Intravitreal injections using prefilled syringes are becoming increasingly prevalent – improving patient treatment and outcomes by getting an efficacious shot of medicine directly into the eye. Opportunities abound in this still evolving area of ocular therapy innovation, but significant challenges remain. On the surface, for example, adapting the design of a normal prefilled syringe (PFS) for intravitreal use might seem relatively straightforward. But that’s far from being the case.
Overcoming the regulatory challenges of smart ophthalmic devices
This article is the first in a series exploring the theme of delivery to the eye, a growing area of interest in ophthalmology that spans drugs, implants and gene therapies. In it, I’ll unpack the challenges of prefilled syringe development, and draw on our experiences here at Cambridge Consultants to reveal how innovators can best begin to plot a path to success. Let’s start with the PFS, first used by healthcare professionals and patients for parenteral (administered elsewhere than the mouth and alimentary canal) injections under the skin or into muscle.
It is only in recent years that PFS has made its way into the field of intravitreal injections. These are performed into patients’ eyes for the treatment of conditions such as wet age-related macular degeneration (AMD), diabetic retinopathy and diabetic macular oedema. Examples include Lucentis® (ranibizumab) and Eylea® (aflibercept), both anti-VEGF injections that come in a ready-to-use PFS.
At first glance, it might look as if the same PFS design has found its way into the intravitreal injection space. But the devil is in the details. Along with colleagues, I’ve made the PFS journey from parenteral to intravitreal application. So, let me highlight some of the key differences and challenges and discuss some potential improved solutions, based on publicly available information.
Tackling the issue of sterility
Endophthalmitis, an inflammation of the interior cavity of the eye most commonly caused by an infection, is a major concern associated with intravitreal injections. It poses a significant challenge in relation to maintaining sterility of the clinical environment in which the injection is performed, the aseptic practice of the ophthalmologists and also in terms of how the sterility of the PFS and its contents is achieved and maintained throughout manufacturing, shipment, storage and use.
A key difference between an intravitreal and normal PFS is that the former must be sterile both inside and outside, whereas the latter does not have to be sterile on the outside. What might sound like a simple additional requirement poses a tremendous challenge to the design, manufacturing and packaging of an intravitreal PFS. These unique challenges span the syringe material that protects the contents from the ambient air; the design that enables ease of filling the content aseptically and preserves it during shipment, storage and use; the packaging that allows terminal sterilisation and ease of unpacking without compromising sterility; and the design that facilitates ease of use and reduces use errors.
Ensuring dose accuracy
Intravitreal injections are typically very small doses of 0.05mL (i.e. 50µL) or less, equivalent to a drop of liquid. When you compare this dose with a 1mL normal PFS, it is 20 times less. Any slight variation from the intended dose could result in a significant underdose or overdose in terms of both percentage and therapeutic effect. For example, if there is an error of 0.02mL for a normal 1mL PFS, it would cause a small 2% inaccuracy in the dose, whereas the same amount for an intravitreal injection will cause 40% underdose or overdose – a big difference!
An underdose of such a magnitude for an intravitreal injection may mean compromised or no therapeutic effect, whereas an overdose into an eye, which is roughly 20mm in diameter, could cause detrimental intraocular pressure (IOP) and, in rare cases, drug toxicity and other complications.
So, what are the design challenges in achieving a dose accuracy with an intravitreal PFS? The answer can be found by first understanding the sources of dose inaccuracies. They could come from different sources – the tolerances in the bore diameter of the syringes; the inconsistencies in the shape of the neck of the syringes; the irregularities in the geometry of the stoppers; and the unpredictability of the dead volumes of the syringes and needles.
The other most likely source is the usability of the product, for example a user’s inability to remove any air bubbles and align the stopper precisely with the dose mark. Therefore, the solution lies in the manufacturer’s ability to minimise or eliminate the sources of inaccuracies, compensate for any residual potential inaccuracies (e.g. by over-filling the PFS), and incorporate thorough human factors engineering into the development process.
Even when all the design and manufacturing related sources of inaccuracies have been addressed or compensated for, it is still difficult to predict and control users’ behaviour. Shall I align the tip of the stopper with the dose mark? Or shall I align one of the ribs on the stopper? Maybe I should use the flat bottom of the stopper as that looks like a more defined reference point. These are some of the genuine questions and behaviours exhibited by experienced ophthalmologists and retina specialists.
Needless to say, if one aligns the bottom of the stopper with the dose mark with some of the marketed intravitreal PFS, they are unlikely to deliver a dose to the patient, without even realising it. Imagine this from the patient’s perspective. They have undergone all the pain and inconvenience, not to mention the risks, for nothing. To top it off, they may be self-funding their expensive treatment (in this case no-treatment) and their condition may deteriorate further as a result.
Dealing with bubbles and floaters
A PFS injection of small air bubbles into subcutaneous tissues may not have much effect on the patient. But an injection of air bubbles into a patient’s vitreous cavity may cause complications. This is another difference between a normal and intravitreal PFS. Although literature suggests that an injection of small air bubbles into an eye are likely to get resorbed within a couple of days, they may affect vision temporarily because of the bubble-related floaters. Large air bubbles, on the other hand, could result in a high IOP and related complications.
Another concern with air bubbles is that they tend to stick to the syringe wall and get trapped within the dead spaces, making them hard to expel during priming of the syringe. These bubbles then take up a significant proportion of the 50µL volume set, hence compromising the actual amount of medication delivered to the eye. In the worst case, air bubbles, if drawn from the ambient air during priming (design allowing), may result in an infection of the eye – one reason why the Lucentis PFS plunger rod is not attached to the stopper.
Besides air bubbles, other particulates such as droplets from the lubrication (usually silicone) used to lubricate the syringe wall for smooth stopper movement, and fine particles rubbed off from the stopper or syringe wall, may also cause floaters and other complications to the eyes. Most of these may cause no effect or only a minor local irritation to the skin when a normal PFS is used.
So, what is the design challenge and the solution? The following are all key to the success of an intravitreal PFS: the selection of the syringe, plunger, cap material and the state-of the-art manufacturing process (for example low siliconization achieved by Lucentis) to reduce particulates; utilising bubble-free filling technologies; ergonomic design of the user-interface; and effective instructional materials tested and validated via human factors studies.
Improving usability and efficiency
The likelihood of potential use errors and their consequences are greater with an intravitreal injection compared to a normal parenteral injection. For example, if a user inserts the needle of a subcutaneous PFS into the skin at a 60° angle as opposed to the intended 45°, it might hurt the patient a bit more or – in the worst case – compromise the therapeutic effect to a very small degree.
But now let’s think about the needle insertion into the eye for an intravitreal injection. It has to be precisely 3-4 mm away from the limbus towards the centre of the globe, or the needle may damage the lens or other internal tissues. As another example, if your hand moves whilst depressing the plunger with a normal PFS, the patient might feel a bit more pain or discomfort, or it may cause a minor laceration. But if this happens with an intravitreal injection, the consequence could be extremely severe.
There are many opportunities for significant use errors, some already described above – not removing the air bubbles, not setting the dose accurately and failing to maintain sterility during use. All of these errors could result in harm to patients and compromise their treatment considerably.
Another important point of note from an ophthalmologists’ or retina specialists’ perspective is the efficiency of the use process. These experts perform a large number of intravitreal injections per day. Therefore, even a small reduction in time per injection would save them a significant amount of time overall, hence increasing their throughput.
Although it might appear that an intravitreal PFS has simple ergonomics and room for improvement is limited, an application of a thorough human factors engineering process, coupled with a robust risk management system, will identify potential use errors, appropriate mitigations and opportunities for improvement.
The process focuses on understanding the users’ needs (both obvious and latent), considering the subtleties in the user-interface to cater for their needs and designing out problems through an iterative process of evaluations and improvement. All this makes the product safe and effective with the addition of increased user satisfaction.
Looking beyond PFS
It is fair to say that intravitreal prefilled syringes currently on the market have tackled some of the many challenges very well. But it’s important to remember this. With a rich domain knowledge and critical design thinking, they can be improved further, as some challenges still persist. Moreover, even if a new manufacturer wants to achieve only what these marketed products have achieved, they must consider of the intellectual property (IP) around some of the design solutions. It is a narrow space fraught with challenges.
Maybe the next step is to look beyond the use of a PFS, and also outside the intravitreal space. The science is evolving and so have some of the ophthalmic treatment methods and approaches. For example, some of the sources I’ve consulted suggest that biodegradable and non-biodegradable implants provide sustained drug delivery to eyes, so improving the treatment outcomes.
Perhaps it’s also time to look beyond intravitreal drug delivery to suprachoroidal (the space between the sclera and choroid that traverses the circumference of the posterior segment of the eye) and subretinal (beneath the retina) injections, which focus on providing localised delivery of existing treatment options and of new gene and cell therapies, improving outcomes and minimising side effects. These new methods require sophisticated, but not necessarily complex, delivery systems. As the technology advances, we’ll certainly see more treatment options for patients as well as great opportunities for our clients.
We’ve already helped a number of clients in the intravitreal drug delivery space and have developed a great understanding of needs – from those of the clients through to users and other stakeholders. The wider team is adept in the subtle design challenges and complexities around IP issues, and has a track record of proactively tackling the challenges to create opportunities. Needless to say, I’d be happy to discuss the topic – and any relevant ambitions that you might have – in more detail. Please don’t hesitate to drop me an email. Meanwhile, look out for the next article in this series, as my colleague Tim Phillips explores the potential for innovation in intraocular lens delivery devices.