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.

Quantifying the Vial Capping Process: Residual Seal Force and Container Closure Integrity.

Capping completes the closure of parenteral drug products in the final packaging container and is critical in maintaining an integral seal to ensure product quality. Residual seal force (RSF) is considered the sole quantifiable attribute for measuring seal "goodness" and potentially enables nonsubjective, consistent setting of cappers across manufacturing sites. However, the consistency and reliability of RSF measurement and data have been scarcely reported, and the relationship between RSF and container closure integrity (CCI) remains poorly understood.Here, we present a large data set generated from a commercial capper and the results from a laboratory capper of glass vials and rubber stoppers with aluminum caps. All RSF values exhibited significant variability. We evaluated four potential sources of variability: the capper, the RSF tester, the time-dependent nature of RSF, and the components. We determined that the capper, the tester, and the time-dependent nature are not main sources. Dimensional tolerances of the packaging components were the root cause for the container closure system (CCS) configurations tested in this study.This study correlated RSF with CCI (via helium leakage), although CCI is not sensitive to RSF; CCI was maintained even for loosely capped vials with no measurable RSF. This was attributed to the stopper's two sealing surfaces: the valve seal and the land seal. A methodology capable of differentiating the two seals' functions demonstrated that vials with only the valve seal always passed leakage testing for a selected CCS configuration in this study, while vials with only the land seal failed CCI at low RSF values. This observation allows proposal of a low RSF limit that is safe even when the valve seal is defective. Simplified statistical analysis of commercial capping data, with the input of sample size, allowed the relationship between RSF's low limit and an allowable failing rate to be established. Overall, despite the inherent variability of RSF, this study shows that it is a feasible parameter for capping process quantification and demonstrates the potential of RSF measurement in capper setup.LAY ABSTRACT: Pharmaceutical vials are typically closed off with an elastomeric stopper that is secured onto the vial with an aluminum crimp cap (or seal) such that the entire assembly is meant to protect the vial's contents from external contamination. Therefore, the capping process is critical for ensuring container closure integrity. Characterizing the effectiveness of a seal in a nonsubjective and quantifiable manner is challenging. In this communication, we report the evaluation of residual seal force measurements (the compression force that the crimp cap exerts on the stopper) to evaluate capping for a large set of samples generated on both an at-scale commercial capper and a benchtop laboratory capper. We propose a test methodology, based on a statistical approach, for establishing permissible lower residual force limits that would provide a high degree of confidence to the capping process. This is a useful tool for consistent capper setup and capping process quantification.

Residual Seal Force Testing: A Suitable Method for Seal Quality Determination of (High Potent) Parenterals.

Vial capping plays a critical role in the drug product manufacturing process owing to the complex interplay of several adjustable process steps. Seal quality and integrity and containment assurance are essential for parenteral pharmaceuticals, as the vial's content may be contaminated or, in the case of highly potent drugs (e.g., antibody drug conjugates), may bear a risk of contamination. The residual seal force (RSF) method can enable further insight in capping equipment settings independently of the container closure system (CCS) and their resulting seal quality.The present study investigates the accuracy of the RSF method focusing on different force settings, RSF development over time, distance between capping plates and vial neck (roller-axis), time point of flip-off button removal, and internal and external vial pressure differences (flight simulation and vials closed under vacuum).Results show that the forces used on an RSF tester should be kept low to minimize CCS deformation, and a period of stable RSF values after the initial decrease should be implemented between capping and RSF measurement to increase accuracy. Variations in the distance between the capping plates and vial neck (roller-axis) can result in incomplete crimps or visual defects of the seals. In addition, the time point of flip-off button removal as part of the sample preparation had no significant impact on RSF measurements. Finally, pressure differences between the vial interior and exterior had no significant impact on the RSF data.LAY ABSTRACT: Vial capping plays a critical role in the drug product manufacturing process due to the complex interplay of several adjustable process steps. Seal quality, integrity, and containment are essential for parenteral pharmaceuticals, as the vial's content varies and may be contaminated, sensitive to stress, and/or highly potent (eg, antibody drug conjugates). The residual seal force (RSF) method can enable further insight in capping equipment settings independently of the container closure system and their resulting seal quality.In this study, we determined RSF values by applying different force settings of the RSF tester and investigated the influence of sample preparation on the determination of RSF. Furthermore, the capping process parameter roller-axis was evaluated by RSF and visual inspection. In addition, we investigated the influence of pressure differences of vials on the RSF as they occurred during air transport and products closed under vacuum.

Innovative approach for identifying root causes of glass defects in sterile drug product manufacturing.

In sterile drug product manufacturing, scratched and broken glass containers (i.e., vials) cause product losses, glass particles, equipment contamination and additional cleaning efforts. However, mechanical resistance and exposure of vials to mechanical stress are not sufficiently understood, and no systematic approach for reducing glass-related losses is established. Manufacturers may tackle glass-related losses more rationally if (i) frequencies for inflicting disqualifying damages to drug product containers are known for given forces, (ii) actual exposure in industrial filling lines is quantified and (iii) process enhancements are derived based on collected information. In this work, an innovative approach for exploiting these opportunities, identifying glass defect root causes and reducing glass defects is provided. Devices for quantifying (i) damaging frequencies and (ii) actual exposure are presented and then applied in an industrial case study on sterile drug product manufacturing; finally, (iii) process enhancements are derived and implemented. In the case study, frequencies for scratching vials at given forces as well as breaking forces have been determined. Peak exposure in the investigated filling line was detected at 6 N. As a result of the case study, key machine parts were identified and adjusted.

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.

The Effect of Formulation, Process, and Method Variables on the Reconstitution Time in Dual Chamber Syringes.

Reconstitution time of dried products is influenced by various factors including formulation, process, and reconstitution method itself. This manuscript describes factors affecting reconstitution in a dual chamber syringe using highly concentrated human monoclonal antibody and bovine serum albumin model formulations. Freezing and drying conditions had only minor impact on the reconstitution time, whereas the primary container and thus the geometry of the lyophilization cake played a major role. Prewarmed diluent and agitation decreased reconstitution time. For effective agitation, short displacements and high agitation frequencies were found to be desirable conditions to minimize reconstitution time for a given lyophilization cake while foam formation was minimized. The article also provides general strategies (e.g., reduction of lyophilized cake density, use of an optimized fill finish process, and suitable method parameters) to reduce reconstitution time, especially for drug product presented in a dual chamber syringe configuration. LAY ABSTRACT: Dried drug products need to be reconstituted to a liquid form before being applied parenteral. Reconstitution time is an important attribute and needs to be as fast as possible in order to serve patients' compliance. Reconstitution time is influenced by various factors including formulation, process, and the reconstitution method itself. The article provides general strategies (e.g., reduction of dried drug product cake density, use of an optimized fill finish process, and suitable method parameters) to reduce reconstitution time, especially for drug product presented in a dual chamber syringe. Fast reconstitution of lyophilisates in dual chamber syringe can be achieved by a combination of optimized manufacturing procedures and clear instructions for the end-user (e.g., roll syringe between palms to warm and agitate it to accelerate reconstitution).

Technology, Applications, and Process Challenges of Dual Chamber Systems.

Dual-chamber systems provide an option as a drug and device combination product, when home care and emergency lyophilized products are intended. Nevertheless, until today, there are only a few products on the market, due to the challenges and limitations in manufacturability, product formulation, and product stability in a dual-chamber configuration, as well as economic considerations. This review serves to describe currently available dual-chamber systems and to discuss factors to be considered for appropriate selection and establishing fill-finish processes.

The Pharmaceutical Capping Process-Correlation between Residual Seal Force, Torque Moment, and Flip-off Removal Force.

The majority of parenteral drug products are manufactured in glass vials with an elastomeric rubber stopper and a crimp cap. The vial sealing process is a critical process step during fill-and-finish operations, as it defines the seal quality of the final product. Different critical capping process parameters can affect rubber stopper defects, rubber stopper compression, container closure integrity, and also crimp cap quality. A sufficiently high force to remove the flip-off button prior to usage is required to ensure quality of the drug product unit by the flip-off button during storage, transportation, and until opening and use. Therefore, the final product is 100% visually inspected for lose or defective crimp caps, which is subjective as well as time- and labor-intensive. In this study, we sealed several container closure system configurations with different capping equipment settings (with corresponding residual seal force values) to investigate the torque moment required to turn the crimp cap. A correlation between torque moment and residual seal force has been established. The torque moment was found to be influenced by several parameters, including diameter of the vial head, type of rubber stopper (serum or lyophilized) and type of crimp cap (West(®) or Datwyler(®)). In addition, we measured the force required to remove the flip-off button of a sealed container closure system. The capping process had no influence on measured forces; however, it was possible to detect partially crimped vials. In conclusion, a controlled capping process with a defined target residual seal force range leads to a tight crimp cap on a sealed container closure system and can ensure product quality. LAY ABSTRACT: The majority of parenteral drug products are manufactured in a glass vials with an elastomeric rubber stopper and a crimp cap. The vial sealing process is a critical process step during fill-and-finish operations, as it defines the seal quality of the final product. An adequate force to remove the flip-off button prior to usage is required to ensure product quality during storage and transportation until use. In addition, the complete crimp cap needs to be fixed in a tight position on the vial. In this study, we investigated the torque moment required to turn the crimp cap and the force required to remove the flip-off button of container closure system sealed with different capping equipment process parameters (having different residual seal force values).

The pharmaceutical vial capping process: Container closure systems, capping equipment, regulatory framework, and seal quality tests.

Parenteral drug products are protected by appropriate primary packaging to protect against environmental factors, including potential microbial contamination during shelf life duration. The most commonly used CCS configuration for parenteral drug products is the glass vial, sealed with a rubber stopper and an aluminum crimp cap. In combination with an adequately designed and controlled aseptic fill/finish processes, a well-designed and characterized capping process is indispensable to ensure product quality and integrity and to minimize rejections during the manufacturing process. In this review, the health authority requirements and expectations related to container closure system quality and container closure integrity are summarized. The pharmaceutical vial, the rubber stopper, and the crimp cap are described. Different capping techniques are critically compared: The most common capping equipment with a rotating capping plate produces the lowest amount of particle. The strength and challenges of methods to control the capping process are discussed. The residual seal force method can characterize the capping process independent of the used capping equipment or CCS. We analyze the root causes of several cosmetic defects associated with the vial capping process.

An Impedance-Based Method to Determine Reconstitution Time for Freeze-Dried Pharmaceuticals.

The reconstitution of freeze-dried products is usually determined by visual inspection with the naked eye. This can inevitably lead to significant variability in the ability to detect complete reconstitution of the dried solid. It was thus the goal of our study to assess an automated method to monitor reconstitution of a freeze-dried protein drug product in its primary packaging. A newly developed measuring device was used to measure impedance. This was achieved by detecting minor changes in impedance of the reconstitution medium, which occurred because of solid material dissolving during the dissolution process. This measurement system was capable of consistently detecting the dissolution of the last visible residues of freeze-dried lyophilisates. The endpoint of reconstitution was defined at an impedance change of less than 1 Ω for at least 7 s. Finally, we compared reconstitution times determined by the automated impedance method with results obtained by a visual method. In contrast to human operators, the new method delivered both accurate and precise results. Besides detection of the reconstitution endpoint, the impedance method and apparatus can monitor reconstitution endpoints as well as reconstitution kinetics. This standardized method can therefore advantageously be used for the determination of the reconstitution endpoint.