Drug delivery primary design variable
The shift: delivery is no longer just a downstream consideration
Drug delivery has traditionally been treated as a downstream consideration in biologics development, addressed after the molecule is defined and the process established. That model has shifted. Delivery is increasingly acting as a primary design variable, shaping not only how a therapy is administered, but how it is engineered, manufactured, and purified.
This reflects a broader shift in how therapies are conceived. Development is moving away from designing molecules in isolation and toward designing therapies around real-world use. Delivery is no longer an afterthought applied to a finished product but a defining feature of the product itself.
Designing therapies around real-world use
Today, developers are starting from a different question: how will this therapy be used in practice? Decisions around dosing frequency, route of administration, and site of care are being made earlier, often before lead optimization is complete.
This shift is driven by several converging forces. In chronic disease, treatment economics and patient adherence are critical. Extending half-life is a way to reduce dosing burden and align treatment with real-world use. At the same time, healthcare systems are under pressure to move care out of infusion centers and into outpatient or home settings, increasing the importance of subcutaneous delivery.
Alongside these factors is a growing emphasis on patientcentric design. Administration time, injection burden, and device compatibility are now central considerations. Therapies are expected to fit into patients’ lives, not disrupt them.
Delivery decisions now shape the molecule
As a result, in many cases, delivery is a guiding principle that shapes the molecule from the outset. Choosing a delivery approach effectively commits a program to a specific model of use.
A long-acting therapy designed for chronic administration follows a fundamentally different development pathway from an acute intravenous treatment. A biologic intended for subcutaneous delivery in the home must meet different requirements than one administered in a clinical setting. These decisions cascade through clinical strategy, regulatory pathways, and commercial positioning.
Crucially, they also define the physical and functional properties of the molecule itself.
The downstream consequence: purification is no longer platform-safe
When delivery strategy changes the molecule, downstream processing becomes harder to predict and control. It doesn’t simply adapt, it is often fundamentally redefined. Binding interactions shift, and impurity profiles become more complex. This can include increased heterogeneity in fusion constructs, altered hydrodynamic behavior, and co-elution of structurally similar variants. These effects challenge conventional capture and polishing strategies, and established purification assumptions begin to break down.
For decades, platform purification approaches, particularly for monoclonal antibodies, have provided robustness and efficiency. But as delivery-driven formats emerge, those platforms are becoming less universally applicable. Fusion
constructs, multi-domain proteins, and systems incorporating additional functional components do not always conform to standard capture and polishing strategies.
In these contexts, selectivity, not standardization, becomes the primary requirement.
Albumin fusion: extending half-life, increasing purification complexity
Albumin fusion provides a clear example of how deliverydriven design intersects with downstream processing. By leveraging albumin’s natural recycling pathway, developers can extend half-life and reduce dosing frequency, enabling more convenient treatment regimens.
However, fusing a therapeutic protein to albumin fundamentally alters the molecule’s size, structure, and interaction profile. These changes directly impact chromatographic behavior, affecting how the molecule binds to resins and how it separates from closely related variants and impurities.
Achieving the required purity and yield often demands more selective, format-specific chromatographic approaches. In many cases, standard platform purification strategies are insufficient to fully resolve fusion-related variants or hostcell impurities, requiring higher levels of selectivity than conventional workflows typically provide.
In practice, these challenges are already being addressed through the use of selective capture technologies designed specifically for albumin-based constructs. Such approaches have been applied in both process development and cGMP manufacturing environments, enabling high-purity recovery of albumin-fusion proteins from complex feedstocks while maintaining scalability and robustness.
Hyaluronidase: enabling subcutaneous delivery, adding manufacturing complexity
A similar pattern can be seen with hyaluronidase-enabled delivery systems. By temporarily modifying the extracellular matrix, hyaluronidase allows higher-volume biologics to be administered subcutaneously, supporting the shift away from intravenous infusion.
While this transformation has clear benefits for patient experience and healthcare delivery, it introduces additional manufacturing complexity. Hyaluronidase itself is an active biological component that must be produced and purified to consistent functional performance.
This creates a parallel downstream challenge. Achieving sufficient selectivity, maintaining enzymatic activity, and ensuring scalability require carefully designed purification strategies. These challenges are compounded by the glycosylated nature of the enzyme, which introduces heterogeneity and influences binding behavior during chromatographic separation, while also requiring process conditions that preserve enzymatic activity. Unlike many therapeutic proteins, process conditions must be carefully balanced to avoid loss of enzymatic function while still achieving the required impurity clearance.
As adoption increases, robust and specialized chromatographic solutions become essential to enable reliable manufacture. This is reflected in established purification workflows, where selective chromatography steps are integrated alongside ion exchange and hydrophobic interaction chromatography to achieve the required balance of selectivity, yield, and activity. In particular, ligand chemistries that exploit reversible interactions with glycosylated structures have been successfully implemented at commercial scale, supporting consistent product quality and enzyme performance.
From platform to precision: how downstream must evolve
These examples illustrate a wider trend. As delivery considerations shape molecular design, biologics are becoming more diverse and structurally complex. Platform purification remains effective for many conventional molecules, but its limits are becoming clearer.
Rather than abandoning platform thinking altogether, the shift is toward greater flexibility. Downstream processes must increasingly be tailored to molecular characteristics, with a stronger emphasis on chromatographic selectivity, resin design, and process adaptability.
In practice, this is driving demand for purification technologies capable of resolving closely related variants, handling complex fusion formats, and maintaining performance across a wider range of molecular behaviors.
As these delivery-driven formats become more prevalent, the need for purification technologies with higher inherent selectivity is becoming more apparent. This is particularly true for modalities such as albumin-fusion proteins and enzymeenabled delivery systems, where conventional approaches may struggle to achieve the requirements needed. In these cases, access to proven chromatographic solutions, already applied in real manufacturing processes, can significantly reduce development risk and accelerate process readiness.
CMC in an integrated development model
The implications for CMC strategy are significant. When delivery strategy is defined early, molecular properties and process requirements are effectively co-defined. This creates a higher degree of interdependence between delivery, molecular design, and purification. Changes in one area propagate through the others.
Without early alignment, this increases the risk of late-stage challenges, including process re-optimization or redesign. With early alignment, it creates an opportunity to develop processes that are more robust, scalable, and fit for purpose from the outset.
As a result, downstream capability is becoming a differentiator, not only in process performance, but increasingly as a constraint on which delivery strategies are
feasible at scale. In this context, purification plays a critical role in enabling delivery-driven modalities to reach the clinic and market successfully.
Purification as a design partner
In this evolving landscape, purification must be considered as part of an integrated design process. It is no longer sufficient to optimize separation performance in isolation. Processes must be designed to accommodate variability in molecular format, maintain consistency across development stages, and support long-term manufacturing requirements.
Robustness, selectivity, and adaptability become as important as yield and purity.
More broadly, this shift is reflected in industry trends. Longacting and delivery-enabled biologics represent a growing segment of the market, driven by chronic disease prevalence, healthcare system pressures, and the need for improved patient experience. Therapies are increasingly differentiated not only by efficacy and safety, but by how they are administered and experienced.
Conclusion: aligning delivery, design, and downstream
Drug delivery is no longer a feature of the final product, it is a defining input into how biologics are designed. As delivery continues to move upstream, the separation between molecular design and process development continues to narrow.
For downstream teams, this has practical consequences. It requires earlier engagement, closer collaboration across functions, and purification strategies that can adapt to delivery-driven complexity without compromising performance.
The organizations best positioned for success will be those that align delivery, molecular design, and downstream processing from the outset, building processes that are not only effective, but inherently fit for purpose.
As delivery becomes a primary design variable, purification must become a primary design consideration alongside it. Translating these innovations into robust, scalable manufacturing processes will be critical.
In practice, addressing these challenges requires purification approaches design for selectivity from the outset.
Astrea Bioseparations works with partners across development and manufacturing to support purification of emerging biologic formats, including albumin-fusion proteins and enzyme-enabled delivery systems.
To explore how these challenges are being addressed, visit astreabioseparations.com or connect with our team.
References
[1] Pharma Excipients. Subcutaneous drugs and permeation enhancers: enabling improved delivery of biologics. Available at: https://www.pharmaexcipients.com/news/subutaneous-drugs-permeation-enhancers/
[2] Walsh G. Biopharmaceutical benchmarks 2022. Nature Biotechnology. 2022;40:1722–1760.
(Industry trends in biologics complexity and modality evolution)