The number of FDA released biopharmaceuticals PFS drug products is increasing. This is because PFS could benefit in accurate dose with less overfill, reduced contamination during clinical administration and even making patients self-administration possible [10], [19]. In the development of PFS drug products, it is important to understand the injectability of a specific drug product. This is closely related to the end user’s capability during the final administration. Generally, higher injection force may lead to challenges in final administration. The injection force (known as dynamic glide force), the maximum force required to deliver the entire drug content from the PFS [11], has received significant attention due to its performance attribute of PFS that Cilurzo and co-authors proposed a low level of medication injection force to improve the end users’ injection convenience and ease of accepting entire dose[8]. Generally, based on the injection position and finger strength, the injection force should not exceed the end user’s thumb finger push strength that can comfortably expel the entire dose smoothly [14]. The patient population differences are also one of the key human factors. For example, heathy adults’ finger strength decreases with aging [9]. Patients with rheumatoid arthritis may also suffer from the loss of hand strength and function [2]. When developing a PFS drug product and setting the upper limit specification of injection force, the target patient populations should be taken into consideration.

Therefore, the identification of the main contributors to injection force in the early phase of drug product development is key to achieving a successful PFS and even autoinjector development. Also, it’s beneficial to obtain a comprehensive understanding of the impact of parameter variability caused by variations in the manufacturing of the drug product. Simultaneously, the PFS components and environmental conditions at the point of use affect the probability of achieving the desired injection force.

The injection force has been described consisting of dynamic injection force and friction force [4]. The dynamic injection force as described the pressure drop in syringe needle by Hagen-Poiseuille’s Law is affected by various parameters such as PFS size, injection speed, needle dimensions, and medication viscosity. Regardless of the selected PFS and plunger stopper combination (those affecting the syringe friction force), the medication viscosity, in particular, determines the final injection force for a staked-in-needle PFS [11].

The PFS drug product is mainly administrated via subcutaneous route. For the subcutaneous administration of biopharmaceuticals, a concentrated protein formulation is normally required. However, this will lead to increased viscosity and introduce challenges in clinical administration (injectability)[10]. Patients may find it is difficult to inject the entire dose and this could possibly result in less dosing accuracy. Thus, it is essential to evaluate the injectability during the PFS drug product development.

The monoclonal antibodies (mAb) solution exhibits different rheological behaviors compare to simple fluids like water (Newtonian). At room temperature and typical manufacturing shear rate (around 10–100 s−1), Newtonian liquids display constant viscosity behavior since Brownian collisions are sufficiently rapid compared to the flow time scale. In the context of mAb solutions at high concentration, several studies have been conducted to understand the intermolecular forces that give rise to self-association or correlated arrangements [27]. Some researchers also discussed non-Newtonian behavior caused by shear modification. Typically, at high concentrations (>100 mg/mL), a dramatic reduction in viscosity could be observed at high shear rates (104 s−1) as compared with low shear rates (10 s−1) [27]. The shear rate could reach 105 s−1 when medication passes through PFS needles (needle diameter around 0.21 mm) targeting finishing 2.0 mL in 10 s [4] [25]. Thus, it is important to simulate the shear-thinning behavior of mAb solutions and evaluate their injectability in real clinical situations. Nevertheless, the environmental temperature also plays an important role in determining the viscosity of protein solution. Generally, the mAb solutions possesses increased viscosity in similar manner under lower temperature. Previous researchers have applied the Hagen-Poiseuille law and incorporated the shear-thinning behavior of protein solutions in modeling hyrodynamic injection force [4], [11]. However, the model still presented some limitations in industry actual application in injection force prediction with vendor provided information. Mis-predicted injection force could lead to inaccurate risk assessments during the design input of a PFS combination product and result in non-comparable selection of PFS components for a specific medication. This could even increase the possibility of major design changes in the later phases of medication development.

This paper uses simulation solutions that simulate Newtonian or shear-thinning rheological behaviors and monitors injectability against medication rheological behavior. This improves the model for predicting the injection force of PFS drug products by considering a large number of input parameters and their associated variability. The impact of injection temperature and tissue counter pressure will be discussed in the evaluation of the injection force. The concentrated mAb medication will be used to verify the improved model. Finally, the human factor's impact on injectability will be considered to define the boundaries of the PFS drug product's design space.