’s process offer advantages in both particle morphology and bulk density when compared to material produced by the more traditional methods of spray drying and lyophilization (Fig. 1). The impact of mAb particle size on the behavior of the drug product has been studied along with viscosity, injection force and syringeability of the formulations confirming the need for spherical particles. This work led to the development of a non-aqueous suspension injectable formulation containing 650 mg/ml of dry powder (ca. 450 mg/ml trastuzumab).  Injection forces measured for this formulation (less than 10N with 27G needle) confirm this falls well within accepted values for SubQ administration. Protein quality and activity along with the stability of the dry particles and the obtained suspension all appear promising (Fig. 2), with potential advantages over traditional aqueous formulations and avoiding the need for cold chain storage.  In addition, no sedimentation or increase in injection force was observed following storage of the suspension in a pre-filled syringe for 4 weeks (Fig. 3).

Conclusion: Dry powder nanoparticles of biological APIs produced using Nanoform’s process offer spherical particles with high density, and improved properties over spray drying and lyophilization, providing ideal properties for a range of formulations and drug delivery routes. A non-aqueous hyaluronidase free SubQ formulation of trastuzumab with ca. 450 mg/ml of mAb has been developed using this process, with injection forces of < 10N using a 27G needle, enabling an injection volume of one third of the marketed 5ml (600 mg) SubQ dose of Herceptin HYLECTA^TM.

References: 1. Aguiar‑Ibáñez, Adv Ther, 2024, DOI: 10.1007/s12325-024-02985-9
2. Moeller et al, Transl Lung Cancer Res, 2024, DOI: 10.21037/tlcr-24-111
3. Lonardi et al, J Immunother Cancer, 2023, DOI: 10.1136/jitc-2023-SITC2023.0616
4. Drill et al, Oncology (Williston Park), 2021, DOI: 10.46883/2021.25920935
5. Johnson et al, JAMA Oncol, 2019, DOI: 10.1001/jamaoncol.2019.0836
6. Tjelma et al, Eur J Obstet Gynecol Reprod Biol, 2018, DOI: 10.1016/j.ejogrb.2017.12.006

Acknowledgements: The authors wish to acknowledge funding assistance from Business Finland.

Figure 1. Dry powder of an IgG produced by Nanoforming (l), spray drying (c) and lyophilization (r).

Figure 2. HPLC monomer analysis of dry powder with different Nanoformed feedstock formulations compared to reference material.

Figure 3. Injection force data for nanotrastuzumab formulation after 0, 2 and 4 weeks.