Pre-filled syringes have become a preferred format, as they make it easier to handle drugs and increase dosing accuracy. In addition, the ongoing biopharmaceutical boom has promoted the growth of the pre-filled syringe market. At the same time, other pre-sterilized packaging types are also on the rise, posing new challenges for pharmaceutical companies. Accordingly, machine manufacturers are working at fever pitch to offer new, more flexible solutions—and are presenting pioneering results.

In comparison to conventional packaging, pre-filled syringes not only offer ease of use and more precise dosing. Modern pre-filled syringes are also characterized by reduced product loss, which is a major advantage when it comes to expensive biopharmaceuticals. These highly individual products, used for instance to treat autoimmune disorders, can best be administered in liquid form using syringes.

Processing: a high degree of automation
As manufacturing becomes more and more automated, manual handling on the part of human operators, and subsequently the chief cause of particulate and bacterial contamination, can be reduced to a minimum. The fully automatic opening of sterile syringe packages has been a standard requirement for new filling lines for some time. Moreover, isolators are becoming increasingly common. They consistently separate the aseptic area from its surroundings. In-process controls are also an important factor in further improving the quality of the filling process. Currently the focus is on determining the filling weight, and on monitoring the presence of the stopper. In the future, there is likely to be more emphasis on additionally checking the quality of the packaging directly before filling. Is the silicone seal intact? Is the safety cap present and still in the correct position? If the answer is no, faulty syringes can be sorted out before the filling process, thus reducing product loss.

Highly automated filling machines with flexible handling units allow syringes to be precisely removed from the nest. As a result, individual syringes can be fed into an integrated inspection station. Further, methods are now available for checking the thickness and distribution of the silicone layer within the syringe. This ensures that the stopper can glide smoothly, which is particularly important for syringes used in auto-injectors. In this context, it is worth mentioning that more and more silicone-free systems are becoming available for plastic syringes. There have also been reports of silicone-free stoppers for glass syringes, which open the door for silicone-free glass systems.

Filling and closing: various methods
In connection with pre-filled syringes, the use of single-use filling systems is increasingly being discussed in the pharmaceutical industry. This approach does away with the need to clean and validate the components that come into contact with the product, which is especially cost-intensive for biotechnological products. In this regard peristaltic pumps are enjoying renewed popularity, since they never touch the material to be filled. This also considerably improves machine availability, as there is no need for time-intensive CIP/SIP (cleaning in place, sterilizing in place) processes.

Once the filling process has been completed, a vent tube is used to close the syringe with a stopper. Due to the biotech boom, coated stoppers are becoming increasingly common. Yet their coating makes them less suited for this method. Vacuum stopper insertion offers an alternative: a vacuum is created inside the syringe, sucking the stopper into place. Though this more complex approach compresses the stopper to a minor extent, it does not allow the stopper to be placed as precisely as with the vent tube insertion method. Depending on the respective requirements for precise stoppering and the desired residual air-bubble size, the output can also be affected.

New packaging types on the rise
There is no stopping the trend toward pre-filled syringes. Countless new projects are based on pre-sterilized syringes—and not just for small batches, but also for high-output lines. Yet other pre-sterilized packaging types are slowly but surely changing from niche products to appealing alternatives for pharmaceutical companies. Manufacturers of primary packaging made of glass—and in the meantime also plastic—are contributing to this change, for example by developing pre-sterilized, ready-to-fill vials and cartridges.

Here the main distinction is made between nest and tray systems: trays are especially intended for use with classic bulk filling machines. Nests can normally be used with machines for syringe processing including automated bag and tub opening, though some adjustments may be necessary, depending on the packaging geometry, material and structure. The broad range of resulting packing formats will confront machine manufacturers and pharmaceutical producers alike with major challenges. In this regard, initiatives like the standardization work done at the ISO would be desirable.

Still no standard method
Another aspect that is now being intensively discussed is the infeed of pre-sterilized packaging types. Though the e-beam has long been the standard solution for decontaminating tubs in high-output lines with isolators, it is generally considered too large for smaller lines. Alternatives currently being explored include tunnels or locks used in combination with plasma, UV light, nitrogen dioxide or hydrogen peroxide. However, none has established itself as standard yet. Aseptic transfer is possible with Restricted Access Barrier Systems (RABS) or with isolator applications, provided a suitable fully automatic bag opener is used, combined with spray disinfection of the bag. In this regard, double bagging for added safety is becoming more common.

The more packaging types can be filled and closed on a single machine, the more space-saving it is for users. This is possible thanks to new combi-machines for flexibly processing various types of primary packaging. By integrating both filling and capping station in a single unit, there is no need for a second machine. Further, the compatibility with various filling systems is a prerequisite for new filling and closing machines. In this regard, combi-filling stations, which can be easily reconfigured to accommodate diverse filling systems without taking up more space, have quickly proven their value. They allow pharmaceutical manufacturers to adapt filling processes to their respective medications and packaging types, while ensuring that all filling systems are in the sterile area.

Higher efficiency, more individualization
Given how costly biopharmaceutical drugs are, efficient filling methods are a priority. The key is to keep product loss to an absolute minimum, and the latest filling technologies deliver almost complete product yield. Here, the focus is above all on the start-up and emptying process steps. A statistical or 100-percent in-process control (IPC) during production ensures that all containers leave the machine with exactly the desired amount of liquid.

In light of the trend towards product individualization, customer-specific, flexible solutions are also taking on a new importance. Clinical studies in particular require the highest-possible flexibility in a very compact space, which can, for instance, be achieved by combining manual, partly and fully automated processes, together with different packaging types. In this case, the infeed can be either manual or semi-automated so as to accommodate the new variety of packaging types, especially with regard to the outer packaging. In turn, the filling is fully automated. To ensure that the individual work steps can be adapted to future types of packaging, the use of robots is advisable, for example for transporting packages from one station to the next. Adding a reserve station at some point in the future is also worth considering.

Complete line concepts
What pharmaceutical producers expect from their systems or lines can vary considerably, depending on their respective therapeutic area, region, or company size. Yet they all share a focus on ensuring the best-possible protection for the product and their machine operators. Accordingly, new filling and closing machines are as a rule characterized by a high degree of automation, and equipped with either RABS or isolators. When they are used with upstream automatic tub and bag openers, and in combination with downstream process steps like inspection, plunger-rod insertion and labeling, the result is a complete filling and closing line—and in the near future, not just for pre-filled syringes, but increasingly for other pre-sterilized containers, too. 

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Klaus Ullherr has a degree in electrical engineering. After working in the electrical industry as project manager for several years, he joined Bosch Packaging Technology’s Pharma Liquid product division in 2000. Since 2002 he is product manager for syringes and filling systems with global product responsibility. Klaus Ullherr is a member of the “PDA Interest Group pre-filled syringes” and works as an expert in the DIN/ISO group for primary packaging. He is a well-known speaker at conferences, specializing in solutions for fill/finish equipment for pre-filled syringes, as well as single-use filling systems.