Low-Volume Aseptic Filling Using a Linear Peristaltic Pump.

The pharmaceutical industry has been confronted with new and complex challenges, particularly with regard to the aseptic filling of parenterals, including monoclonal antibodies and ophthalmologic drugs designed for intravitreal injections, which often require fill volumes <200 µL. In addition to intravitreal administration, microliter doses may be required for applications using highly concentrated formulations and cell and gene therapies. Many of these therapies have either a narrow or unknown therapeutic window, requiring a high degree of accuracy and precision for the filling system. This study aimed to investigate the applicability of a linear peristaltic pump as a novel and innovative filling system for the low-volume filling of parenterals, compared with the state-of-the-art filling systems that are currently used during pharmaceutical production. We characterized the working principle of the pump and evaluated its accuracy for a target fill volume of 50 µL. Our results demonstrated that the linear peristaltic pump can be used for fill volumes ranging from 12 to 420 µL. A deeper investigation was performed with the fill volume of 50 µL, because it represents a typical clinical dose of an intravitreal application. The filling accuracy was stable over an 8 h operation time, with a standard deviation of +/-4.4%. We conclude that this technology may allow the pharmaceutical industry to overcome challenges associated with the reliable filling of volumes <1 mL during aseptic filling. This technology has the potential to change aseptic filling methods by broadening the range of potential fill volumes while maintaining accuracy and precision, even when performing microliter fills.

Assessment of Sensor Concepts for 100% In-Process Control of Low-Volume Aseptic Fill-Finish Processes.

The pharmaceutical industry is currently being confronted with new and complex challenges regarding the aseptic filling of parenterals, especially monoclonal antibodies, particularly for fill volumes <200 µL, which have become increasingly important with the increasing and continued development of intravitreal drugs and highly concentrated formulations. Not only does low-volume filling pose challenges to aseptic manufacturing, but the development of suitable in-process control to ensure reliable and robust filling processes for low-volume conditions has also been difficult. In particular, fill volumes <200 µL exceed limits of accuracy and robustness for the well-established method of gravimetric fill-volume control. Therefore, the present study aimed to evaluate and test novel sensors, which may allow the accurate and precise 100% contact-free measurement of drug-product formulations, with respect to filling volumes. These sensors were designed to be less influenced by inevitable noise factors, such as unidirectional airflow and vibrations. We designed the study using five different sensor concepts, to screen and identify suitable alternatives to gravimetric fill-volume control. The examined sensor concepts were based on airflow, capacitive pressure, light obscuration. and capacitive measurements. Our results demonstrated that all of the tested sensor types worked in the desired low-volume range of 10-150 µL and showed remarkable results, in terms of accuracy and precision, when compared with a high-precision gravimetric balance. A sensor based on capacitance measurement was identified as the most promising candidate for future sensor implementation into an aseptic filling line. This sensor design proved to be superior in terms of both sensitivity and precision compared with the other tested sensors. We concluded that this technology may allow the pharmaceutical industry to overcome existing challenges with respect to the reliable measurement of aseptic fill volumes <200 µL. This technology has the potential to fundamentally change how the pharmaceutical industry verifies fill volumes by facilitating 100% in-process control, even at high machine speeds.

Low volume aseptic filling: Impact of pump systems on shear stress.

Low volume aseptic filling of parenterals, particularly monoclonal antibodies is becoming increasingly important with the development of more and more intravitreal drugs and high concentrated formulations. Especially monoclonal antibodies are very delicate products to fill and the use of the right fill finish equipment plays an important role during process development. Protein aggregation can occur under conditions described in literature and can be influenced by the fill finish processing. The mechanism of product stress inside the filling systems is yet not fully understood. This study evaluated three different dosing systems to assess protein degradation caused by the shear rate during low volume filling of monoclonal antibodies. The newly developed quantitative liposomal shear stress model revealed the highest shear rate in the radial peristaltic pump, followed by the rotary piston pump and the linear peristaltic pump. In contrast to that, we found the highest sub-visible particle counts (>2 µm) in the rotary piston pump. We used computational fluid dynamics for a better and deeper understanding of filling processes inside the different dosing systems. Our results document that the rotary piston pump creates a recirculation zone inside the cylinder, where the protein formulation could be trapped and be exposed to the shear stress multiple times resulting in a cumulative shearing. This finding could serve as an explanation for the highest sub-particle counts in low volume filling using a rotary piston pump.

A Method To Determine the Kinetics of Solute Mixing in Liquid/Liquid Formulation Dual-Chamber Syringes.

Dual-chamber syringes were originally designed to separate a solid substance and its diluent. However, they can also be used to separate liquid formulations of two individual drug products, which cannot be co-formulated due to technical or regulatory issues. A liquid/liquid dual-chamber syringe can be designed to achieve homogenization and mixing of both solutions prior to administration, or it can be used to sequentially inject both solutions. While sequential injection can be easily achieved by a dual-chamber syringe with a bypass located at the needle end of the syringe barrel, mixing of the two fluids may provide more challenges. Within this study, the mixing behavior of surrogate solutions in different dual-chamber syringes is assessed. Furthermore, the influence of parameters such as injection angle, injection speed, agitation, and sample viscosity were studied. It was noted that mixing was poor for the commercial dual-chamber syringes (with a bypass designed as a longitudinal ridge) when the two liquids significantly differ in their physical properties (viscosity, density). However, an optimized dual-chamber syringe design with multiple bypass channels resulted in improved mixing of liquids. LAY ABSTRACT: Dual-chamber syringes were originally designed to separate a solid substance and its diluent. However, they can also be used to separate liquid formulations of two individual drug products. A liquid/liquid dual-chamber syringe can be designed to achieve homogenization and mixing of both solutions prior to administration, or it can be used to sequentially inject both solutions. While sequential injection can be easily achieved by a dual-chamber syringe with a bypass located at the needle end of the syringe barrel, mixing of the two fluids may provide more challenges. Within this study, the mixing behavior of surrogate solutions in different dual-chamber syringes is assessed. Furthermore, the influence of parameters such as injection angle, injection speed, agitation, and sample viscosity were studied. It was noted that mixing was poor for the commercially available dual-chamber syringes when the two liquids significantly differ in viscosity and density. However, an optimized dual-chamber syringe design resulted in improved mixing of liquids.