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A best practices approach to pharma’s most challenging-to-inspect container.
Syringes are arguably the most difficult containers to inspect. Among other obstacles, syringes require unique handling protocols, and their far-ranging shapes and sizes require customized, multi-area inspection that present impediments both to per-item accuracy and overall production speeds. This article explores the various parameters that define syringe inspection and discusses best practices for inspecting syringes with different closure types, as well as syringes holding a variety of drugs, including vaccines and viscous drugs.
While other containers such as vials, cartridges, and ampoules largely “stand still” and can therefore enter the inspection process independently, syringes typically are carried via conveyor and then turned upside-down. To inspect syringes accurately and efficiently, they usually must be rotated with the head pointed upward (i.e., inverted), so that any hidden particles in the funnel can sink down into the liquid for increased inspection detectability. If the syringes are sterilized, the containers are typically in a “nest & tub” arrangement, which requires they be denested by a robotic unit communicating with the inspection machine. This intricate process requires gentle handling and should avoid glass-to-glass contact to mitigate the likelihood of cracks or breakage.
Once in the inspection carousel, the syringes are inverted for inspection. The syringes can be handled by holding them on the upper and lower part using mandrels with customized cups, or below the plunger by a two-finger adaptive gripper. The method of holding syringes by both upper and lower portions allows higher rotation speeds. Syringes with needle shields can be held in this manner, and rigid needle shield formats can be held if the shield has a smaller diameter than the syringe body. Unfortunately, this handling system is not compatible with all closure systems. Gripper systems typically operate at slower speeds, but are well suited for more delicate closure systems such as luer-lock cone. Grippers don’t touch the closure mechanism and therefore present a lower risk of affecting the closure integrity.
As noted, syringes’ inherent multi-component nature makes them complicated to inspect. One of the more challenging parts is the flange because they are typically not exactly flat. This factor frequently foments deceptive shadows and reflections, both of which make it more difficult for inspection stations to determine whether the glass is scratched or otherwise damaged. The solution typically lies in employing appropriate optical and illumination setups to minimize false rejects, in conjuction with more advanced image processing functions.
Another multi-faceted component, the plunger, is an inspection pain point for similar reasons. In fact, plungers can be so tricky that it is often necessary to employ a dual control system to avoid a high level of false rejects. A dual-view optics approach allows for analysis of two spatially coherent views in one image, without the need for duplicate inspection stations. Angled views tasked with inspecting plunger tops are combined with a frontal view monitoring the plunger top’s lateral section. In general, this strategy of combining two complementary views leads to improved inspection performance and lower false rejects. In Figure 1, the region of interest (outlined in green) is shown in a frontal view (right) and an angled top view (left). If an element is detected as an air bubble in one view but not the other, as shown in this figure, it does not need to be rejected.
The comparably small diameters of syringes also present an inspection headache because of the limited space in which particles can move and therefore be noticed. To inspect an injectable drug, the particles in the formulation might be made to move—a process that requires the syringes to be rotated at speeds up to 9000 RPM. Single rotation units on the carousel mandrels meet this need and ensure flexibility in rotating a variety of drugs at speeds best suited to their individual inspection.
Here, though, another issue emerges: while high-speed rotation is sufficient for liquid drugs, what if the container can’t be rotated at high speeds for stability reasons? For example, subjecting many biopharmaceutical drugs to such turbulence could impact their integrity. Furthermore, with highly viscous drugs, particles generally don’t move and therefore cannot be distinguished via this common tactic. In these scenarios, the answer often lies in three-dimensional inspection, which allows a module to infer whether a suspected contaminant is inside or outside the container by analyzing its trajectory; specifically, the radius will be shorter if the foreign matter is inside and longer if it is outside.
Another technique when inspecting syringes is using line-scan cameras. A method especially effective when inspecting turbid liquids, line-scan cameras continuously capture images line by line, then stitch together a comprehensive image from upwards of 10,000 exposures. By rotating the container at high speeds, the particles move toward the container barrel. Line scans are fast and accurate, resulting in a nearly 100% rate of particle detection with very few false rejects (1). Such setups are ideal for inspecting cylindrical surfaces, especially when it comes to cosmetic lateral side inspection, as there are no distortions.
Proper lighting conditions are a prerequisite for identifying anomalies within liquid drugs since, due to a lack of contrast, their identification under natural lighting conditions is infeasible via the human eye or current automatic visual inspection technologies. Light intensity should be sufficient for illuminating the container while providing a moving contrast to identify the smallest particles. Reliable detection must combine the advantages of various lighting methods to detect the widest range of contaminants, as different contaminants react to light in different ways. Figure 2 illustrates using back and lateral lighting to detect both light-absorbing particles and light-reflecting particles.
Some formulations are more challenging to inspect than others. For example, in water-like liquids or light suspensions, dynamic trajectory analysis increases detection probabilities, since particles behave in a statistically measurable way. When drugs present as heavier suspensions, however, other strategies are needed.
For example, a vaccine, presenting as a heavy suspension in a syringe, could not be mixed up completely.While particles that stick to the syringe’s inner wall are inspected, noise in the image related to the spin made it difficult to detect small particulates in the liquid portion. It was also difficult to differentiate clear particles (e.g., white fiber and glass). To solve for this, particle inspection was performed using continuousrotation. Each position in the carousel had an individual servo rotation unit with a specific rotation schedule.The position of some particles were correlated and found to be different relative to their location at the first station. From this position change, it was concluded that these were moving particles.
With gels or highly viscous products such as hyaluronic acid, inspection processes can't rely on spinning the liquid to provide particle motion differentiation. In this case, the container is kept in rotation to cover the full 360° facade and track all visible potential contaminants, as portrayed in the red trajectories in Figure 3. The potential contaminants' apparent speed is used to determine if they are inside or outside the container. They move on "different radiuses" at the same angular rate covering different displacements.
With these drugs, a proper lighting scheme becomes particularly important because certain contaminants, such as white fibers, are more easily visible against a dark background. Similarly, many cosmetic defects, such as thin scratches, are also easier to find against a dark backdrop.
Biopharmaceutical drugs, such as monoclonal antibodies, can be more difficult to inspect than other liquids because of their increased density, higher turbidity, and the greater need to protect product integrity, which limits the available inspection methods. The trend toward higher protein concentration and the resulting higher viscosities creates another challenge for inspection, because “spin and stop” inspection technology becomes ineffective for particle detection above viscosities of 4–5 centipoise.
Turbidity also increases in parallel with protein concentration, which makes discerning acceptable particles from unacceptable ones a real challenge. Process-related impurities are not necessarily harmful if they fall within the compendial guidelines for size and count. But when inspected with current automatic vision inspection systems, high rejection rates can occur due to the elevated difficulty in sizing and counting particles with precision. For this reason, manual inspection of biotech products has been the norm. A more efficient approach would be an automated inspection system that can both identify, size, and count each particle within a container and use historical particle data in clinical lots to make a patient safety-basedassessment to determine whether it warrants rejection.
Protein instability and the generation of agglomerates can be minimized by eliminating mechanical shock during handling. The main driver for protein aggregation is the cavitation effect induced in the liquid that increases the agitation at the air-liquid interface and increases the liquid's local temperature and pressure. Inspection equipment must have smooth product handling while considering overall throughput.
A secondary driver for protein instability is the shear force exerted in the liquid by high-speed spinning, notably when acceleration and deceleration cause the transition from laminar to turbulent flow, destabilizing the meniscus and generating bubbles in the liquid. To reduce the applied shear force, it is advisable to incorporate a cross-correlation inspection system between particle stations, which allows for sequence comparisons that can determine whether or not a particle is inside or outside the syringe. With this method, the container is kept in rotation at a steady speed, and the liquid slowly accelerates to segregate bubbles on the top and bottom in a controlled manner while particles are located at different heights and can be detected during inspection.
Syringe inspection continues to be among the most challenging facets of the post-production pharma quality control process. In a scenario where both containers and their ingredients must be thoroughly inspected, both syringes and the varying drugs they deliver pose unique pain points concerning handling, visual detection, and minimizing false rejects. A best-practices approach to syringe inspection means careful consideration of both the type of syringe and the type of ingredient it houses, and the optimal use of lighting, rotation speed, and inspection technologies and methods.
1. Stevanto Group, “Automatic Visual Inspection of Difficult-to-Inspect Lyophilized And Opaque Products on a Combi Machine,” Presentation at PDA Visual Inspection Forum (October 2020).
Andrea Sardella, PhD, is pharma inspection product development manager for Stevanato Group, email@example.com.
Vol. 34, No. 5
When referring to this article, please cite it as A. Sardella, “The Ins and Outs of Syringe Inspection,” BioPharm International 34 (5) 2021.