Understanding the Pathway from Vial to Prefilled Syringe

Editor’s Take: The move from vial to prefilled syringe is easier to manage when formulation, device and manufacturing considerations are addressed early.

Achieving a successful drug development program requires a significant amount of planning and discussion to allow for a smooth transition between developmental stages. Starting with the initial stages of formulation development, pathway-directed planning can facilitate progress through meticulously defined phases, with each phase helping to elucidate the drug’s profile as the program amasses robust safety and efficacy data.

Yet as clinical pipelines are increasingly populated by intricate specialized modalities such as mRNA, vaccines, complex proteins, and antibody-drug conjugates, the challenges of drug development can become more acute, especially for high-concentration parenteral formulations. For many drug developers, those challenges come into focus as the development program advances into clinical Phase IIB/III. This requires them to consider the optimal mode of drug delivery: Will the final configuration be in a vial, or in a more user-centric conduit such as a prefilled syringe (PFS)? 

The fundamental challenge facing drug development organizations is selecting the most appropriate clinical pathway: whether to proceed with a vial through to commercial launch or to transition mid-development to a single-dose, single-use prefilled syringe (PFS). While vials offer speed and a well-established, low-risk route to the clinic, they may not fully address the evolving demands for patient-centric drug delivery.

Therefore, there are many factors that make PFS an attractive option, not least of which is the convenience of faster, simpler, and more accessible delivery of drug product to the patient, along with more accurate dosing and reduced risk of user error. Those benefits can translate into enhanced usability, increased safety, and greater adherence to the medication regimen, culminating in a more satisfying patient experience. A PFS presentation can also relieve providers and clinical staff of the burden of drug administration, thereby saving time, costs, and resources. In addition, a PFS can be a less wasteful and more sustainable solution due to accuracy of fill for single dose delivery and the need for fewer administration materials. Finally, the improvement in clinical outcomes resulting from ease of use and avoidance of medication errors can help to de-risk later development for pharma companies, particularly those seeking to develop a combination product, which can be a key differentiator at commercial launch.

On the other hand, the transition from vial to PFS comes with challenges, many of which are due to the associated functionality required by the end-user of a PFS versus the storage focus of a vial. Factors such as the impact of the container material on the drug product, the new interfaces to which the fluid path is subjected, the additional functionality of the primary container, the complexity of the fill-finish process, as well as usability requirements, all carry varying levels of risk. Understanding the interaction between these risk factors and the different levels of risk they pose is essential to a holistic understanding of what it takes to navigate a smooth transition from vial to PFS (Figure 1).

Key considerations in transitioning from a vial to a PFS

Fundamentally, the inherent challenges of PFS development are rooted in the move from a traditional, well-understood system, such as a vial, to a more complex one that must fulfill both static and dynamic functionality (Figure 2). Static functionality refers to all aspects of the system that maintain drug product quality throughout the entire storage and shelf-life of the product. Examples of static functionality include maintenance of container closure integrity, prevention of microbial ingress into the container, and loss of water vapor from the container itself. At the time of use, the system must also perform dynamic functions that allow the PFS to safely and effectively deliver its contents to the user by enabling a smooth and easy movement of the plunger upon injection.

Facilitating the vial-to-PFS transition requires evaluation of several key technical assessments in changing configurations, due to the formulation being exposed to new materials, interfaces, and stresses that are not present in the vial. Silicone oil, applied as a thin layer to ensure smooth movement of the rubber stopper along the syringe wall during injection, is one example of a new material or interface in a PFS. Tungsten residues is another example. The potential impacts of silicone-drug or tungsten-drug interactions, along with the associated risk of particle formation, should therefore be assessed as early as possible in the development program.

Examples of new stresses in a PFS include different surface area-to-volume ratios of the material- contacting surfaces, as well as differing ratios for the drug product and air column in the syringe. Also important are the shear stresses that may be exerted upon the drug product during injection. Ultimately, understanding drug performance in a PFS is key to a successful transition in primary containers. Such an understanding can result from consideration of several key technical aspects, including:

• Container closure integrity testing (CCIT): Typically conducted as a single, static measurement in a vial, CCIT is a multifaceted assessment of a PFS, taking into account the functionality of the plunger stopper alongside the impact of the air bubble on plunger movement during air transportation.

• Injection forces: These are influenced by drug formulation (viscosity) and the selection of needle diameter.

• Drug interface to the packaging: This pertains to the impact of silicone and tungsten on the drug formulation and particle formation, along with the associated leachable profile.

Smoothing the transitional path

Studies designed to support the vial-to-PFS transition must be well thought out to address all possible scenarios for the final product across its entire shelf-life such a transportation modes and possible misuses. Such a comprehensive approach helps to ensure product and functionality integrity in accordance with the intended stability profile. Although these studies are time-consuming and require the availability of the final formulation, they can accelerate the PFS development timeline.

Of course, adhering to that timeline depends greatly upon choosing the right time to incorporate a PFS into a drug development plan, as well as the right time to bring it into the clinic. These considerations must encompass both the technical and patient-centric aspects of drug delivery and are best addressed in the early stages of drug development.

Thorough early-stage planning can have significant ramifications for late-stage drug development. For a PFS, initial development should begin upon achievement of the formulation stage design freeze, to achieve a stable formulation in the new primary container. This stage is critical, as the PFS plays a significant role in ensuring the drug remains safe at the point of use. Furthermore, the PFS itself must be capable of undergoing a robust manufacturing process. 

Once a baseline for performance has been established, methods suitable to the specific configuration can be developed, and data collated accordingly for both drug quality and PFS performance (Figure 3).  

Ensuring a smooth transition from PFS development to PFS manufacturing can de-risk the entire pathway. All functions, including formulation development, analytical development, process development, and device development, must therefore work in harmony to devise plans for addressing obstacles in transfers, and must do so early and efficiently.

The emergence of new and increasingly complex modalities, materials, and interfaces makes for an ever-changing landscape not only for the PFS, but also for the biologic products they are designed to deliver. Adding to that complexity is the market’s determined movement towards self-injection, a trend that underscores the importance of a focused, singular development timeline facilitated by early planning. Employing a holistic and methodical approach that incorporates device functionality while minimizing impact in the drug-device interface can facilitate creation of a de-risked, customized pathway for vial-to-PFS bridging. By allowing patients to receive their drugs in a faster, more accessible, and convenient manner, such an approach serves the ultimate goal of getting the right product to the market faster for greater patient engagement.

Flora Felsovalyi, PhD, serves as Head of Pharmaceutical Services for Integrated Biologics at Lonza. She brings over 20 years of experience leading combination product development in the medical device and pharmaceutical industries, specializing in parenteral drug delivery. In this role, she leads a team responsible for developing and offering device-related services to customers, as well as non-GMP manufacturing of prefilled syringes. Throughout her career, she has authored 8 patents and four peer-reviewed journal articles and contributed to various stages of the development lifecycle, from conceptualizing and inventing new subcutaneous injection devices to the commercial implementation of dual-chamber and ocular injection devices. Prior to joining Lonza, she worked at Roche as an early-stage formulation scientist and device team leader. She holds a bachelor’s degree in agricultural and biological engineering from Cornell University, a master’s degree in biomedical engineering, and a PhD in chemical engineering from Columbia University in the City of New York.

Sahrah Parveen, PhD, is Senior Principal Scientist and Group Lead, Medical Devices and Combination Products, at Lonza Integrated Biologics. She brings more than 20 years of experience across the full product lifecycle, from early development through post-market surveillance, with expertise in diagnostic devices, implantable devices, and parenteral drug delivery systems. At Lonza, she has led the implementation of pre-filled syringe offerings and developed bespoke solutions to meet customer needs. She also leads the Device Development and Assembly Group and is an expert in combination products and vial-to-PFS transition. Before joining Lonza, she was a senior consultant in the medical device and parenteral sectors and held roles at Abbott, Novartis, and Roche, where she specialized in pre-fillable syringe technologies. She holds a bachelor’s degree in applied chemistry from Nottingham Trent University, a PhD in Chemistry from the University of New Mexico and a postdoctoral fellowship from Texas Christian University, Texas. Sahrah has co-authored 7 scientific publications.