The number of people suffering from diabetes globally is growing at an unprecedented rate. More and more countries are seeing an increase in those afflicted and in need of medication. Pharmaceutical manufacturers have been improving and developing a wide range of anti-diabetic drugs in recent years. Many of them are injectables and come in pen cartridges. Like any medical product, they require particular care during all process steps to rule out contamination or container defects. Advances in inspection technology help manufacturers keep pace.
According to the International Diabetes Federation, 540 million people worldwide are currently living with diabetes. More than 90% of them suffer from type 2. The latter is expected to rise sharply in the future, especially in rapidly growing economies such as India or China. The socio-economic changes taking place in these countries lead to a higher life expectancy, more sedentary activities, and a diet including more sugars – all risk factors for lifestyle-related diseases such as type 2 diabetes. Additionally, the improved access to healthcare leads to more cases being diagnosed.
Shift toward more preventive treatment
The strong rise of type 2 diabetes has prompted the medical community and pharmaceutical manufacturers alike to focus more on preventive treatments wherever possible. While type 1 diabetes always requires patients to inject insulin or biosimilars because their bodies cannot produce it, patients with type 2 diabetes typically still have the ability to produce some insulin. They may, however, have a deficiency, an insensitivity, or a resistance to it. These issues can be treated with a range of antidiabetic agents that target the release and processing of insulin in the body, such as biguanides, sulfonylureas, or incretin mimetics. While these types of medication have been on the market for some time, their popularity is now increasing rapidly.
The incretin mimetic semaglutide has gained popularity in recent years. The FDA approval of a high-dose injectable version in June 2021 (January 2022 in the European Union) that needs to be administered only once a week has boosted demand. Additionally, semaglutide-based drugs have also been approved as anti-obesity medication for long-term weight management in adults, as they lower appetite and slow down digestion in the stomach. By preventing or reducing obesity, incretin mimetics not only reduce comorbidities such as cardiovascular or kidney disease, they also limit a major risk factor for type 2 diabetes itself and thus work effectively as a preventive medication.
Product safety and quality come first
In the treatment of diabetes, pen systems that can be equipped with cartridges containing insulin or other medication have long surpassed all other injection systems, mainly due to their ease of use and relatively inexpensive production. The pens are loaded with cartridges – a glass cylinder that is closed on the top end by an aluminum cap with a puncture membrane and at the bottom end with a rubber stopper. The processing of a cartridge includes many steps: washing, siliconizing, sterilizing, filling and closing in the isolator, then inspection, and tray loading. The cartridge is exposed to different temperatures, pressures, and movements during these processes. Filling and closing machines with a capacity of up to 600 units per minute are considered state-of-the-art and are installed in the market in large numbers. The higher the speed, however, the more the cartridges, stoppers, and caps are subject to physical stress. This could result in cracks, chips, or fractures that lead to breakage on the way to the patient or during usage.
The product itself could also be contaminated. Intrinsic contamination can occur during the many steps of the filling and closing process and include packaging material particles or process-generated matter such as metal or glass. Extrinsic particulate matter, on the other hand, has its origin in the production environment and can consist of dust, fibers biotic contaminants, or even human hair or skin. Inherent particles, finally, are those originating from the formulated product itself. At all these points, inspection technology comes into play: it is a key quality safeguard for pharmaceuticals and contributes significantly to patient safety.
SD technology – the original particle inspection
One of the original automated inspection principles is the static division (SD) system, which was developed by Eisai Machinery, now part of Syntegon. It derives its name from the ability to differentiate static from moving objects. It transmits light through the solution, which is then focused onto a linear array of optical sensors. Before inspection, the container is rotated to put the liquid contents and any present particles in motion, and then suddenly stopped. The liquid and present particles continue moving by inertia for a definite time, during which signals from the SD sensor array are read out.
The moving foreign particles momentarily block a portion of the transmitted light casting a shadow over the sensors, which is detected as a time-dependent differential signal. These differential changes in light intensity can only be caused by moving particles, in contrast to any other possible static shadows arising from, for example, dust particles or imprints on the container surface. Since its introduction in 1975, SD technology has undergone various improvements and currently inspects most parenteral products in clear solutions in over 50 countries worldwide.
Camera-based systems for every angle
Camera systems can be an alternative or an add-on feature to SD inspection in specific cases. For example, some drugs are filled with a small air gap at the top of the cartridge. It is, however, crucial to prevent too much air inclusion as this would result in incorrect dosage or air bubbles in the shot during application. To this end, automated inspection machines such as the AIM series from Syntegon include cameras, which provide a side view of the stoppers. The cameras check how much the septum of the stopper bulges outward on each cartridge. Too much pressure, i.e., incorrect filling of the cartridge, results in a septum bulge exceeding the norm. If the cameras detect abnormal stopper measurements, they automatically transmit the result to the machine controls, and the cartridge in question is ejected.
Possible cracks from the side and from below are especially critical in cartridges. This section presents the plunger side interface to the injection pen in the subsequent manufacturing process. Cracks in this area can lead to cartridge breakage during pen application. The neck of the cartridge is especially prone to cracks. These are often difficult to detect since the air gap makes it hard for cameras to differentiate between measuring the filling level and detecting potential cracks. Automated camera systems using the latest CCD (charge-coupled device) and CMOS (complementary metal oxide semiconductor) sensor technologies in combination with specially designed optics and LED lighting can help here. Some inspection machines for cartridges are equipped with more than 30 cameras.
High voltage for CCIT
A recent trend in the inspection of insulin or antidiabetic drug cartridges is the additional use of Container Closure Integrity Testing (CCIT) with high-voltage leak detection (HVLD). More and more pharmaceutical manufacturers are starting to employ this additional method to stay ahead of increasingly strict quality requirements. HVLD technology utilizes the electric conductivity of parenteral products: the filled cartridges are placed between electrode probes that apply high AC voltages of up to 30 kV. While the glass container itself is non-conductive, the product inside is.
This means that intact and completely sealed cartridges yield only a small electric current signal. In contrast, conductive defect channels in the isolating barrier, even on the low end of the micrometer scale, cause increased signal. Thus, defective cartridges can be reliably identified and rejected before contaminants (or products) could potentially cross the container closure barrier. In addition to findings of visual inspections, such test results may alert manufacturers to problems in the fill/finish process – and allow them to react early.
Pressure from many fronts
The current high demand for state-of-the-art insulin and other antidiabetic drugs is expected to increase in the future. At the same time, the growing diversification of antidiabetic medication means manufacturers must be able to react to fast-changing market demands. However, neither the need for high output nor for flexibility should compromise product and patient safety. Antidiabetic drug manufacturers are facing pressure from multiple fronts, making the choice of inspection equipment all the more important.
Integrated platforms that combine multiple inspection processes offer the advantage of a smaller footprint. This makes them a good solution for pharmaceutical manufacturers seeking to optimize their use of production space while optimizing product quality even further. Alternatively, dedicated machines can be installed end-of-line. This option offers manufacturers the opportunity to enhance their inspection process without having to replace existing machines. In any case, machines will need to deliver high output, while also being able to reliably inspect both a variety of cartridge formats and product characteristics to compete in the antidiabetic drug market.
Syntegon is taking part at Achema Frankfurt, 10-14 June 2024, at stand C71 in hall 3.1 to present technologies and services.
