By Tim Sandle, Ph.D.
The presentation of pharmaceutical preparations in the form of prefilled syringes continues to grow. The addition of drugs in prefilled insertable and disposable cartridges is driven by manufacturing economics (including the avoidance of overfill, common with dispensing into vials, which saves on product yield); clinical preference, including better accuracy of dose delivery and avoiding the cross-contamination that can occur with a separate syringe and vial;1 and an expansion of medications that can be self-administered by the patient in the home. The syringe plays a dual role in the prefilled syringe product — as a container closure system and as a delivery device.
Prefilled syringes vary in terms of their method of manufacture, method of filling syringes with a drug product, and the types of syringes available.2 Several variations are required due to product incompatibility in particular drug combinations and material types.3 Products in prefilled syringes must be chemically, physically, and biologically stable and, based on the route of administration, the combination product must be sterile and apyrogenic. Product manufacturing requirements are set out in the ISO 11040 standard, such as Part 8, which presents the “Requirements and test methods for finished prefilled syringes.”4 One important aspect of assessing prefilled syringes relates to the integrity of the filled syringe. The process of assessing integrity is generally more complex than the process of assessing glass vials due to the presence of more sealing areas. This article looks at the broad requirement, together with a recent innovation for integrity testing based on X-rays.
The syringes provided for filling need to be sterile and, once filled, products are subject to terminal sterilization, such as by ethylene oxide, radiation, or moist heat (where the medicine is not rendered inefficacious by the sterilization method)5 or presented as an aseptically filled product.
Assessment Of Empty And Filled Syringes
Testing empty syringes prior to filling generally relates to physical tests, such as flange break resistance and needle penetration. The FDA and EMA have an additional requirement that the syringe unit is sterile for sterile medicines. The significance of sterility extends to the release of the syringe, which requires a review of the sterility assurance of the batch. Included within the sterility assurance framework is the sterility test, for which a specialized adapter is required to enable the sequential testing of syringe contents and needle surfaces using compendial membrane filtration sterility test methodology.6 Sterility testing typically forms part of the end-product release test and as an end-of-shelf-life test for those batches selected for stability trials.
Container Closure Integrity
For both aseptically produced and terminally sterilized syringes, a critical factor is the integrity of the syringe once it has been filled. This is assessed through qualification testing, designed to assess the suitability of container closure systems to maintain a sterile barrier against potential contaminants. Replicating environmental factors is important, such as the temperature, humidity, vibration, and pressure to which the combination product will be subjected when stored and distributed. For reasons of transportation, do not fill syringes to their full extent, to help minimize the potential for leakage due to excessive sideways pressure applied the plunger during storage.
The most common method to assess integrity is the deterministic dye ingress method (where a 1 g/L solution of methylene blue is used as the dye), although there are alternative methods such as probabilistic microbial ingress (using the bacterium Brevundimonas diminuta) as well as high-voltage leak detection and vacuum/pressure decay testing and emergent methods such as X-ray imaging analysis. As well as these methods to demonstrate integrity (and hence the maintenance of sterility), vibrational effects can also lead to particulate generation. Aside from the selection of the method, arguably the most important factor is ensuring a statistically representative number of samples is used so that any common cause defects can be assessed. The assessment of strength and integrity must also apply to the outer packaging to assess the suitability of the packaging seal.
Traditionally, professionals in our industry deploy a combination of a microbial and physical test, although the direct microbial test has fallen out of favor in recent years. The microbial test involves either a whole or partial immersion method, with whole immersion preferred when it is necessary to test the integrity of both the syringe hub and the plunger. The physical dye intrusion test is a simple and rapid test to evaluate batch to batch syringe performance, enabling a greater number of syringes to be tested.
X-ray Imaging Analysis
X-ray imaging analysis enables a large number of syringes to be processed, and it potentially offers a faster and more accurate result than either the direct microbial test or other physical tests. With speed, we can process hundreds of syringes per hour using this technology, placing it ahead of most other methods. The test is also nondestructive, which confers a further advantage.
The method originated with tableting, where a tablet microstructure is examined to assess the proportion of the crystal particles.8 The technology involves using a low energy X-ray source, with image recognition and processing technology. The application of low energy means that the contents of the syringe are not subjected to any significant rise in temperature. Radiation is produced with a focal range, and it is the focus diameter that defines the spatial resolution. This manifests as a series of X-ray pulses. The technology can be used to identify syringes with bent needles and needles that puncture the caps.9
An X-ray based system is also capable of detecting functional defects such as syringes with poor needle alignment. As technology advances, artificial intelligence trained against image recognition will be able to aid in the interpretation of the X-ray images (radiographs), including processing images of fracture planes.
Professionals in the pharmaceutical and medical device industries could use this technique not only for analysis of defects and failures but also to characterize geometries and morphologies during the process and package development stage. Moreover, as well as providing a method for the assessment of integrity, professionals in our industry are applying energy dispersive X-ray spectroscopy to troubleshoot foreign matters in pharmaceutical drug products.
Integrity testing of prefilled syringes is an important part of the sterility assurance system, especially to demonstrate that integrity is maintained as part of transportation. Various technologies are available, and X-ray microtomographic imaging is an emerging method that has the advantage of being a nondestructive technique for quantifying the risk of syringe integrity across three dimensions. While the method remains in its infancy, it has the potential to speed up the time and accuracy of prefilled syringe medicinal release.
- Van Grafhorst JP, Foudraine NA, Nooteboom F, Crombach WHJ, Oldenhof NJJ, Van Doorne H. Unexpected high risk of contamination with staphylococci species attributable to standard preparation of syringes for continuous intravenous drug administration in a simulation model in intensive care units. Crit Care Med 2002;30:833–6
- Sacha, G., J. Rogers, A., Miller, R. (2015) Pre-filled syringes: a review of the history, manufacturing and challenges, Pharmaceutical Development and Technology, 20:1, 1-11, DOI: 10.3109/10837450.2014.982825
- Eakins M. The design and construction of pre-filled syringes. Am Pharm Review. 2007;10(6):47–51
- ISO 11040-8:2016 Prefilled syringes — Part 8: Requirements and test methods for finished prefilled syringes, International Standards Organization, Geneva, Switzerland
- ISO 11607-1:2019 Packaging for terminally sterilized medical devices — Part 1: Requirements for materials, sterile barrier systems and packaging systems, International Standards Organization, Geneva, Switzerland
- Challener, C. Test Methods and Quality Control for Prefilled Syringes, Pharmaceutical Technology Biologics and Sterile Drug Manufacturing eBook (May 2019).
- Parenteral Drug Association P. PDA Technical Report No. 27 (TR 27) Pharmaceutical Package Integrity. 1998
- Turner, T., Gajjar, P., Fragkopoulos, I. et al Measuring the Particle Packing of l-Glutamic Acid Crystals through X-ray Computed Tomography for Understanding Powder Flow and Consolidation Behavior, Crystal Growth & Design 2020 20 (7), 4252-4263
- Hindelang, F., Zurbach, R., Roggo, Y. Micro Computer Tomography for medical device and pharmaceutical packaging analysis, Journal of Pharmaceutical and Biomedical Analysis, 108: 38-48, 2015
About The Author:
Tim Sandle, Ph.D., is a pharmaceutical professional with wide experience in microbiology and quality assurance. He is the author of more than 30 books relating to pharmaceuticals, healthcare, and life sciences, as well as over 170 peer-reviewed papers and some 500 technical articles. Sandle has presented at over 200 events and he currently works at Bio Products Laboratory Ltd. (BPL), and he is a visiting professor at the University of Manchester and University College London, as well as a consultant to the pharmaceutical industry. Visit his microbiology website at https://www.pharmamicroresources.com.