Highly efficacious, innovative medicine needs cutting edge delivery systems to match, and pre-filled syringes (PFS) are stepping up to the plate.
The PFS space is one of the fastest growing sectors in pharma, expected to be worth $9.7B by 2025,1 thanks in part to their greater patient safety profile and lower manufacturing costs.
But pre-filled doesn’t translate to easily filled. The increase in biologic drugs, which has been driving the PFS boom, presents particular obstacles, and there’s no one size fits all approach.
In this article, we will chart the rise of the PFS, outline some common challenges, and explain how partnership is the only route to success.
The PFS Boom
Driven by the trend toward biological medications, the PFS space has seen huge growth in recent years.
This new breed of “living” medicines, made possible by rapidly evolving technology and an ever-greater understanding of the underlying mechanisms of disease, has proven to be nothing short of life-changing for people living with long-term conditions.
Administering these medicines, however, presents a challenge. High levels of gut degradation rule out the oral route, meaning they must be delivered parenterally.
PFS has emerged as a more suitable method than traditional needles and vials for a number of reasons. It is better suited to emergency situations and remote areas, for example, and is ideal for the self-administration required for the delivery of many monoclonal antibodies used in long-term conditions.
They also can reduce costly dosing errors by facilitating the provision of exact doses and help boost medication compliance thus helping people to avoid negative health complications. Crucially, the level of pressure needed to inject highly viscous biological products makes the use of vial-based syringes extremely challenging in the burgeoning realm of self-administration.
Put simply, the PFS and biological medicines booms are happening at the same time because the two are intrinsically linked.
As many “first wave” biological products reach the end of their patent period, biosimilars are increasingly entering the marketplace. Since 2016, more than 502 have come on-line and many more are in the pipeline.
In addition, the extraordinary potential of gene and cell therapies is beginning to show its hand. Clinical trials suggest that cell therapies could revolutionize cancer care, and that gene editing may even be able to, for example, reverse blindness caused by specific genetic mutations.
In 2018, the FDA had 500 active investigational new drug applications involving gene therapy products, and $2.3B in funding has been pumped into private gene therapy companies over the last 10 years.3
Such innovative products will need cutting-edge, patient-centric administration systems. And as medicine stands ready to take its next giant leap forward, PFS stands ready to deliver them.
Patient-Led Design
While the synergy in the rise of biological medicines and PFS is clear, the relationship between product and delivery system is fraught with challenges. We must remember that PFS are not all-purpose vessels, and that selecting the right design is not a straightforward process.
Each complex protein or peptide has a unique formulation and will differ in use and safety profile. It means that each individual product requires custom manufacturing, sterilization, filling, and compliance procedures.
When designing these processes, PFS professionals must consider a wide range of factors, such as the product’s efficacy, active pharmaceutical ingredients (APIs), characteristics and safety profile – as well as the need and preferences of the end-user.
During the drug development journey, pharmaceutical and biotechnology companies are increasingly speaking with the people they serve to ensure products are feasible, suitable, and tackle unmet needs. Consultation and patient engagement are equally important in the development of novel drug delivery systems.
One of the main benefits of PFS administration is the ability it gives patients to self-administer their medication at home, rather than traveling to see a healthcare provider. It means people must be able to use their devices safely and effectively in a non-medical setting.
Some patient groups, such as those with chronic conditions that affect dexterity for example, will have difficulty handling certain sizes or shapes of PFS. How the device is operated will also need to be tailored to the typical characteristics of the end-user.
It doesn’t matter how ground-breaking and innovative a treatment is, it will make no impact on outcomes if the patient is unable or unwilling to use it.
Technical Challenges
PFS manufacturing presents several technical challenges which, again, must be considered on a product-by-product basis.
The high viscosity of biological products, which hampers clean dispensing, is probably the most debated of all these. Often, the medication solution will “stick” to the tip of the filling needle as it withdraws from the syringe, creating a trail. Not only does this result in expensive product waste, but it makes fill levels unreliable and can lead to safety-compromising dosing errors.
As with all things PFS, there is no one single solution. Reducing viscosity through heat is not usually an option, as biologic solution stability is often temperature dependent. Other approaches have used fill needle movement to break surface tension, but this can lead to a build-up of static charge when filling products more than 1,000 centipoise into polymer syringes.
AMRI’s solution involves using a high-speed camera to film the needle motion, then aligning the retracting motion of the needles to the velocity of the pump motion dispensing of product. This process, which implements a short pause above the final liquid level, ensures the remaining product disconnects from the needle tip. It is effective, but still must be adapted to suit each individual medicine.
The choice between glass or plastic syringes has become a hot topic in recent years. Plastic is common in biologics where product viscosity requires a PFS that allows for a consistent gliding force during administration. However, it is not the right solution for every product and filling polymer products is not easy.
Improperly programmed machine movements or even minor equipment impairments can cause scratches, and while vacuum stoppering is commonly employed to overcome this, again, it does not suit every product. Customized processes, based on experience and expertise, are needed to ensure error-free filling and stoppering.
Ensuring the product is biocompatible with the drug delivery system, its components and materials is another safety-critical, not to mention regulatory mandated, process. The formulation of an injectable product will dictate a range of potential complex interactions with the syringe components and packaging, all of which can have serious ramifications for the manufacturing process and the quality, efficacy, and safety of the end-product.
Factors such as the potential of polymer or glass to interact with the product, the drug’s glass absorption parameters, pH changes, and potential extractables and leachables must all be assessed in the system design process. User-related factors, including the duration of contact between patient and PFS, and the nature of patient/delivery system interaction, will also influence PFS design and selection.
Navigating this complex tapestry of patient centricity and technical challenges requires in-depth understanding of the processes, techniques and products involved, and can only be approached on a case-by-case basis. At AMRI, an in-house analytical team serves as a valuable resource for our clients, providing expertise in extractables and leachables (E&Ls), container testing, heavy metal detection, and significantly aids in optimizing container closure design for a given product.
Partnering for Success
As outlined above, there is no one size fits all solution to matching products to an appropriate PFS delivery system. Each product is unique and requires bespoke mechanical, technical and compliance processes.
Overcoming the multitude of manufacturing and process challenges – and fulfilling the potential of this promising product/delivery system coupling – requires partnership.
With the average drug development pathway taking 10 years and costing $2.6B,2 the biological medicines marketplace is fiercely competitive. There is little room for error, but by combining pharmaceutical and drug delivery expertise early on in the development process, partnerships can ensure new medicines are safe, effective, easy to use, tackle unmet patient need – and make it to market as quickly as possible.
Developer/CDMO partnerships offer an agile PFS approach that adapts to the needs to each product and its end-users. As individual patient groups will have varying requirements of the product itself, and the packaging it is supplied in, the PFS design and development is usually most effective when it evolves in parallel to product design and development. In fact, many drug developers now work with their chosen PFS supplier as early as phase I.
Conclusion
The rise of biological medicines has played a major role in the growth of the PFS market. By necessitating a shift from oral to parenteral administration they have created a need for state-of-the-art, innovative delivery systems.
It is a trend that is set to continue as more biologics and biosimilars come online and as the promise of next generation gene and cell therapies come to fruition.
Dispensing highly viscous solutions, minimizing E&Ls and ensuring biocompatibility, all while developing delivery systems that suit individual patient groups, however, present unique manufacturing, compliance, filling and dispensing challenges.
By integrating expertise in areas such as drug processes, substance processes and analytics, CDMOs can streamline and optimize product development. Close working relationships, both within the organization and with partners and clients, can speed up problem solving and facilitate the creation of customized solutions.
Crucially, by working with PFS CDMOs, drug developers can benefit from their specialist expertise and expect shorter, smoother development pathways. Strong partnership working is the only way to ensure the innovative drug products of the future are delivered effectively, fulfil their potential and, ultimately, save lives.
References
- Barba, V. (2019). Prefilled syringe market to hit $9.7bn by 2025. https://www.biopharmareporter.com/article/2019/08/19/Prefilled-syringes-market-growth
- Agbogbo, F. (2019) Current perspectives on biosimilars. https://link.springer.com/article/10.1007/s10295-019-02216-z
- Elverum, K., & Whitman, M. (2019). Delivering cellular and gene therapies to patients: solutions for realizing the potential of the next generation of medicine. https://www.nature.com/articles/s41434-019-0074-7
Author Biography
Anish Parikh, AMRI’s Vice President, Drug Product Sales & Marketing, has more than 25 years of R&D, sales and marketing experience in the pharmaceutical industry. He earned his bachelor’s degrees in molecular biology and biochemistry (MBB) as well as psychology from Rutgers College at Rutgers University in New Brunswick, NJ.