Biosimilar anti-VEGF- is prefilled syringe (PFS) a challenge?

Biosimilar anti-VEGFs are emerging as a wave with a series of biosimilar ranibizumab approvals in the last 2 years across the globe by various regulatory agencies including the United States Food and Drug Administration (US-FDA) and European Medical Agency (EMA) [1]. Furthermore, multiple biosimilar aflibercept molecules are in the final stages of regulatory approval process [2]. Once the aflibercept patent expires, these molecules will be available for clinical use.

We have observed that many of these approved biosimilar anti-vascular endothelial growth factor (anti-VEGF) molecules and candidates in the pipeline have prefilled syringes (PFS) testing in their clinical trial protocol. However, to the best of our knowledge, no manufacturer has however yet started trials on patients using prefilled syringes. The US-FDA approved the reference molecule (Lucentis, Genentech, USA) in the year 2006 [3]. However, the PFS of Lucentis was approved by the US-FDA in the year 2016 (0.5 mg) and 2018 (0.3 mg) [4]. Furthermore Aflibercept (Eylea, Regeneron, USA) received US-FDA approval in 2011 [5]. However, PFS of Eylea was approved in 2019 [6]. Similarly, though brolucizumab (Beovu, Novartis, USA) received US-FDA approval in 2019 [7], it received PFS approval in June 2022 [8]. Faricimab (Vabysmo, Roche, USA) received FDA approval in Jan 2022 [9]. but PFS are not yet available for clinical use. PFS provides many advantages such as reduced injection time, possible reduced risk of endophthalmitis, possible reduction in intraocular air bubbles and silicone oil droplets, and possible improved precision in the volume and dose of the intravitreal medication administered. It was thought to be very simple to introduce prefilled syringes. However, prefilled syringes for intravitreal therapy pose a significant challenge when compared to prefilled syringes in any other field of medicine. The multiple challenges and complexities in developing PFS have led to the delay in their approval compared to vials for all anti-VEGF agents licenced so far for the therapy of retinal diseases. This manuscript will discuss the potential difficulties that biosimilar companies potentially face in developing prefilled syringes for the trials and regulatory approval.

Sterilization

This is the most important differentiator between a PFS for intravitreal injection compared and any other intradermal PFS like insulin. The most feared complication of intravitreal injection is endophthalmitis if sterility is not maintained. For a PFS of any other speciality, sterilization is required only for the content and inner walls of the syringes. However, for an intravitreal PFS, sterilization of the outer wall is as important as sterilization of the inner wall and contents because it must be stored, shipped and used in a sterile environment. This makes the manufacturer’s job extremely challenging due to the need of terminal sterilization once the PFS is packed. Companies involved in the manufacturing of intravitreal PFS need to choose a material that can sustain terminal sterilization without affecting the drug and plunger movement. Polycarbonate glass is often the material utilized for the same. However, some of the biosimilar companies are exploring different options. For instance, Alteogen filed an international patent cooperation treaty (PCT) application for the PFS formulation (made of plastic) of 'ALT-L9', a biosimilar candidate for aflibercept [10].

Floaters

The origin of post-injection floaters could be due to two factors. First, while filling or priming the syringe, some air is trapped and is difficult to remove as it might compromise the drug volume. Furthermore, silicone which is used for the inner lining of the syringes and needles to ensure smooth flow and penetration, might get dislodged and cause a permanent floater due to injection of a silicone bubble into the eye. Biosimilar companies need to make sure that they use either silicone free syringes or low silicone syringes such as is used in originator molecule Lucentis.

Drug volume inconsistency

There has been reports from aflibercept PFS that it can cause a higher intraocular pressure after the procedure when compared to the vial [11]. Root cause of this phenomenon is still not well understood. However, a few possible hypotheses are proposed. For example, this can be because the injection syringe and vial syringes have different syringe diameters. Another potential factor could be human error while using PFS syringes, as sometimes the apex of the plunger is aligned with the mark which might lead to a larger volume getting injected leading to a higher IOP. When the innovator company has not made their proprietary data available, it is difficult for the biosimilar companies to obtain the proper plunger and diameter.

With improvements in technology it is possible for the above challenges to be solved by the biosimilar companies. However, patent protection by the other companies that already have PFS in this space might limit the ability of biosimilar companies to work in this direction. They need to achieve and overcome these challenges without infringing the existing patented design technologies. This could be a hurdle for biosimilar companies in bringing the PFS into the market, as this is a very narrow space and room for further innovation is limited. There are various areas where biosimilar companies need to work with innovative thought such as right material for the syringe, design of plunger which might be of help in avoidance of marking issue, appropriate material for the cap of PFS and preferably non silicone syringes which are available now. Furthermore, the manufacturing process during the filling of the drug must be done carefully to prevent formation of air bubbles.

The major advantage of biosimilar medications is their lower cost with similar efficacy and safety. The PFS biosimilar option might be of help in reducing the cost further as the extra volume of drug which is used in the vial can be saved. However, the cost in research and development necessary to achieve the PFS may counteract this. It will be interesting to see how biosimilar companies will face this challenge and bring the option of PFS into the marketplace, along with the vial. We foresee the possibility of additional regulatory requirements for the approval of biosimilar PFS.

Author contributions

AS: conception, analysis, drafting, integrity check, final approval. AL, NP, NK, AR, BDK; drafting, revision, analysis, integrity check.

Funding

BDK acknowledges an unrestricted grant to the Gavin Herbert Eye Institute from Research to Prevent Blindness.

Competing interests

AS: CONSULTANT: for Novartis, Allergan, Bayer, Lupin and Intas, Speaker fee Biogen. AL: CONSULTANT: Allergan, Novartis, Roche, Notal Vision, Fiorsightslabs, Beyeonics, Bayer Health Care. AR: Employee Intas Pharmaceuticals Ltd. FB: CONSULTANT: Allergan, Bayer, Boehringer- Ingelheim, FidiaSooft, Hofmann La Roche, Novartis, NTC Pharma, Sifi, Thrombogenics, Zeiss. BDK: CLINICAL RESEARCH:, Alimera, Allegro, Allergan, Apellis, Boehringer Ingelheim, Clearside, Genentech, GSK, Ionis, jCyte, Novartis, Regeneron; CONSULTANT: Alimera, Allegro, Allergan/AbbVie, Boehringer Ingelheim, Clearside, Coherus, EyeBio, Eyedaptic, Galimedix, Genentech, Glaukos, IvericBio, jCyte, Novartis, Ocular Therapeutix, Regeneron, Revana, Theravance Biopharma. The other authors declare no competing interests.