(M1330-01-04) Injectability for High Concentration Monoclonal Antibody Formulations

Purpose: Understanding viscosity, syringeability and injectability is essential and is an important part of the strategy to develop high concentration antibody formulation for subcutaneous administration. Developing high concentration mAbs formulation (≥ 150 mg/mL) for subcutaneous delivery is now in great demand. The mAbs with high concentrations usually exhibit high viscosity and physical instability of the protein due to change in colloidal properties resulting in aggregation, causing administration by injection a challenge. Therefore, strategies for developing high concentration requires several considerations, such as selection of excipients- stabilizers, buffer, pH to creating a suitable environment for the antibodies/proteins to remain in solution, and to also have attributes like lower viscosity to allow for administration by injection. In this study, the injectability of antibody formulations is discussed.

Methods: To obtain concentrated antibody formulations, suitable buffer, pH, and excipients were evaluated by iterative process utilizing Stability Fingerprinting®. The viscosity of formulations was measured using an EMS-1000s viscometer. The injectability was determined using a Texture analyzer where initial break-loose force, dynamic glide force, and maximum force were measured using 25, 27, and 30G BD needles with 2.2 ml fill. The force measurement consisted of a displacement rate of the formulation filled in a syringe that related to an injection rate. The relationship between syringe-needle types and the viscosity of high concentrated mAbs was evaluated.

Results: Three antibody formulations (> 150 mg/ml) for subcutaneous delivery were developed through an iterative process of selecting suitable buffer, pH, stabilizers, and surfactants. The lead formulations for the three antibodies evaluated are presented below. The stable lead formulations are listed in Table 1.

Table 1: List of High concentration mAbs with viscosity ≤20 cP

Antibody	pH	Excipients	Concentrations (mg/mL)	Viscosity (cP)
mAb1 (IgG1)	5.5	Histidine, Trehalose, Methionine, Polysorbates 20	150	14
mAb2 (IgG2)	5.3	Acetate, Proline, Sorbitol, Mannitol, Poloxamer	210	18
mAb3 (IgG2)	6.2	Histidine, Arginine, Glutamic acid, Sorbitol, Polysorbates 80	200	20

The injectability of these formulations was assessed for break through force, dynamic glide force, and maximum force. Each antibody was tested at three injection rates and three needle gauges; the results for 15 sec injections are listed in Table 2. An aqueous glycerol solution with viscosity of 21.5 cP was also studied for injectability as control. A representative profile of injectability for the antibody at 150 mg/ml, using 25G and 27G needles, is presented in Figure 1.



Table 2: Dynamic Glide Force (N), Initial break through force (N) and Maximum force (N) for 15 sec injections.

Formulation	Viscosity (cP)	25 G 5/8” needle	27 G 1/2” needle
		Dynamic Glide Force (N)
mAb1 (IgG1)		12.28	36.19
mAb2 (IgG 2)		15.91	41.81
mAb3 (IgG 2)		20.67	41.62
72 % w/w Glycerol		18.97	51.80
		Initial Break Through Force (N)
mAb1 (IgG1)		12.42	35.75
mAb2 (IgG 2)		15.95	41.19
mAb3 (IgG 2)		20.74	40.89
72% w/w Glycerol		19.22	52.26
		Maximum Force (N)
mAb1 (IgG1)		12.52	36.93
mAb2 (IgG 2)		16.16	42.17
mAb3 (IgG 2)		21.01	42.39
72 % w/w Glycerol		19.28	53.01

Figure 1: Injectability of mAb1 (150 mg/ml) using 25G and 27G needles at

Conclusion: The high concentration antibody formulations were obtained by an iterative process through Stability Fingerprinting®. Injectability tests allowed for the characterization of high concentration antibody formulations with respect to initial break through force, dynamic glide force and maximum force. The data for 25G and 27G needles obtained helped in the selection of delivery rate based on formulation viscosity and suitable injection force. The dynamic glide force for 27G needles was 2-3 times the force measured for 25G needles in the 15 sec injection. For all formulations studied, the 30G needles were unsuitable due to excessive injection force.