(T1030-01-03) Stability of Therapeutic Monoclonal Antibodies during Infusion with Elastomeric Pumps Intended for Home-Based Therapy

Purpose: Majority of monoclonal antibodies (mAbs) are administered to patients through intravenous infusion and typically within a hospital setting. A shift towards home-based therapy for various products has been underway in recent years, which was initially driven by the pandemic. This approach offers other advantages besides reducing infection risks during pandemics, such as easing the strain on hospital capacity, and lessening the burden of hospitalization on patients. Elastomeric pumps are devices that can be used for home-based therapy. They are sterile medical devices designed for single use, comprising an elastomeric reservoir enclosed within a rigid casing. Elastomeric pumps have been used for analgesics and antibiotics but not for delicate APIs such as proteins. Filling processes of these pumps may impact product quality by potentially introducing physical stresses, such as shear, exposure to various interfaces, and other mechanical stresses such as cavitation. Additionally, certain devices may shed extrinsic particles that could lead to presence of impurities and aggregation of mAbs. While there is interest in using elastomeric pumps for administration of mAbs, and a few reports indicate that some hospitals have already started using them, there is a lack of valid data demonstrating the stability of mAbs in these pumps. This is particularly crucial as the characterization and control of aggregate and subvisible particle formation during administration play a vital role in ensuring the safety of mAbs. In order to quantify subvisible particles and aggregation of Erbitux (cetuximab) and Herzuma (trastuzumab), serving as examples of two marketed antibodies, flow imaging microscopy (FlowCam), high pressure size exclusion chromatography (HPSEC), dynamic light scattering (DLS), UV-VIS spectroscopy, and nanoparticle tracking analysis (NTA) were employed in this study. The investigation utilized Easypump® II, a commonly used elastomeric pump, as a model device. In short, the aim of this study was to investigate the stability of mAbs that undergo infusion using an elastomeric pump.

Methods: The common practical method recommended for administration using elastomeric pumps was used. Regarding the mAbs, following the FDA's application guidelines for cetuximab and trastuzumab, we considered potential worst-case scenarios in which trastuzumab, would be administered to a 60 kg woman receiving 2 mg/kg over 60 minutes, and cetuximab, to a woman with a body surface area of 1.6 m² receiving 250 mg/m² over 60 minutes. The Easypump® II ST, with a capacity of 50 mL and a flow rate of 50 mL/hr, was filled with the product. Cetuximab was directly injected into the pump, while trastuzumab was first reconstituted with ultrapure water and then diluted with saline 0.9%, following the product guideline. After keeping the filled pump at room temperature for one hour, the sample run was initiated. Sampling was conducted in four steps: 1) In vial: sample from the vial or falcon used to dilute, 2) In syringe: sample from the syringe before transfer to the pump, 3) Before filter cut: sample from the pump 20 minutes after starting the flow of the filled pump, and 4) After filter cut: sample from the pump 25 minutes after the starting the run and following the removal of the in-line filter. The experiments for trastuzumab and cetuximab were repeated three times, and in each instance, two samples were taken at each step. For Saline, the experiments were also conducted three times, with one sample taken at each step each time. Finally, all samples were examined using FlowCam, HPSEC, DLS, UV-VIS, and NTA to quantify subvisible particles, aggregation, and any structural changes.

Results: The HPSEC data (Fig. 1) indicate that the area under the curve (AUC) of the monomer peaks, for both trastuzumab and cetuximab, was constant for all samples. Additionally, there were no discernible peaks before or after the main peak, suggesting the absence of any degradation. The FlowCam data illustrated a similar trend for saline and cetuximab, indicating a decrease in the number of particles by the in-line filter. However, after cutting the filter, due to the absence of the filtration, the number of particles increased and appeared to be equal to those in vial/falcon and syringe. The baseline particle count for trastuzumab was higher than the other two; nonetheless, it followed the same trend (Fig. 2). DLS data (Fig. 3) revealed similar radii and polydispersity index values across all samples for trastuzumab, and cetuximab, indicating the absence of major aggregation or nanometer-sized particles. NTA data were consistent with the DLS findings showing no change in the number of particles before and after using the pump.

Conclusion: Based on the results, it can be concluded that the employed elastomeric pump did not increase the number of subvisible particles or induce any aggregation in cetuximab and trastuzumab samples.

References: Nejadnik, M. R., Randolph, T. W., Volkin, D. B., Schöneich, C., Carpenter, J. F., Crommelin, D. J. A., & Jiskoot, W. (2018). Postproduction Handling and Administration of Protein Pharmaceuticals and Potential Instability Issues. Journal of Pharmaceutical Sciences, 107(8), 2013-2019.

Fig. 1: Area under the curve (AUC) of monomer peaks obtained by high-pressure size exclusion chromatography (HPSEC) of cetuximab and trastuzumab samples collected at the four described steps.

Fig. 2: Concentration of particles obtained by FlowCam for trastuzumab samples collected at the four described steps. Inset shows a magnified presentation of the number of >10 and >25 µm particles

Fig 3. Particle radius obtained by Dynamic light scattering of cetuximab and trastuzumab samples collected at the four described steps.