Modern pre-filled syringes offer greater safety and ease-of-use but their development has not been without challenges in terms of contamination. Susan Birks reports on the latest developments designed to enhance the quality of sensitive biological drugs
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. 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, for today’s biological, protein-based drugs, pre-filled syringes can pose many quality issues due to siliconisation, tungsten residues and leachables. Glass delamination, gas permeability and ease of sterilisation are other considerations when developing syringe formats.
With so many materials, the chances of an interaction between a drug and the syringe components increases dramatically
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 lubricant inside the syringe barrel. With so many materials, the chances of an interaction between a drug and the syringe components increases dramatically, and the risk is especially high for sensitive biological drugs.
Needle safety and syringe disposal can be a further issue to consider. There are various needle options 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 pre-fills are mainly used for self-administration purposes. Many pre-filled devices also offer automatic needle shielding or retractable needle options.
In January 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 in this field.
The number of drugs that require injection into the vitreous body of the eye has increased during the past two decades
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, a very low particle burden level, as specified in USP <788> particulate matter in injections (less than 300 25µm particles per container) and USP <789> particulate matter in ophthalmic solutions (less than five 25µm particles per ml) – see Table 1.
|Table 1: IVT injections set high requirements regarding purity and cleanliness|
|Particulate matter requirements|
|USP <788> Particulate matter|
|USP <789> Particulate matter|
in ophthalmic solutions:
|≥ 10μm||< 3000 per container||< 50 per ml|
|≥ 25μm||< 300 per container||< 5 per ml|
|≥ 50μm||not defined||< 2 per ml|
Silicone contamination must also be kept as low as possible as it can initiate the agglomeration of proteins during storage. This can arise when silicone oil or silicone oil emulsion is used to lubricate the inner wall of the pre-fillable syringe glass barrels. One option for minimising the amount of free silicone oil is thermal fixation of the silicone oil on the glass surface in a process called baked-on siliconisation.
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. As the drugs are expensive, 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.
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 be considered. Among the new technologies that Fakler said could help improve designs were: baked-on silicone glass syringes, silicone-free glass or polymer syringes, dosing aids, dedicated auto injectors and integrated safety devices.
Use of intravitreal drugs (e.g. those delivered to the macula) is on the increase
Several manufacturers have come up with pre-filled syringes designed to overcome some of the contamination issue. Anil Kumar Busimi, Head of Global Product Management, Schott (Schweiz) reviewed the benefits and limitations of glass pre-filled syringes compared with polymer-based pre-filled syringes.
Schott’s most recent offering is syriQ InJentle, a staked needle pre-fillable glass syringe that offers improved drug stability and a gentle application to meet the needs of biotech medications. syriQ InJentle is the first staked needle syringe with baked-on silicone. These syringes limit the contact materials to glass and rubber, equivalent to the materials drugs are exposed to when housed in vials. Through its advanced design, the company has reduced the risk of interaction between the drug and the silicone.
On the other hand, some manufacturers propose the use of polymer pre-filled syringes rather than glass. Stuart Harris, Sales and Marketing Manager at Zeon, discussed the use of 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. It was said by Harris to offer excellent and accurate mouldability and it 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.
Plajex is designed to meet the needs of a wide variety of drug types, including those requiring low reactive containers
William Dierick, Senior Manager, Technology Development, Global Pharmaceutical Solutions, Terumo Europe, described his company’s plastic ready-to-fill syringe with innovative needle technology. Called Plajex, the silicone oil-free pre-filled syringe is 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. Dierick 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,’ he said.
His 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 the OXY-CAPT multilayer plastic syringe with oxygen absorbing resin. This is said to impart an excellent oxygen barrier, to provide strength, and to be low in extractables. Suitable for pharmaceutical use and as a replacement for standard glass containers, 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 a 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 now available and a syringe is under development, he said.