This case study is the first to address the risk, at the device-to-vial interface, of a spike pushing a stopper into a vial. It was performed after healthcare workers at cancer care hospitals complained about the risk of possible exposure to hazardous injectable drugs during the transfer if the spike pushed the stopper into the vial. This case study took a three-step approach to understand the device-to-vial interface, and the factors that determine stopper push-in force threshold and spike puncture force, respectively. The results show that the stopper push-in force threshold varies with the spike size, stopper properties, and stopper design; while the spike puncture force is determined by spike design, spike surface lubricity, stopper properties, and stopper design. The case study suggests that, to mitigate the risk of stopper push-in, the spike puncture force needs to be significantly lower than the stopper push-in force threshold, measured with a flat tip test probe having the same outside diameter as typically used spikes. In addition, although some factors which impact stopper push-in force threshold also impact spike puncture force in the same trend, such as stopper material, other factors which impact stopper push-in force threshold do not impact spike puncture force, and vice versa. For example, the spike length and cross section area contribute to stopper push-in force threshold but do not have significant impact on puncture force. It would be misleading to just compare the absolute values of spike puncture forces but neglect the dimensional factors. From the stopper and spike compatibility perspective, the case study provides a methodology to quantify the risk of stopper being pushed into the vial by the spike, and suggests a process to prevent the stopper push-in from occurring. The study also shows that the human factor is another important element in the stopper push-in issue. It emphasizes the need for a joint effort for risk mitigation across the board among stopper manufacturers, spike manufacturers, pharmaceutical manufacturers, device manufacturers, and hospitals (pharmacies & healthcare workers). Device and drug developers need to properly select and test stoppers and containers with intended spikes. Healthcare workers need to use compatible stoppers and spikes, and need to use them correctly.
Objectives
Particles due to fragmentation present a clear risk to the patient. Reported fragmentation rates vary, and an insertion angle at 45°, as opposed to 90°, has been proposed as a mitigation strategy. So, this study evaluated the fragmentation rates induced by single-use hypodermic needles using different angled penetration techniques.
Methods
Needles underwent fragmentation testing using two penetration techniques. In method 1, the needle was inserted through the stopper at 45° and rotated to 90° upon exiting the stopper underside, and in method 2 the needle was rotated only after the bevel was fully enveloped by the stopper. Methods were tested with 18, 20, and 22-gauge needles with bevel faced up, down, and sideways. Fragmentation data sets were subjected to ANOVA and a fit to a General Linear Model was attempted to ascertain the significance of needle size, bevel position, and penetration method; p-values less than 0.05 indicated statistical significance.
Results
Incidence varied from 0 to 49% and depended on the test method. Needles larger than 22-gauge induced fragmentation the most when the bevel was down. The bevel up position induced fragmentation the least. Generation of large fragments designated “cores” depended on all factors examined, and generation of small fragments designated “fragments” depended on all factors except for the penetration method.
Conclusions
Clinical context and intended application need to be communicated to manufacturers and considered for functional testing when devising end-user recommendations which must reflect a combination of factors.
The quality of the products/processes has been improved remarkably since robust design (RD) methodology is applied into the practice manufacturing processes. A model building method based on the dual responses methods for multiple and time oriented responses on a drug development process is employed in this paper instead of the previous methods that handle the static nature of data and single response. Subsequently, the optimal solutions of a multiple and time series RD problem are obtained by using the proposed augmented weighted Tchebycheff method that has a significant flexibility on assigning weights. Finally, a pharmaceutical case study associated with a generic drug development process is conducted in order to illustrate the efficient optimal solutions from the proposed model.
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