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Pharmaceutical Manufacturing and Packing Sourcer

The Future of Processing


According to various reports by VisionGain, Frost and Sullivan, the World Health Organization, and others, the worldwide market for prefi lled syringes has been growing for two decades, and increasingly encompasses biotechnology products. For equipment manufacturers, this development has implications for the future of processing syringes, in particular for the filling and closure process.

Prefilled syringes have developed from a niche product to the primary container of choice. The advantages these syringes have over traditional packaging not only includes ease of use, but also the fact that modern prefi lled 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 eliminate the dangerous risk of dosing errors.

Whatever the speed, equipment manufacturers need to keep up with the development of the pharmaceutical market environment. They should always seek to push the limits further and set new standards. There are several trends with mid- and long-term infl uence on the processing of prefi lled syringes, which will be further explored in this article.

Trends that Influence Prefilled Syringe Processing

Production of prefilled syringes is a multi-step process ranging from manufacturing, siliconising and sterilising syringes – as well as their relevant plastic components – to fi lling and closure processes, and so-called medical devices. Quality assurance and qualifi cation are always key prerequisites to support risk minimisation.

A major trend is the ongoing boom in biotechnology. Biotechnologicallyderived drugs can accomplish results in the human body that have been unachievable 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 perceived as a second-rate solution due to its more complex process.

The extent of automation in production will continue to increase, at least in industrialised countries, as this clearly benefits product quality. And because of their potential to minimise manual interventions, which are the main cause for particles and germ cell entry, automatic solutions are highly 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 in 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 of improving 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.

Primary packaging 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 diversifi cations and customer-specifi c solutions will increase. We find the following midand long-term scenarios to be realistic.

Possible Future Developments in Processing

Standardisation of Plastic Packaging

All syringes should be able to be processed on all machines. Hence, the most important parameters should be equally independent of the manufacturer. These parameters include materials, dimensions, and features such as the connection of tub and stretch sheet.

Optimised 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 fulfil 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 fi nal product is ready for medical use without any intermediate steps. As primary packaging, prefi lled syringes are closer to the patient than ampoules or vials are.

Fully automatic bag and tub opening are trending in industrialised 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.

For bag opening, semi-automatic processes are still accepted. This does not apply to the introduction of tubs into the sterile room, in particular for zone crossing from cleanroom C to A. A main driver for the discussion is the electron beam sterilisation 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 brings several issues to the table. Where exactly is the border between zones C and A? When and where should the bag be opened? The more precisely these questions can be answered from a technical perspective, the more the e-beam will face challenges to be successful apart from or even with the isolator.

Filling Process: Rising Requests for Single-Use

Single-use filling systems are an important element for filling syringes. Biotechnology is a significant driver for this trend as well. Cleaning and validating parts of the product in processing biotechnological products is so expensive and time-consuming that the introduction of single-use systems makes sense. In this context, peristaltic pumps are becoming interesting again. Because peristaltic pumps do not have contact with the product that is to be filled, only the tube has to be switched. Moreover, the pharmaceutical industry often uses peristaltic pumps during drug development. Filling volumes typically vary between 50 microlitres and three millilitres.

Testing before Filling

How can the syringe be tested before it is filled with an expensive drug? Possible check parameters could be the completeness of the nest, the existence of tip closures and the identification of bent needles. In order to check syringes prior to filling, camera systems can be used; but although control systems on filling equipment have long been called for, companies tend to disclaim their use for technical and business reasons. Reasons given for this include cost and excessive impact on the laminar flow. Yet compared to the other trends discussed in this article, these systems are the most likely to be implemented.

Different Closure Methods

After filling is complete, vented placement is the usual stoppering technique used. A stopper is placed inside a tube that is then inserted into the syringe. As the tube is removed from the syringe, a pin holds the stopper in place.

Driven by the biotech boom, more stoppers that incorporate coating will be used. They are often too sensitive for vented placement. An alternative stoppering technique is vacuum placement. A vacuum is pulled in each syringe, and the vacuum draws the stopper into the syringe. Vacuum placement does not compress stoppers as much as vented placement does. However, vacuum placement contains more variables and places stoppers less precisely. Furthermore, the method requires more time and decreases the syringe-filler line speed.

Indeed, the market has already decided that fewer new projects are being launched for bulk. Presterilised syringes are prevailing. Yet some production lines still have a very high output, whereas presterilised syringes are designed for much smaller batches and disposal issues have a low ranking. Maybe in this particular field the development will change but there is no evidence yet.

Conclusion

Overall, the trend towards prefilled syringesis irreversible. Biotechnology will continue to determine the development of this packaging in the future, and 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 in turn leads to better quality and higher yield. Most of the drugs in this field are very expensive and are often used in medical devices (auto-injectors). Disposable filling systems will be used more extensively. Given the success of pre-sterilised syringes, the industry might also start thinking about pre-sterilised vials and cylindrical ampoules – niche products today perhaps, but still ones to watch for the future. Indeed, we should keep in mind that nested syringes themselves were once billed as ‘exotic’.


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Klaus Ullherr is Product Manager at Robert Bosch GmbH. He holds a degree in Electrical Engineering, and worked as a project manager in the electrical industry for several years. In March 2000 he joined Robert Bosch GmbH in the Packaging Technology, Pharma Liquid product division. During his first two years with Bosch as Project Manager he took over responsibility for handling complex customer orders. Since 2002 he has been product manager for syringes and cartridges with global product responsibility. His main functions encompass market analysis, development of new products and overall business strategy. He is a member of the PDA prefilled syringes interest group and works as an expert in the DIN/ISO group for primary packaging. Furthermore, he is a renowned conference speaker, covering trends and solutions for fill/finish equipment.
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