Making critical defects such as bent needles or punctured protective caps recognizable. This task is solved for the first time by the Heuft Syringer for the in-line inspection of pre-fillable syringes. Pulsed X-rays are used for this purpose already in the manufacturing process of the booming disposable injection instruments. They are made of glass, polymer or copolymer and are composed of several components: pre-fillable syringes are among the more complex pharmaceutical primary packaging materials. As needle-based ready-to-use injection instruments, they simplify the parenteral administration of drugs, vaccines, anticoagulants and biologics such as insulin. At the same time, they also make it safer: the use of such single-use syringes effectively helps to minimize the risk of wrong or overdoses and drug misuse. In many cases, the patients can administer the injection themselves without having to call in medical professionals.
Due to these and other advantages, pre-filled syringes are becoming increasingly important on the global pharmaceutical market. The coronavirus pandemic and the current run on so-called "slimming syringes" with the active ingredient semaglutide have driven this development forward and accelerated it even further, with analysts expecting the market to almost double in size by 2028, from USD 7.87 billion in global sales this year to USD 13.33 billion in five years - with an annual growth rate of over 11 per cent.
Accordingly, comprehensive verification of their quality, functionality, safety and integrity is becoming increasingly important. EU GMP Annex 1 "Manufacture of Sterile Medicinal Products", which came into force on August 25, 2023, thus now requires a 100 percent visual inspection for container closure integrity testing during the finishing process of pre-filled syringes: Immediately after filling and closing, each of them must therefore be checked using visual methods. However, we see a different situation during the assembly and packaging process at pre-fillable syringe manufacturers, where this is not yet required. Nevertheless, they are already doing everything technically possible to establish a powerful in-process control (IPC) that goes beyond a mere random check of packaging integrity. They are thus increasingly relying on the Heuft Syringer for the continuous inspection of all units produced. It is the only one of its kind to carry out a radiometric inspection instead of a visual inspection in order to visualise critical faults after the final assembly step before the syringes are placed in the nest, which can occur when the protective bonnets are fitted and remain hidden to the human eye in the same way as conventional camera technology.
We are talking about bent, deformed and crookedly positioned cannulas in the needle shield as well as about punctured soft or rigid needle shields (SNS / RNS), which threaten the sterility of the packaging and the microbial purity of its future contents. For the syringe manufacturer, the timely identification of these critical defects guarantees higher production quality. For pharmaceutical manufacturers, it offers effective protection against the costly waste of packaging and medicines: Affected single-use syringes are not only discovered and disposed of when the high-priced preparation is already contained, but are removed from circulation long before they are filled.
For the first time, cannula angle and needle shield puncture detection is made possible by using our patented pulsed X-ray technology developed and manufactured in-house, which was launched 20 years ago to make foreign objects such as glass splinters and critical defects visible in filled food and beverage containers. Continuously developed further, the special radiometric process has also been used in the pharmaceutical sector since 2015. Designed as a compact detection module for integration in linear throughput, the Heuft Syringer has already enriched the IPC of more than 30 production lines for the production and assembly of pre-fillable syringes worldwide with a new in-line inspection approach for previously unexamined quality and safety aspects.
Two X-ray images of each syringe are taken and calculated stereoscopically. This is done without contact and can be carried out in both continuous and intermitted motion. Even in high-speed lines, where a huge number of units are assembled and mounted in a short time, the X-ray inspection keeps pace and, in conjunction with full-field image converters, generates two high-resolution images that are denoised and specifically analyzed by our in-house developed hardware and software for real-time image processing based on artificial intelligence (AI) in order to identify different features of the pre-fillable syringes, their cannulas and protective caps as clearly as possible. Each of them acts as a reference so that the relative position of the injection needle in relation to the central axis of the syringe body as well as to the outer edges of the needle guard can be precisely determined for an accurate needle angle detection.
The pulsing ensures that the images are also as free of motion blurs: unlike conventional X-ray scanners, radiation is not emitted continuously during in-line inspection, but in each case only one X-ray flash with individually adjustable voltage, length and intensity, which lasts for a maximum of one millisecond and thus freezes the image. X-ray detection is only activated electrically at the brief moment when an injection instrument to be examined passes the inspection station. This means that up to 99 percent of the operating time there is no emission at all. The intensity of an average X-ray measurement with this patented pulsed technology is just 0.000015 Gray, almost 7,000 times below the limit value for mandatory marking of irradiated products in the pharmaceutical sector. Instead of the 10,000 permitted for this sector, the radiation energy of such an X-ray pulse is only 70 kilo-electron volts. At ten microsieverts each, its radiation dose is 30 times lower than the amount of natural radioactivity that each human person absorbs every day through food alone.
Accordingly, more complex radiation protection measures and devices are not required; the few necessary shielding tasks can be achieved with the use of simple constructive means. This facilitates direct integration of the Heuft Syringer in the tightest of spaces, making it easy to retrofit into existing machines and lines. In applications where, for example, a clear view of the inspection area is one of the requirements, the use of standard leaded glass components is completely sufficient. Thanks to its own type approval by the Federal Institute of Physics and Technology (Physikalisch-Technische Bundesanstalt), which has been published by the Federal Office for Radiation Protection (Bundesamt für Strahlenschutz), no particular approval procedures are required in Germany to install the detection unit. At the same time, numerous regulations to be observed in daily operation are no longer required. Only a qualified radiation protection officer needs to be appointed. The safely enclosed X-ray module is also suitable for use in hygienically sensitive laminar flow areas.
Bent needles, incorrectly fitted or damaged Luer lock screw adapters and tamper-evident closures and, above all, punctured SNS and RNS are made visible for the first time during the production process of pre-fillable syringes. This even applies to needle shields that are only tapped but not completely pierced and can cause so-called micro-hooks on the needle. These are tiny deformations of the cannula tip that can make an injection impossible or unnecessarily painful.
However, X-ray detection occasionally reaches its limits when the contours of certain types of needle shields are not always sufficiently pronounced in the X-ray image to be used as a reference for the exact measurement of the respective cannula angle, leaving only the syringe body. However, our developers are already working on a new solution to further increase the reliability of detection and precision of cannula angle determination in such rare cases. Conversely, the slim module is capable of completely replacing optical detection units, for example for a simple presence check of the needle shield: Pre-fillable syringes in which this is completely missing are detected by the pulsed X-ray technology in any case, so that manufacturers are increasingly dispensing with additional optical checking equipment. Conventional and completely new categories of critical faults and defects are detected with the Heuft Syringer, which is available in four different housing variants for safe integration in different applications and environmental conditions. As an alternative to direct integration into pre-fillable syringe processing machines, it is also available as a stand-alone unit. In detail, it consists of a housing in which the X-ray generators as well as the associated electronics and pneumatics are accommodated, a control cabinet with the above-mentioned full-field image converters and a network-compatible control unit with a human-machine interface and audiovisual user guidance.
With tamper-proof, personalized access rights, a complete audit trail log and batch balancing including counter statistics, the latter meets the FDA requirements of 21 CFR Part 11. In-house programmed software ensures the seamless recording, network-based transmission and long-term archiving of operating and batch data, test logs and detection images. Basic documentation and validation obligations in accordance with GMP and GAMP5 are thus reliably fulfilled. Integration projects are always qualified and implemented using the V-model in accordance with GAMP5. GMP compliant validation then takes place during the overall acceptance of the pre-fillable syringe assembly line.
As a fundamental component of quality management, the X-ray module not only enriches the IPC with completely new inspection approaches and detection options, but also Good Manufacturing Practices for the production of pre-fillable syringes as a whole: instead of random checks of a few, a 100 percent X-ray inspection of every single one of them takes place, making the previously invisible visible and thus contributing to the required patient safety and at the same time preventing unnecessary waste of packaging and medicines.
