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The Rise of Pre-filled Syringes

Prefilled syringes, as the name suggests, are syringes filled with a measured dose of drug, diluents, or contrast agents used during diagnostic imaging procedures. Recent technological developments in prefilled syringes have expanded their applications to new areas and have enhanced comfort for end-users, including patients, physicians and technicians. In addition, the technological advances in design and manufacturing of prefilled syringes have enabled pharmaceutical companies to market lyophilised drugs and biological drugs. Roots Analysis' comprehensive research on this topic is available at this link.

 

Two of the most important developments have been the introduction of multi-chamber syringes and silicone-free technology for lubrication of syringe components. The latter has assured freedom from particulate contamination and thus safety, stability and potency of sensitive drugs. Another development, more to do with the safety of prefilled syringes than the type of product packaged, is the incorporation of safety features within the syringe to eliminate needlestick injuries. Previously, prefilled syringes were used with add-on safety devices but inbuilt safety mechanism has increased safety and convenience of use.

 

 

Dual/Multi-Chamber Syringes

 

 

Pharmaceutical companies have achieved success with prefilled syringes containing liquid formulations. However, some protein-based drugs are formulated as powders to improve their long-term stability. According to Vetter International, more than 30% of the parenteral drugs approved by the US FDA in the past three years have been for lyophilised substances. Most of the lyophilised drugs are currently available in vials and sold with diluents and syringe for reconstitution.

 

 

TABLE 1 Prefilled Syringes for Lyophilised Drugs

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Prefilled syringe manufacturers have developed dual / multi-chambered syringes for lyophilised drugs. In dual-chamber syringes, a stopper in the middle of barrel serves as a barrier between two chambers. The lyophilised drug is packaged in one chamber and the other chamber is filled with diluent with another stopper. On application of pressure on the plunger by user, the diluent moves to the front chamber and reconstitutes the lyophilised drug.  Their use reduces the medication errors associated with reconstitution. They also reduce the time taken to reconstitute the drug before administration, making them helpful in emergency situations. Additionally, with the use of dual-chamber prefilled syringes, 1 ml of active substance requires an overfill of 6%, compared to an overfill of 20% or more while packaging in vials to ensure accurate dose.

 

Pharmaceutical companies have only begun to package lyophilised drugs in dual/multi-chamber syringes. Examples of such drugs include Xyntha (Pfizer) and Prolia (Takeda).

 

Vetter Pharma’s Lyo-Ject has been present in the market for more than 20 years now. Introduced to the market in 1990s, the Lyo-Ject dual-chamber prefilled syringe has now started to gain significant attention from the pharmaceutical companies. In August 2011, Unilife developed and introduced the first multi-chamber prefilled syringe with automatic safety feature. The company's Unifill EZMix syringes feature two or more primary drug containers within a single glass barrel to store a combination of liquid stable or lyophilised drugs along with up to 1ml of diluent for reconstitution. It is available with either a fixed (staked) needle for drugs indicated for subcutaneous injections, or with attachable needles of up to 1.5 inches in length.

 

In June 2012, Arte Corporation and ProJect Pharmaceutics announced the development of a novel lyophilised dual chamber prefilled syringe system. The device called Lyo-DCPS stands for lyophilised dual chamber prefillable syringe. It will be delivered in standard nests and tubs and can be filled on nested syringe fillers. The diluent can be prefilled in the first chamber and autoclaved for sterilisation. The pharmaceutical companies can fill drug solution in the second chamber and transfer the syringes to freeze drier for lyophilisation. The special design of the syringe enables the system to open by itself inside the freeze drier causing the lyophilisation of drug solution in presence of the diluent. The innovative system is expected to be available in early 2013.

 

Another novel dual chamber prefilled syringe system has been developed by Bioneer:FARMA, a unit of Bioneer A/S, Denmark. The unit has developed an innovative plunger-in-a-plunger closed prefilled system that does not let excess air enter the syringe and thus delivers accurate dose.

 

 

Silicone-free Syringes

 

Another important development in prefilled syringes has been the introduction of silicone-free lubrication techniques. Traditionally, silicone-oil is used as a lubricant in syringes to ensure smooth gliding behaviour of plunger inside the barrel. But some drugs are silicone-sensitive and cannot be used inside a silicone coated syringe. Protein-based drugs especially are more susceptible and show aggregation induced by silicone particles. Secondly non-uniform distribution of silicone causes variability in gliding forces, which can result in incomplete injections. This is particularly problematic when syringes are used with auto-injection devices where there is no manual control. Silicone oil coating also generates sub-visible particles which can contaminate the drug product.

Some companies have developed new coatings, which are used either inside the barrel or on rubber plungers, to avoid siliconisation of prefilled syringes. Some silicone-free prefilled syringes available in the market include Daikyo CZ syringes (West Pharmaceutical Services) and Plajex (Terumo Europe).

 

West Pharmaceutical Services uses a fluoropolymer based barrier film technology - FluroTec. West FluroTec is a fluorocarbon film made from a modified ethylene-tetrafluoroethylene (ETFE) copolymer. The film reduces the absorption and adsorption of the drug product and provides an effective barrier against organic and inorganic extractables. Fluoropolymer film also serves as a barrier between the drugs and elastomeric components, reducing the potential for leachables. West’s Daikyo CZ syringes comprise of FluroTec laminated plunger.

 

Another silicone-free coating known as TriboGlide has been introduced by TriboFilm Research Inc. and IVEK Corporation. TriboGlide lubrication system utilises patent pending Perfluoropolyether (PFPE) chemistry, crosslinked through an Atmospheric Plasma Immobilization process. TriboGlide reduces particulates in the drug medium and increases stability of biological drugs. Perfluoropolyether, the precursor for TriboGlide has a higher cohesive energy density than silicone-oil, thus reducing the tendency to migrate. Additionally, the crosslinked lubricant reduces the extractables in drug and lowers break-free and extrusion forces. TriboGlide is compatible with glass and plastic syringe materials such as COC & polypropylene and can be sterilised by steam, ETO, and gamma radiation.

 

Becton Dickinson has introduced an innovative immobilised silicone coating: cross-linked silicone, XSi.  The proprietary XSi coating reduces the silicone-related sub-visible particles (SbVPs) count by more than 90% when compared to conventional lubrication. This novel coating does not introduce any new material in the fluid path and is compatible with autoinjectors. The BD XSi technology is ready for adoption and requires no alteration to existing prefilled syringe manufacturing or filling processes.

 

 

Prefilled Safety Syringes

 

Last decade recorded a large number of cases of needlestick injuries in healthcare industry. Healthcare workers around the world experienced exposure to infectious agents like hepatitis B virus (HBV), hepatitis C virus (HCV) and Human Immunodeficiency Virus (HIV). In 2002, the World Health Organisation (WHO) reported that of the 35 million healthcare workers, 2 million experience percutaneous exposure to infectious diseases each year. High incidences of blood-borne pathogen transfer resulting from unsafe needle practices led a transition to the mandatory use of safety devices. With safety on top of the mind of health industry and governments worldwide, various laws and legislation were passed to protect workers from needlestick injuries. In 2000, US became the first country to pass Federal Needlestick Safety and Prevention Act, a legislation requiring use of safety-engineered devices in healthcare facilities. The move was soon followed by other international markets, mainly in Europe, enforcing safety laws in their regions. European Union introduced a directive in May 2010, and the member countries have to ensure the implementation of the provisions of the directive in to their national legislation by 11 May 2013. Regulatory authorities now carefully scrutinise devices for safety features. 

 

Traditionally, prefilled syringe manufacturers source needle guard devices from elastomeric components manufacturers. These safety devices can be attached to prefilled syringes over the barrels. The safety devices can be passively or manually activated upon completion of injection. These ancillary devices slide an external plastic sheath over the entire prefilled syringe or they have a needle retraction system which upon activation retracts the needle back into the barrel to protect the user from needlestick injuries. The disadvantage of using these clip-on safety devices is that they are often much larger in size than the syringe itself which increases the overall cost relating to packaging and shipping. The ancillary safety products can increase pharmaceutical packaging, transport and disposal volumes by up to 70%.

 

Manufacturers of prefilled syringes, in compliance with safety laws, are adopting the trend to incorporate safety features in their devices. According to MedPro Safety Products, about 15% of the prefilled syringes market has converted to safety devices. The percentage of prefilled syringes with integrated safety features is even lower. Currently, Unilife Corporation’s Unifill syringes are the only marketed prefilled syringes with integrated safety feature. In addition, there are pipeline products from MedPro Safety Products and Globe Medical Tech.

 

Unifill ready-to-fill syringes comprise of automatic safety features fully integrated within the glass barrel. The production of Unifill syringes commenced in March 2011 at the company’s manufacturing facility in York, Pennsylvania. The validation phase for Unifill syringes was completed in June 2011, with the company commencing the supply of Unifill syringes to Sanofi in July 2011. The pharmaceutical company has exclusive rights for the Unifill syringe for antithrombotic agents and vaccines, and an additional four smaller sub-groups, until June 30, 2014.

 

MedPro Safety Products is also developing prefilled safety syringes with fully integrated passive safety mechanism. Their device is designed to accept prefilled cartridges of some common drugs or specified dosages of pharmaceutical medicines. This would require the pharmaceutical companies/contract manufacturers to insert drug cartridges in the device. According to the company, the device is fully compatible with existing pharmaceutical manufacturing lines and contract cartridge filling lines. In March 2010, MedPro entered in to an agreement with Belgium-based Helvoet Pharmaceutical N.V., for development and distribution of its prefilled safety syringe system. The product’s market entry is anticipated this year (2012).

 

Globe Medical Tech, a US based medical device developer, has a prefilled safety syringe auto retractable needle technology. The technology is compatible for use with glass or plastic syringes and for single or dual-chamber prefilled syringes. Globe Medical’s technology is available for licensing worldwide or regionally.

 

In addition, Terumo Europe has developed K-Pack Surshield hypodermic needles with integrated encapsulating protection feature, whereby the needle is never exposed. These new hypodermic needles are compatible for use with prefilled syringes.

 

The potential of prefilled syringes is only beginning to be recognised and we can expect the manufacturers to come up with more innovative designs in the future, driven by their increasing demand. Most of the developments will be focused on increasing the ease of use and safety of the devices, as the market for self-medication increases.

 

 

 

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