Meet the authors
David Schmitt, PhD, Head of Formulation Development at Lonza
Flora Felsovalyi, PhD, Head of Pharmaceutical Services at Lonza
Orla McGarvey, PhD, Head of Process Development at Lonza
Michael Jahn, PhD, Head of Forensic Chemistry at Lonza
It’s a new era for biologic therapies, one defined by patient-centered delivery and increasingly complex formulations. The rising demand for patient-centric treatment solutions has given a boost to the self-administered drug market, which was valued at $22.79 billion in 2024 and is expected to grow at a compound annual growth rate of 10.3% from 2025 to 2030. That growth, in turn, is driving the industry’s shift toward biologic products – particularly monoclonal antibodies, Fc-fusions, and bispecifics – that require high doses in small volumes.
The availability of self-administered, high-concentration biologics is key to meeting the evolving needs of patients, providers, and health care systems. Hence this trend supports the growing use of prefilled syringes (PFS) and autoinjectors as a new standard for subcutaneous delivery, especially for patients with chronic diseases. In addition, drug companies operating in crowded therapeutic markets are increasingly relying on PFS formats as a lifecycle management strategy that helps them differentiate their products by emphasizing enhanced convenience, an improved patient experience, and more efficient delivery. Those selling points translate into tangible benefits: reduced dependence on clinics, greater patient independence, and improved adherence.
However, the shift to high-concentration biologics comes with its own challenges, not only in terms of formulation stability but also in manufacturing and delivery options. These challenges can be de-risked by addressing them at the appropriate time in the development process.
As daunting as they may seem, the challenges of high-concentration biologics formulation development are surmountable, as increasing numbers of pharma and small biotech companies are finding out. Many are turning to contract development and manufacturing organizations to help them with early integration of formulation design, container compatibility, and fill-finish strategy. Additionally, use of predictive tools such as Design of Experiments, protein stability maps, and in-silico modeling can help optimize the development of stable formulations designed to be manufactured and administered effectively. Such optimization should be at the core of a unified development plan across formulation, analytics, device and process development as well as manufacturing, as a means to accelerate timelines and facilitate commercial scalability.
Addressing the challenges
High-concentration formulations introduce complex physical and chemical properties that can compromise usability and stability, as well as present other challenges across the entire drug product lifecycle. Those challenges can complicate even those unit operations that are typically straightforward, such as mixing, filtration, and filling. Often, those challenges are further magnified in small-volume delivery formats such as PFS and autoinjectors, requiring careful coordination with device design.
In particular, increased protein concentration raises viscosity, making it harder to push fluid through a narrow needle. Patients may therefore experience longer injection times and discomfort from using more force than for a typical manual injection. High viscosity can also impact drug substance processing and drug product manufacturing steps, especially during ultrafiltration/diafiltration, potentially resulting in blockage of membranes and columns during downstream protein purification.
However, before giving into the elevated viscosity challenge, remember the importance of devising formulation strategies such as modifying ionic strength or introducing viscosity-lowering excipients to improve syringeability without sacrificing stability. Design of Experiment methods can be used to identify optimal combinations of pH, buffer systems, and excipients that reduce viscosity while maintaining target concentration in a predictable timeframe for any molecule type.
High-concentration formulations also carry an increased risk of protein aggregation and degradation because of molecular crowding and environmental stress. Aggregates threaten efficacy and heighten the risk of immunogenicity. External stressors like shaking during shipping or freeze-thaw cycles during storage can accelerate degradation pathways. Fortunately, tools such as protein surface mapping and in-silico modeling can help predict aggregation-prone regions and other molecular liabilities, thereby enabling targeted excipient strategies. Another tool, protein stability maps, provides visual representations of how a molecule behaves across different pH and buffer combinations, guiding optimal formulation selection. Robust confirmatory stability studies, conducted under ICH guidelines, can ensure that the final formulation remains stable under real-world conditions, including long-term storage.
It is also crucial to monitor for surfactant degradation, which can compromise long-term product integrity and stability. Surfactants help prevent protein aggregation at the interface of the drug product and container surfaces. Surfactants – especially of the polysorbate type – can degrade over time through oxidation or host cell protein – e.g. lipase – catalyzed hydrolysis. Host cell protein concentration increases with the active protein concentration, which typically leads to increased polysorbate hydrolysis, leading to free fatty acid particle formation or loss of protein stabilization.
Optimizing PFS success
Successfully delivering high-concentration biologics in a PFS requires more than a stable formulation. It demands a cross-functional approach in which formulation development, device characterization, and process design are addressed holistically.
Understanding the compatibility of the formulation with its intended delivery system as early as possible can reduce late-stage risk, clearing a smoother path to scale-up. Key drug product-related parameters such as fill volume, viscosity, and bubble size can ensure the desired functionality of the syringe for a given syringe type and needle gauge. Human factors and usability testing help confirm that the formulation-device combination supports ease of use for patients and healthcare providers. These steps are crucial because misalignment between formulation and device can lead to performance issues, patient non-adherence, or costly redesigns later in development.
High-concentration biologics developers and manufacturers should treat PFS development as a strategic, parallel process — not a downstream handoff. Considering their impact, PFS formats are not always needed in the clinic except in unusual circumstances; it is often more timely and less expensive to take a vial into the clinic until the overall program risk is reduced. Nevertheless, introducing PFS formats early in development allows for integrated usability insights, real-world simulation, and streamlined regulatory preparation. Stability studies, conducted under ICH conditions and in the final PFS configuration, simulate the rigors of real-world handling, such as temperature excursions and agitation, helping to confirm product robustness.
A robust development program is one that aligns analytics with process development, integrating formulation screening, device development and process readiness. Predictive tools like DoE, stability maps, and in-silico modeling enable data-driven formulation optimization that supports process scalability. Extractables/leachables testing and oxidative stress simulations provide essential insights into long-term compatibility with the final container. Additionally, coordinating formulation and process development allows for efficient tech transfer, consistent scale-up, and faster progression toward commercial readiness.
Successful delivery of high-concentration injectable biologics is shaped by how early and effectively formulation, analytical and process development, and container and manufacturing decisions are connected and integrated. It is no longer sufficient to solve viscosity, stability, and container compatibility in isolation; one must assess these interconnected requirements holistically, in the early stages of drug technical development. Starting the development process by aligning formulation and process design with the intended delivery system helps to de-risk development, reduce time to clinic, and avoid late-stage reformulations. Those benefits are particularly important for advanced modalities for which usability and stability are tightly linked, making early iteration and coordination essential.
As injectables become more popular, well-executed, high-concentration PFS products will continue to offer measurable value across the health value chain. Patients will benefit from greater independence, fewer clinical visits, and more flexible treatment routines. The PFS presentation will also help the health care system by reducing administrative burden and training requirements while minimizing medication errors. Manufacturers will gain efficiencies through lower overfill, streamlined cold-chain logistics, and reduced supply complexity.
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