(M0930-12-77) Low Dose Compatibility Testing With and Without Surfactant in Polyethylene Terephthalate (PETG), Glass, and Polypropylene Container Types for Large Molecule Analysis

Purpose: Novel Aspects: Evaluation of low dose (0.01 mg/mL) samples comparing the effect of surfactant in multiple vehicles utilizing different container types to improve compatibility of large molecule formulations. Emergent strategies for biological therapeutic (large molecule) formulations continue to evolve. However, several challenges still exist in improving compatibility of low dose (0.01 mg/mL) formulation samples. Various types of polysorbates, Tween^® 20 and Tween^® 80 have been shown to improve formulation compatibility.^1,2 The purpose of this research was to explore low dose formulation sample compatibility and stability using different vehicles with and without surfactant in polyethylene terephthalate (PETG), glass, and polypropylene container types.

Methods: Container types tested were polyethylene terephthalate (PETG), glass, and polypropylene. Sample concentrations tested were 0.01 mg/mL and 1 mg/mL. Vehicle formulations were as follows, Vehicle 1: 10mM Histidine, pH 6.5; Vehicle 2: 10mM Histidine, 8.5% sucrose, 0.05% Tween^® 20, pH 5.8; and Vehicle 3: 10mM Histidine, 8.5% sucrose, 0.05% Tween^® 80, pH 5.8. To evaluate container and vehicle compatibility, a Protein A HPLC method was used for analysis.

Results: Formulation samples diluted in Vehicle 1: 10mM Histidine, pH 6.5: 0.01 mg/mL samples in PETG containers had a mean % theoretical result of 63.1% with a %RSD of 2.1; in glass containers had a mean % theoretical result of 52.6% with a %RSD of 3.6%; and in polypropylene containers had a mean % theoretical result of 70.2% with an %RSD of 2.6. The 1 mg/mL control in polypropylene containers had a mean % theoretical result of 104.6% and a %RSD of 0.5. 4 days and 20 hours stability results in Vehicle 1: 10mM Histidine, pH 6.5: 0.01 mg/mL samples in PETG had a mean % difference from baseline of -14.6% when stored at room temperature and -17.0% when stored under refrigerated conditions; in glass had a mean % difference from baseline of 7.0% when stored at room temperature and 6.9% when stored under refrigerated conditions; and in polypropylene had a mean % difference from baseline of 11.6% when stored at room temperature and 12.0% when stored under refrigerated conditions. Formulation samples diluted in Vehicle 2: 10mM Histidine, 8.5% sucrose, 0.05% Tween^® 20, pH 5.8: 0.01 mg/mL samples in PETG had a mean % theoretical result of 95.8% and a %RSD of 0.6; in glass containers had a mean % theoretical result of 87.2% and a %RSD of 1.1; and in polypropylene containers had a mean % theoretical result of 96.1% and a %RSD of 2.1. The 1 mg/mL control in polypropylene had a mean result of 103.4% and a %RSD of 0.2. 4 days and 20 hours stability results in Vehicle 2: 10mM Histidine, 8.5% sucrose, 0.05% Tween^® 20, pH 5.8: 0.01 mg/mL samples in PETG had a mean % difference from baseline of 6.7% when stored at room temperature and 5.3% when stored under refrigerated conditions; in glass had a mean % difference from baseline of 3.5% when stored at room temperature and 4.9% when stored under refrigerated conditions; and in polypropylene had a mean % difference from baseline of 4.9% when stored at room temperature and 3.2% when stored under refrigerated conditions. Formulation samples diluted in Vehicle 3: 10mM Histidine, 8.5% sucrose, 0.05% Tween^® 80, pH 5.8: 0.01 mg/mL samples in PETG had a mean % theoretical of 96.4% and a %RSD of 1.0; in glass had a mean % theoretical of 88.3% and a %RSD of 1.1; and in polypropylene had a mean % theoretical of 96.2% and a %RSD of 1.7. The 1 mg/mL control in polypropylene had a mean % theoretical result of 104.3% and a %RSD of 0.3. 4 days and 20 hours stability results in Vehicle 3: 10mM Histidine, 8.5% sucrose, 0.05% Tween^® 80, pH 5.8: 0.01 mg/mL samples in PETG had a mean % difference from baseline of -19.8% when stored at room temperature and 6.7% when stored under refrigerated conditions; in glass had a mean % difference from baseline of -7.9% when stored at room temperature and 0.0% when stored under refrigerated conditions; and in polypropylene had a mean % difference from baseline of 5.7% when stored at room temperature and 4.0% when stored under refrigerated conditions.

Conclusion: Results demonstrate that 0.01 mg/mL samples in vehicle with surfactant had improved compatibility compared to vehicle without surfactant. Tween^® 20 and Tween 80^® had similar effect of improving compatibility. Polypropylene demonstrated the most consistent compatibility. Data also demonstrate that glass is less compatible. Low concentration samples are not compatible with PETG, glass, or polypropylene in the absence of surfactant. Findings indicate that surfactant will be used in the vehicle for low concentration dose formulations in future studies.

References: 1. Wang, S.; Wu, G.; Zhang, X.; Tian, Z.; Zhang, N.; Hu, T.; Dai, W.; Qian, F. Stabilizing Two IgG1 Monoclonal Antibodies by Surfactants: Balance between Aggregation Prevention and Structure Perturbation. Eur. J. Pharm. Biopharm. 2017, 114, 263–277.
2 Gerhardt, A.; McUmber, A.C.; Nguyen, B.H.; Lewus, R.; Schwartz, D.K.; Carpenter, J.F.; Randolph, T.W. Surfactant Effects on Particle Generation in Antibody Formulations in Pre-Filled Syringes. J. Pharm. Sci. 2015, 104, 4056–4064.