Reported by: Klaus Ullherr, Product Manager (PA-PH/BUD13), Robert Bosch GmbH & Fahad Hussain, Editor, Pharma Mirror. Special thanks to Dr. Bernd Sennhenn, Abbott GmbH & Co. KG, for his constant support and the interesting discussions that lead to this article.
According to various reports by VisionGain, Frost and Sullivan, the WHO, and others, the worldwide market for prefilled syringes has been growing for two decades. Prefilled syringes introduced convenience for and accuracy to self-administered drugs. They are easy to handle and always ready to be used. The emergence of biotechnology is another main driver for the development of a market that achieves double-digit growth rates. For equipment manufacturers this development has implications for the future of processing syringes, in particular for the filling and closure process.
Bosch packaging Pre-filled syringes
Prefilled syringes have developed from a niche product to a primary container of choice. The advantages prefilled syringes have over traditional packaging not only include ease of use. Modern prefilled syringes reduce the need for vial over-filling. With the advent of biotech drugs with high development costs, this is advantageous as it means less waste and moreover helps eliminating the dangerous risk of dosing errors.
Whatever the speed, equipment manufacturers need to keep up with the development of the pharmaceutical market environment. Bosch has always sought to push the limits further and set new standards with its development of peristaltic pumps, vacuum filling and stoppering systems, and the successful FXS line for the processing of presterilized syringes in nests. The company began serving the syringe market over 20 years ago and today is one of the world’s leaders in sterile filling of ampoules, vials, cartridges and syringes. There are several trends with mid- and long-term influence on processing prefilled syringes we will further explore in this article.
Trends that influence pre-filled syringe processing
Production of prefilled syringes is a multi-step process ranging from manufacturing, siliconising and sterilizing syringes as well as relevant plastic components to filling and closure processes, and so-called medical devices. Quality assurance and qualification are always key prerequisite to support risk minimization.
A major trend is the ongoing boom for biotechnology. Biotechnologically-derived drugs can help accomplish results in the human body that have been inapproachable for common therapies. In this market segment, highly individual products of high quality and value are produced in small batches.
In general, biotechnological and chemical drugs are best supplied in liquid form filled in syringes. As a result, syringes themselves are a booming market. And although it is often required, freeze drying to improve shelf life is being perceived as the second-best solution due to its more elaborate process.
The extent of automation in production will continue to increase, at least in highly industrialized countries, as this clearly helps leveraging product quality. And because of their potential to minimize manual interventions, which are the main cause for particles and germ cell entry, automatic solutions are intensely sought after. For example the fully automatic opening of sterile syringe packaging has long been a standard requirement for new filling lines.
In-process-control plays an important role for further improving the quality of prefilled syringes by helping to prevent syringes not in line with specifications from being finally packaged. Modern filling equipment therefore should at least open up the possibility to improve quality by providing in-process-control. This applies not only to filling weight but also to other variables such as closure elements and siliconisation. Regulatory requirements for the use of Process Analytical Technology (PAT) are expected to be expanded.
The primary packaging market is a dynamically developing market that requires answers to this challenge. Established manufacturers increase their production capacities, while new manufacturers enter the market. Moreover, the number of diversifications and customer-specific solutions will increase. We find the following mid- and long-term scenarios to be realistic.
Possible future developments in processing
Standardization of plastic packaging: All syringes should be able to be processed on all machines. Hence, the most important parameters should be equal independent of the manufacturer. These parameters include materials, dimensions, and features such as the connection of tub and stretch sheet.
Optimized silicon distribution: From a PAT point of view, examination of silicon distribution should take place before filling – even more so as highly automated filling machines with flexible handling units are already able to pick predefined syringes from a nest. Thus, single syringes could be fed into a line integrated control station easily. Formerly, syringes have only been checked as to whether they were siliconised at all. Today there are methods to examine the thickness and distribution of the silicon layer inside the syringe, as stoppering should fulfill its sliding function in autoinjection devices with minimal silicon entry. However, these methods are in a relatively early stage of development, and more data must be collected. In the long run, new coatings could become serious alternatives with the use of plasma technology being one example.
The perspective of an equipment manufacturer
Prefilled syringes are of special interest for equipment manufacturers in the sense that the final product is ready for medical use without any intermediate steps. As primary packaging, prefilled syringes are closer to the patient than ampoules or vials are.
Fully automatic bag and tub opening are trending in industrialized countries, and beyond. Due to intensive competition the speed of development for new solutions is very high. Different solutions have been established in the market in a short period of time.
Semi-automatic processes are partly being accepted for bag opening. This does not apply to the introduction of tubs into the sterile room, in particular for zone crossing from clean room C to A. A main driver for the discussion is the electron beam sterilization tunnel for the surface decontamination of tubs. The solution is almost a standard on high performance production lines with isolators. Then why is e-beam not being used on restricted access barrier system (RABS) lines? This basic question initiates the discussion of several issues: Where exactly is the border between zones C-A? When and where should the bag be opened? The more precise these questions can be technically answered, the more e-beam will face challenges to be successful apart from or even with the isolator.
Conclusion
Overall, the trend towards prefilled syringes is irreversible. Biotechnology will determine the development of this packaging in the future. For equipment manufacturers this implies the development of individual solutions for individual product features. It also requires a better process understanding on the basis of PAT which means better quality and higher yield. Most of the drugs are very expensive and are often being used in medical devices (auto injectors). Disposable filling systems will increasingly be used. Given the success of pre-sterilized syringes, the industry might also start thinking about pre-sterilized vials and cylindrical ampoules. A possible niche product today – but still tomorrow? Keep in mind that nested syringes have also once started as an “exotic product”.
