As the market for prefilled syringes grows, an increasing number of drugs are being administered in this way. However, with usability requirements intensifying, manufacturers must ensure their products are safe and straightforward to use within non-medical settings. Paul Jansen, associate vice-president of medical device development at Sanofi, explores how the latest advancements in prefilled syringes and auto-injectors are moving healthcare from the hospital to the home.
Demand for prefilled syringes is on the up. Comprising close to a quarter of the total injectable drug-delivery systems market, this is one of the fastest growing segments in healthcare, and it would seem that, for manufacturers, there are promising times ahead.
With sales of $6.9 billion expected by 2018, syringes of this kind cater to an expanding patient demographic: people with chronic conditions who need, or prefer, to administer their own medicines. The race is on to improve the associated technologies, ensuring that the new generation of prefilled syringes can adequately accommodate tomorrow's drugs.
Homeward bound
"Healthcare systems around the world are trying to move healthcare out of the hospitals and into the home. As a result, we see that an increasing number of patients are becoming responsible for self administration of their medicine," explains Paul Jansen, associate vice-president of medical devices at Sanofi. "This shift is driving the need for intuitive drug delivery systems that allow the patient to get their medication safely and correctly." Sanofi is one of the key players in this field. Over the years, it has developed a number of drugs administered by auto-injection, most notably the anticoagulant Lovenox, which helps reduce the risk of deep vein thrombosis and pulmonary embolism. Patients can successfully self-inject Lovenox after receiving training from a healthcare professional and by adhering to the labelled prescribing information.
There are also further drugs in the Sanofi pipeline, which will require self-administration with a device. Together with its partner Regeneron, the company has three lead compounds at a late stage of development that have undergone clinical trials in prefilled syringes. Top of the list is Alirocumab, which is being studied for its ability to reduce levels of 'bad' cholesterol. Having reached its final stage trials, it will be competing against similar offerings from Pfizer and Amgen when it seeks FDA and EMA approval later this year.
Sarilumab, for rheumatoid arthritis, has shown some strong stage-III results, and is currently undergoing a six-study end-stage programme. Meanwhile, Dupilomab, for atopic dermatitis, is due to begin phase-III studies in the coming months.
As biologics become increasingly prevalent, we can expect to see more and more examples. Estimates vary, but it is thought that around 60-70% of the drugs currently in clinical development are biologics, and at Sanofi the proportion is higher still. The vast majority of these - such as vaccines, anticoagulants and monoclonal antibodies - are expected to be approved for parenteral administration.
Whereas small molecule drugs can usually be taken orally, complex proteins and peptides are rarely effective in pill form. Prone to enzymatic degradation, as well as poor penetration through the intestinal membranes, complex molecules of this kind may need to be injected directly into the bloodstream. This is why less invasive forms of delivery are such a hot topic - and why, in the meantime, minimising patient discomfort is critical.
"The patient is now being asked to do something that was previously happening when they were either in the hospital or in the doctor's office, so in order to ensure the drug gets administered properly we have to make it easy for them," explains Jansen. "This drives you towards drug device combination systems where needles are not visible and it's convenient and safe. The preferred system, based on volume and size, is prefilled syringes placed into auto-injectors."
Power of the pen
Prefilled syringes have clear advantages as primary containers, in that they ensure the patient obtains the exact dosage required while minimising the risk of contamination. Although there are many variations, the device typically consists of a single dose of drug with needle attached, and a barrel made from glass or (less commonly) plastic.
Frequently, this is stored in an auto-injector, a pen-like device that keeps the needle tip shielded before injection. The user need only press a button, which inserts the needle and delivers the requisite quantity of medication. From the patient's point of view, this is a straightforward process, requiring little in the way of advance preparation.
For the manufacturer, matters are rather more complex: they are tasked less with creating a device and more with building an entire system. This means considering the patient requirements at a very early stage of development.
"One of the things we've all learnt over the years is that you can't develop these products independently," says Jansen. "You can't have the R&D department develop the formulation for the drug and then have the manufacturer of the prefilled syringe put it into the device at the end. So we put together a collaborative team right upfront, and everyone works closely together to make sure the system will work."
"The patient is now being asked to do something that was previously happening when they were either in the hospital or in the doctor’s office, so we have to make it easy for them."
This goes beyond ensuring the drug is biocompatible with its container. Long subject to the designer's discretion, usability is now a regulatory requirement, and manufacturers must be able to show that their syringe makes sense for the intended patient group. Can they confirm that the patients know what to do and, furthermore, are capable of doing it?
This is certainly a challenge, and the bar for approval is being set progressively higher as regulatory agencies tighten their requirements. Still, the logic is clear. A prefilled syringe should not be designed for use in an 'ideal' hospital environment, but rather should be created with contextual factors in mind.
At its most basic, this means ensuring that all relevant design factors - size, shape, weight, needle size, presence or absence of a button - are determined by patient insights. For instance, you need to be sure that the entire dose is being delivered, and that in turn means paying attention to how much force the patient can apply.
At the other end of the spectrum, it involves tailoring a device towards a particular condition. Take Sarilumab, Sanofi and Regeneron's investigational compound for rheumatoid arthritis. As is well known, patients with rheumatoid arthritis may struggle with manual dexterity, and so a device must be developed to accommodate these limitations.
"They have a great deal of difficulty getting their hands wrapped round a small cylindrical device, as well as manipulating the device and getting the cap off," explains Jansen. "So we've done a lot of testing to determine the best shape and design to allow the patients to use it."
Safe side
Most auto-injectors also include safety features that are automatically activated after injection, covering the needle. Designed to protect users from injury, these mechanisms vary greatly but are generally deployed without any direct action needed.
"Whenever you develop these products, they have to be safe," says Jansen.
In many cases, advanced delivery systems of this kind are not so much a burning necessity as they are the icing on the cake. Where manufacturers have difficulty developing a proprietary device, they can still present the patient with the prefilled syringe on its own without flouting any usability requirements.
Such devices do, however, remove a stumbling block for many needle-shy users. When Sanofi launched its voice-guided epinephrine auto-injector, Auvi-Q, in February 2013, its usability factors were widely commended. Providing patients with aural and visual cues, including a five-second injection countdown, the device features an automatic needle retraction mechanism and an alert light to signal when the full dose has been delivered. It is designed for patients suffering anaphylaxis - an emergency situation that doesn't give them long to prepare.
Prefilled syringes and auto-injectors are not always straightforward to develop, and they do pose unique challenges. For instance, while long shelf life is often cited as a benefit, the manufacturer must make doubly sure that the product remains stable over time. This is particularly the case when dealing with highly viscous fluids like monoclonal antibodies, where any temperature changes can impede the function of the device.
That said, their popularity, ingenuity and range of applications looks set only to grow. Jansen feels that one of the key trends for the future will be a movement away from disposable prefilled syringes to cartridge-based or more flexible containers.
"As volumes grow, this will give an even greater design space," he explains. "You may be able to put your drug into a container like a toothpaste, which would allow you to do a number of different things in terms of how to deliver a dose. So I believe we'll find the container part of the system changing, and that in turn will change the outcome of the whole system."
The onus here is on designers to work round a demanding set of requirements. They must factor in the needs of a user base that is not specially trained to administer medication, and may indeed face certain physical difficulties in doing so. But as healthcare moves into the home, devices of this kind will continue to play a front-line role. When used as designed and directed, prefilled syringes and auto-injectors can empower patients to take an active role in their own care.
Paul Jansen is a professional engineer with almost 30 years’ experience in medical devices design, development, manufacturing and lifecycle management, and has several patents to his name. He is an active member of ISO.
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