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Shifts in pharmaceutical packaging have spurred tremendous growth in the pre-filled syringe fill/finish industry.
The pre-filled syringe industry is rapidly expanding, with a projected compound annual growth rate (CAGR) of 13.9% between 2021 and 2028 (1). Fill/finish is an intricate process requiring many steps in its procedure, from filling and stoppering to labeling and secondary packaging. Often, this intricate process is automated and includes various inspection methods. Commonly, container closure integrity (CCI) testing is left out of the automated process and is either conducted manually with outdated, probabilistic methods or not conducted at all, increasing risk of error.
In any manufacturing process, there is risk. Equipment issues and human error are unavoidable at times. In pharmaceutical production, this error equates to potential safety issues for the patient. Quantitative and deterministic CCI test methods aim to find these errors before reaching the patient, and further mitigate risks to patient safety.
Breaches in sterility come with many different defect profiles. Commonly, crack defects appear near the neck or heel of vials from impact or excessive crimping. Prefilled syringe defects form where the needle is fused to the glass or cracks in the barrel. Sterility breaches occur in the stopper/plunger area when molded poorly, or debris, such as a fiber, is present. These defects may allow bacteria and microbial ingress into the product, voiding sterility and increasing patient risk.
Biologics are typically high risk, costly, and created in small batches. Along with being parenteral-based products, biologics’ sensitive nature requires CCI to avoid recalls, product loss, and life-threatening patient risk.
Proper CCI testing of biologics must be non-destructive, quantitative, deterministic, scalable, and capable of detecting defects per manufacturer risk assessment. Adhering to these requirements leaves few CCI testing methods. Vacuum decay and MicroCurrent high voltage leak detection (HVLD) are not only the most popular CCI methods, but two of the most effective scalable technologies.
Best utilized when testing small-molecule products, vacuum decay has cemented itself as a go-to method for CCI. Vacuum decay as a CCI testing method is recognized by ASTM F2338, USP 1207, and is an FDA consensus standard (2). Utilizing a vacuum source, a vacuum is applied to a test chamber. Vacuum is then held within the test chamber for a period of time during the equalization stage, and then moves into a test stage where the loss of vacuum is measured by a transducer. Vacuum decay is not only suitable for lyophilized products with large amounts of headspace, but beneficial for liquid leaks as well. The difference in headspace versus liquid leaks is the amount of vacuum required to conduct the test, as well as the physical attributes of the product inside the package system. Headspace leaks are typically tested at 500mbar of vacuum. This allows measurement of the gas inside the package without evacuating the entirety of the volume during the evacuation stage. Liquid leak detection is conducted at high vacuum, less than 5mbar, where the goal is to vaporize liquid and measure the change in gas pressure.
Although suitable with a large quantity of applications and product types, vacuum decay struggles to detect microleaks in packages containing large-molecule solutions. The issues with vacuum decay are not left unsolved with HVLD standing at the forefront of CCI methods for large-molecule products.
MicroCurrent HVLD utilizes a high voltage and detection probe to scan the glass or polymer parenteral for potential breaches in sterility. The parenteral acting as a capacitor is rapidly spun, allowing the liquid product to coat the inside walls of the parenteral. Defects in the parenteral cause a large spike in voltage as liquid is detected. Unlike traditional HVLD, MicroCurrent HVLD utilizes less than 50% voltage and produces nearly no ozone. These innovations combined with extremely low current electricity prevent the breakdown of biologic products. Given that defects are detected through a liquid path, large-molecule and viscous products are able to be tested.
Both previously mentioned test methods can be used as benchtop technologies or can be fully automated into production lines. Although scalable, deterministic, quantitative, and non-destructive, they each have their limitations. MicroCurrent HVLD requires the parenteral to be cylindrical, glass or plastic, and have a minimum of a 30% liquid fill. Vacuum decay is typically only suitable for small-molecule products and may have longer testing times than HVLD. Both of these technologies are capable of testing a variety of products despite their limitations which accents their scalable nature.
These scalable technologies can be semi- or fully-automated for statistical analysis or 100% inspection of pre-filled syringes or other parenterals. When conducting CCI testing, scalability is a necessity. In-depth analysis and laboratory-based testing should match inline testing. Using the same validation ensures automated systems are working in a robust, repeatable, and reliable manner. Scalability can be broken down into three main
categories: laboratory, semi-automated/automated statistical sampling, and 100% inline testing. The difference between these three methods of scalability is the frequency of testing. High-testing frequency ultimately reduces risk of not only recall, but potential patient harm.
The European Union’s Annex 1’s 2022 revision aims to increase testing frequency for products with high defect rates (3). The revision specifies all fusion sealed, small-volume parenterals must be subjected to 100% CCI testing with a deterministic method. The regulatory agency notes that visual inspection is not an approved deterministic inspection method. This new guidance has driven the need for automated and semi-automated inspection during times of high labor costs and labor shortages.
Automated systems host a multitude of benefits, but greatest of all is their ability to increase testing frequency and limit human interaction. Limiting human interaction assists in mitigating human error. As the technology advances, risk decreases, providing a higher quality product and a safer pharmaceutical industry. The industry cannot exceed its current state without keeping the science of quality in mind.
TMR. Prefilled Syringes Market–Global Industry Analysis, Size, Share, Growth, Trends, and Forecast, 2021-2028. 2022.
ASTM. Standard Test Method for Nondestructive Detection of Leaks in Packages by Vacuum Decay Method. Dec. 2, 2020.
European Commission. EU GMP Annex 1 : Manufacture of Sterile Medicinal Products. 2022.
Tyler Harris is an applications engineer at PTI.
Vol. 36, No. 3
When referring to this article, please cite it as T. Harris. Automated Inspection of Pre-filled Syringes and Biologics During Fill/Finish. BioPharm International 36 (3) 2023.