Rapid growth and increased competition in the biotechnology industry are driving the need to differentiate among products. Improvements in product presentation form, evolving from vials to pre-filled syringes (PFS), and other quality attributes are key strategic factors one must consider in order to succeed in an increasingly competitive marketplace. Prefilled syringes offer several advantages for drugs requiring parenteral injection. On one hand, pharmaceutical companies can benefit from reduced cost of goods by eliminating overfill that are required by traditional packaging of vials/ampoules. On the other hand, patients and healthcare workers can benefit from a dosage form that is ready-to-use, improved dosing accuracy, and reduced risks associated with filling and using a syringe. Importantly, all these benefits can reduce overall healthcare cost by improving patient compliance.

In the years 2005 through 2007, unit sales of PFS have risen about 22% (Ref.1). The worldwide market for PFS has increased to an estimated 2.7B units in 2010 and the total revenues in this market are predicted to reach $3.9B in 2015, $4.6B in 2018 and $5.2B in 2021 (Ref. 2, 3). The growth in PFS market along with the adoption of the needle-stick safety and prevention laws worldwide have stimulated the Needle Safety Device (NSD) market in the past decade. However, despite its growing popularity, development of PFS as a method of drug delivery also has its own hurdles and risks.

Prefilled syringes act both as drug delivery vehicle and the primary container for drug products. Therefore, they are required to provide seal integrity, drug compatibility and stability throughout the shelf life of the drug product. Glass, the traditional material of construction for PFS has also been challenged. There have been cases of huge financial loss and damaged corporate reputation in the pharmaceutical industry associated with recalls of valuable combined products due to glass breakage (Ref 4). Apart from its heavy and brittle nature, residual tungsten in the glass barrel from the bore opening process can cause protein degradation. Drug stability under high pH value also presents another risks associated with glass barrel.

Furthermore, prefilled syringes currently available on the market do not have integrated needle-stick prevention function; they all require certain add-on sheaths or other devices to render the syringe sharp safety, retrofitting of said external device onto the glass barrel also comes with additional risks of subjecting an expensive drug through another assembly process.

1. http://www.ondrugdelivery.com/publications/Prefilled_syringes_%2007.pdf
2. PREFILLED SYRINGES: Drugs, Devices and Disease Therapeutics (Greystone report, May 2009)
3. Pre-Filled Syringes: World Market Outlook 2011-2021 (Visiongain report)
4. http://www.fda.gov/Safety/Recalls/EnforcementReports/ucm247463.htm

In order to address the unmet need for a PFS that is break-resistant, free of heavy metal, and features an integrated safety system, MCI is developing an innovative Integrated Plastic Pre-fillable Safety Syringe (iPPFSS), with brand name as mentioned above, made of COC or COP polymer. The design is fully integrated with MCI’s patented user-controlled automatic needle-retracting mechanism which has been proven in automated mass production of safety syringes for clinical use. Although the same technology platform is employed for prefillable version, certain configurations have been fine-tuned to enhance container closure integrity. Furthermore, the dimensions of the prefillable syringes are adjusted to accommodate conventional ready-to-use fill/finish system as well as sterilization process so that manufacturing switching cost is eliminated or minimized.

In order to shorten the time required for product development and commercialization, standard and FDA compliant products from leading suppliers will be used for all the components that in contact with the active pharmaceutical ingredient, such as plunger (stopper or piston) and needle shield.

iPPFSS takes advantage of innovative material design and manufacturing flexibility, eliminates glass breakage and provides a great life cycle management tool for drug products in PFS. It could ensure the quality of syringes before fill and reduces waste of precious drugs due to added assembly process which is occasionally needed with the add-on devices. Its compact design saves costs in cold storage, shipping, handling (lower density/weight) and waste disposal.

　　Pre-filled syringe (PFS) has become an attractive container closure option due to cost savings and improved patient acceptance. It is known that compatibility between drug formulation and container closure is a regulatory requirement due to the influence drug stability has on its safety and efficacy. The content and morphology of Sub-Visible Particle (SbVP, size range from 2 to 100 mm) in drug product is a sensitive indicator of stability and an important quality parameter that has gained increased attention from regulatory bodies in both US and EU, due to its link to product safety.

　　The purpose of this study is to compare stability of two different pharmaceutical molecules in two types of PFS – a traditional glass PFS and a novel PFS that is made of polymer with a integrated, built-in, safety feature to prevent needle stick injury named . To achieve this objective, Leukocyte Growth Factor (LGF) Biosimilar and Enoxaparin Sodium (ES) solutions were subjected to accelerated stress testing by agitation in order to simulate the stress that occurs due to routine shipping. Agitation can lead to drug instability, especially protein pharmaceuticals, by exposing the molecules to air-liquid interface, which leads to protein unfolding and subsequent aggregation. Dynamic Image Analysis (FlowCAM), a sensitive method capable of obtaining quantitative and morphological information, was used for real-time monitoring of SbVPs in these drug products.

Drug Product Study I: Stability of LGF Biosimilar in Glass and PFS Following Exposure to Vortex Stress

　　Some irregularly shaped SbVPs were detected in the original LGF Biosimilar solution (in vial) (Fig. 1A), which is likely due to protein aggregates that are formed under sub-optimal formulation conditions. Following exposure to rigorous agitation stress, the concentration of Silicone-Oil (Si-Oil) SbVPs and Non-Silicone-Oil (Non-Si-Oil) SbVPs increased significantly in both types of PFS (Fig. 2). Based on morphological features of the particles, the round SbVPs are likely released from the silicone oil film coated on the inner wall of PFS, and the irregularly shaped SbVPs are mainly consisted of aggregated protein from LGF Biosimilar1-4. Compared to Glass PFS (Fig. 1B), the level of Si-Oil and Non-Si-Oil particulates found in LGF Biosimilar are approximately ten times lower in PFS (Fig. 1C). Therefore, it can be concluded that LGF Biosimilar is likely to be more stable in PFS than Glass PFS during routine shipping and handling.

Fig. 1 The SbVP images of Leukocyte Growth Factor Biosimilar with vortex 60min.
(A) in vial
(B) in Glass PFS
(C) in PFS

Fig. 2 The SbVP content of LGF Biosimilar in Glass PFS and PFS with vortex 15, 30 and 60 min.

Drug Product Study II: Stability of Enoxaparin Sodium in Glass and PFS Following Exposure to Shaking Stress

Initially there were a few small black SbVPs, most likely air-bubbles, in the ES solution (in vial, Fig. 3A). Following shaking at 300rpm for 3 days, most SbVPs of ES found in PFS are small white round Si-Oil particles that were released from inner wall of PFS (Fig. 4). Compared with both types Glass PFS (type 1 and type 2), fewer SbVPs were formed in PFS (Fig. 4), and there were no Non-Si-Oil type SbVP in PFS (Fig. 3B). These data suggest that PFS is superior to glass PFS for maintaining stability of ES under shipping stress.

Fig. 3 The SbVP images of Enoxaparin Sodium with shaking at 300 rpm for 3days.
(A) in vial
(B) in
(C) in Type 1 Glass
(D) in Type 2 Glass

Fig. 4 The SbVP content of Enoxaparin Sodium in Glass PFS and with shaking at 300 rpm for 0, 3 days.

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