Syringes have played a vital role in administering parenteral therapies, and in helping to ensure such therapies are microbially sterile and free of contaminants. But as more vaccines are required in developing countries and more therapies are being self-administered, designing innovative delivery solutions that match the payer’s needs while maintaining a high standard of quality, efficacy and safety for the end-user has become a key challenge.
Pre-filled syringes are one of the developments aimed at meeting these changing needs and now represent one of the fastest-growing segments of the injectable drug delivery arena. Their ability to offer the benefits of increased dosing accuracy, safety and convenience over traditional vial and syringe formats is driving growth.
Pre-filled syringes can pose quality issues for today’s biological, protein-based drugs
In a recent report1, SNS Research estimated that the pre-filled syringe market would account for more than US$3.2bn in revenue by the end of 2015 and is forecast to see a compound annual growth rate of 13% between 2015 and 2020, reaching almost $6bn in revenue by the end of 2020. However, pre-filled syringes can pose quality issues for today’s biological, protein-based drugs, due to siliconisation, tungsten residues and leachables. Glass delamination, gas permeability and ease of sterilisation are other considerations when choosing a syringe format.
The syringe is a complex multi-component product and one where the drug may come into contact with the glass, needle, needle glue, needle shield, plunger, and silicone oil used as a lubricant inside the syringe barrel. With so many materials, the chances of an interaction with a drug and the syringe components increase dramatically, especially with sensitive biological drugs.
Needle safety and syringe disposal can be a further issue. There are various needle options to consider ranging from staked-in (where the needle is manufactured as part of the syringe) and luer cone or luer lock designs. Staked pre-filled syringes are primarily used in medical and emergency situations (where rapid treatment may be vital), whereas luered-prefills are mainly used for self-administration purposes. Many pre-filled devices also offer automatic needle shielding or retractable needle options.
The number of drugs that require injection into the vitreous body of the eye has increased during the past two decades
Earlier this year, industry experts gathered at the 7th Annual Pre-filled Syringes Conference, in London, UK, organised by SMi, to discuss the design challenges and review developments. Alphons Fakler, Senior Packaging Engineer, Novartis, highlighted some of the complex issues companies such as his face when developing one of the most demanding preparations – that for intravitreal (IVT) administration.
The number of drugs that require injection into the vitreous body of the eye has increased during the past two decades, explained Fakler. They are now routinely used to treat endophthalmitis, viral retinitis, age-related macular degeneration (AMD), cystoid macular edema, diabetic retinopathy, uveitis, vascular occlusions, and retinal detachment.
IVT injections have stringent requirements regarding purity and cleanliness, in particular, very low particle burden levels (see Table 1). Silicone contamination must also be kept as low as possible as sometimes when silicone oil or silicone oil emulsion is used to lubricate the inner wall of the pre-fillable syringe glass barrels it can initiate the agglomeration of proteins during storage. One method of minimising the amount of free silicone oil is thermal fixation of the oil on the glass surface – baked-on siliconisation.
| Table 1: IVT injections set high requirements regarding purity and cleanliness | ||
| Particulate matter requirements | ||
| USP <788> Particulate matter in injections: Microscopic method | USP <789> Particulate matter in ophthalmic solutions: Microscopic method | |
| ≥ 10μm | < 3000 per container | < 50 per ml |
| ≥ 25μm | < 300 per container | < 5 per ml |
| ≥ 50μm | not defined | < 2 per ml |
Tungsten residues also need to be minimised. Tungsten pins are used during syringe manufacture to keep the bore open while the cone is shaped. As a result, metal and metal oxide particles may be deposited on the glass during the process. This residue can also lead to protein aggregation and formation of proteinaceous particles. Some suppliers have tried replacing tungsten pins with other materials, such as transition metals. However, leachables from these components also need to be ruled out.
Fakler highlighted that for IVT injections, syringe dimensions have to be very tight, as volumes are small (usually 10µL) but dose sizes are critical. The low fill volume also makes the filling process challenging. The drugs are expensive, thus drug loss during preparation of the injection must be kept to a minimum and this is where pre-filled syringes can help as they give rise to less waste.
Removal of air bubbles in syringes can be difficult and tactile feedback of successful delivery is also desirable
Other challenges are in ergonomics, as health professionals hold and inject syringes in different ways. Removal of air bubbles in syringes can be difficult and tactile feedback of successful delivery is also desirable. There is also a need for features that help users measure the dose during the injection process, he said.
The syringes must be sterile on the outside but the drugs often cannot withstand heat-sterilisation. Secondary packaging also has to be sterilisable. Thus, when choosing materials for components or syringes, matters such as gas permeability and irradiation capability should also be considered.
Fakler’s wish list for future delivery formats included having:
- Simplified closure removal for easy use
- No need for needle assembly, priming or alignment to dose mark
- A design that prevents injection of large volumes
- A filter in the fluid path, as well as sharps injury prevention features
- No air bubbles and a design that preserves sterility.
New technologies that Fakler said could help improve designs included: baked-on silicone glass syringes, silicone-free glass or polymer syringes, dosing aids, dedicated auto injectors and integrated safety devices.
Cartridges vs syringes
Recent times have seen the development of many prefilled cartridges for use in parenteral injections and Christian Olesen, Finished Products & Medical Devices Manager, nne pharmaplan, considered the advantages of cartridge-based devices, especially in situations such as delivering vaccines in the Third World, where products are often administered by untrained nurses who may have to carry out as many as 200 injections a day. This makes it important that devices are easy and intuitive to use, cost competitive, safe and reliable.
Ideally, the vaccine should be filled and administered to an exact dose, yet Olesen said that overfilling is a problem with many current syringes. ‘To get 1ml, you often have to put 2–3ml in the syringe,’ he said, adding that current devices are often overfilled by as much as 20%.
It was important to cut costs by simplifying the design and eliminating expensive purchased parts. Economies of scale could be achieved, he suggested, by using fewer and cheaper parts, minimising dead space and considering a durable device/platform.
The end user still needs safety, reliability and no cross contamination, Olesen said, as well as a sterile barrier that is intuitive to use and which must be intact until just before use. Disposability of needle/mouthpieces and devices is also important. He proposed a cartridge-based platform as the best option because such cartridges are ‘cost-effective, easy to produce and fill’. The one he proposed had one moveable activation part, the activation mechanism was at the fingertips, it had minimal dead space, used fewer and cheaper parts, provided a durable device/platform, had a disposable needle/mouthpiece and an intuitively usable sterile barrier.
‘A cartridge-based platform can be easily designed to accommodate both oral and injection-based vaccinations,’ Olesen said, leading to significant cost-savings through reduced overfill, greater economies of scale and uniform filling operations. The fact that the cartridges have to be mounted by the user was, for Olesen, the only negative, whereas he saw many negatives for syringes (see Figure 1).
Figure 1: Syringes versus cartridges
Courtesy of nne pharmaplan
‘This novel approach to multiple-vaccination administration from a single platform could be a game changer,’ he said. He believes that the market will rapidly move to cartridges for new highly viscous and expensive drugs in future.
Better materials
The industry is producing new materials that may have advantages over glass and more traditional plastics. One such new material discussed at the conference by Stuart Harris, Sales and Marketing Manager, Zeon, was cyclo olefin polymer (COP), marketed by Zeon as Zeonex. This material apparently looks and feels like glass and is tough but not brittle.
While Zeonex is more expensive than glass, it is tungsten-free, compatible with proteins, and resistant to delamination. According to Harris, it offers excellent and accurate mouldability and has the strength required for the injection of viscous drugs. Its properties are retained at cryogenic temperatures and it requires no lubricants or processing aids. In tests the material has also shown lower protein absorption than glass, and as well as drug compatibility, it has a high moisture barrier. It can also be sterilised with gamma, ethylene oxide and steam.
The company already has products on the UK market and while the material’s oxygen barrier property is not the best, there are processes available to enhance it, said Harris.
While Zeonex is more expensive than glass, it is tungsten-free, compatible with proteins, and resistant to delamination
William Dierick, Senior Manager, Technology Development, Global Pharmaceutical Solutions, Terumo Europe, described his company’s plastic ready-to-fill syringe with innovative needle technology. Plajex is a silicone oil-free pre-filled syringe designed to meet the needs of a wide variety of drug types, including those requiring low reactive containers. It has a staked needle in a cyclo olefin polymer device, providing lower reactivity with proteins, lower sub-visible particles, excellent strength and clarity, and can be steam sterilised for a ready-to-fill nested presentation.
According to Dierick, it is free of silicone oil, tungsten and glue; has a higher resistance to breakage; and can be autoclaved. He said Terumo’s proprietary moulding process results in fewer defects with a higher-strength syringe. ‘Plajex will provide a higher yield in your filling and packaging operations since it does not have the inherent defects (pits, stones, air lines, cracks) or fragility of glass.’
The company’s tapered needle technology also reduces injection forces for viscous products and improves patient comfort with such products. Mitsubishi Gas Chemical (MGC), meanwhile, described its trademarked OXY-CAPT multilayer plastic syringe with oxygen absorbing resin. This is said to impart an excellent oxygen barrier, to provide strength, and to low in extractables.
Suitable for pharmaceutical use, the product consists of an outer layer of COP providing a water vapour barrier; a middle layer that provides an oxygen barrier and oxygen absorption; and an inner layer of COP providing water vapour barrier and the drug contact layer.
According to Shun Ogawa, Research Manager, MGC, unlike existing oxygen absorbing resins that often encounter problems after absorbing oxygen – such as loss of strength or high levels of low molecular weight extractables – MGC’s glass-like gas barrier is characterised by low extractables, low protein adsorption and low weight. It is easy to dispose of and has a high break resistance and high transparency. It is also compatible with gamma, electron beam and ethylene oxide sterilisation. An OXY-CAPT vial suitable for steam sterilisation is already available and syringe for steam is under development, he said.
Meanwhile, some glass manufacturers have set out to improve their syringe offering. Anil Kumar Busimi, Head of Global Product Management, Schott (Schweiz), reviewed the benefits and limitations of glass pre-filled syringes and the options for polymer-based pre-filled syringes on the market. Schott’s own syriQ InJentle, is a staked needle pre-fillable glass syringe designed to offer improved drug stability and a gentle application to meet the needs of biotech medications.
Reference
1. http://www.researchandmarkets.com/research/2fl639/the_prefilled)
Cartridge systems could provide a novel and cost-effective approach to multiple vaccination administration Slide courtesy of nne pharmaplanFeatured companies
- Companies:
- Zeon Corporation
- SMi Group
- Novartis
- Terumo
- Mitsubishi Group