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Optimizing Formulation, Process Design, and CMC to Achieve Target-Appropriate Biodistribution
An Interview with:
- Evan Turek, Senior Director of Business Development
- Theresa Logan, Head of Laboratory Operations
Lipid nanoparticles (LNPs) and polymer-based delivery systems have transformed the drug development landscape, enabling the development of new classes of nucleic acid medicines and advanced therapeutics. Yet despite promising early-phase data, many programs stall before reaching the clinic. Achieving target-appropriate biodistribution while ensuring manufacturability, scalability, and CMC robustness remains a central challenge.
To explore how formulation, process design, and CMC must evolve to meet this challenge, we spoke with Theresa Logan, Head of Laboratory Operations, and Evan Turek, Senior Director of Business Development at Phosphorex.
Why does biodistribution remain such a persistent hurdle for advanced drug delivery systems?
Theresa Logan (TL): For advanced delivery technologies, specifically LNPs, biodistribution has been a long-standing challenge, as most formulations naturally accumulate in the liver and spleen due to the protein coronas they accumulate. This has worked well for vaccines and hepatic targets, but as we work toward addressing broader therapeutic applications, this default distribution pattern is limiting. It restricts selective targeting of alternative tissue types, constraining therapeutic flexibility and increasing the risk of off-target exposure, immune activation, and toxicity.
However, significant progress is being made in engineering target-appropriate biodistribution through formulation composition, lipid or polymer chemistry, particle architecture, such as the use of conjugated targeting ligands, and corresponding process design.
How do formulation and process design work together to influence biodistribution?
Evan Turek (ET):Among some in the industry, there's a tendency to segment formulation, process design, and CMC into considerations that are more discrete than they should be. Specifically, many think of a formulation's structural and compositional activity relationship as a nearly exclusive determinant of clinical potential. This approach neglects the importance of a composition's inherent relationship with clinically relevant process design and CMC, leaving manufacturability, scalability, and regulatory readiness at risk. In reality, these disciplines are deeply interdependent.
A formulation that shows promising biodistribution in the lab may behave very differently when scalable mixing methods, purification and concentration techniques, and filtration steps are introduced. Without trained expertise in the design and optimization of scalable processes and their impact on the control of critical quality attributes (CQAs), a formulation's efficacy can be significantly disrupted as development advances.
Many candidates show promise in preclinical models but falter when transitioned to clinically relevant manufacturing conditions. But a specialized partner can identify these scalability risks before a lead candidate is even selected. By guiding innovators through small-scale feasibility and re-optimization, these partners ensure a balance of both scalable and efficacious critical quality attributes (CQAs). This harmony is essential for reproducibility in vivo performance and successful scale-up, ultimately preventing the costly waste of time and materials associated with process failure.
How do biodistribution, patient safety, and process design challenges differ between LNPs and polymeric delivery systems?
TL: During early feasibility, LNP-based systems often appear relatively simple to produce, allowing rapid test article production and dosing for expression in preclinical models. However, early-phase simplicity quickly becomes more complex as programs advance and innovators better understand the delicate and dynamic relationships among CQAs such as particle size and polydispersity index (PDI), process scalability challenges, and accompanying in vivo translation difficulties. For instance, the shear sensitivity of an LNP in a scalable downstream process may lead to particle aggregation, and stem from the specific properties of ionizable and helper lipid(s) selected at a small scale.
In the case of polymeric nanoparticles, the vehicle may exhibit superior inherent shear stability; however, it may also display a high propensity for premature cargo release during the extended process hold times required at larger manufacturing scales for clinical production. An experienced service provider like Phosphorex has the expertise to preserve the biodistribution and tolerability-dependent CQAs through process development for scale-up.
ET: Polymeric delivery systems are inherently complex from the outset. Varying payload concentration requirements often need robust formulation optimization. The connections between polymer chemistry, vehicle physical properties, and in vivo half-life warrant more process development diligence than a self-assembling lipid composition. These demands make early development less prescribed, but in some applications can ultimately yield a fabrication process with fewer risk exposures than an LNP. Importantly, polymeric systems can offer greater functionality for tuning biodistribution profiles, particularly for applications where liver accumulation is undesirable.
As a result, polymeric nanoparticles can enable alternative administration route strategies that LNPs may struggle to support, provided there is sufficient formulation, process development, and CMC expertise to manage and scale these intricate systems.
How do early-phase formulation decisions shape downstream manufacturability and clinical viability?
ET:We're still seeing too many cases of innovators nominating a small-scale formulation as the lead development candidate based solely on small-animal readouts. These lab-scale formulations too often have good data, but insufficient process feasibility and/or stability assessments, exposing the advanced drug delivery system innovator or adopter to significant risk. When the formulation candidate focuses only on chemistry, components, and molar ratios, teams miss the opportunity to design a delivery system that can realistically progress to clinical production. For “right first time” success, innovators or adopters should proactively conduct feasibility evaluations for GMP production at both clinical and commercial scales.
TL: Many programs fail not because the underlying structural activity relationship is flawed, but because early formulation decisions cannot support larger-scale development, much less clinical release for human use. Even in the earliest phases, formulation decisions should be made with the GMP operation in mind to avoid limitations and challenges that can waste time and precious material.
What role does downstream processing play in achieving target-appropriate biodistribution?
TL: Downstream processing is all too often underestimated, particularly for lipid nanoparticles, yet it plays a critical role in determining whether on-target activity is preserved as a program advances. The selected unit operations and process conditions, such as tangential flow filtration (TFF), can each significantly influence particle size distribution, lipid composition maintenance, and RNA-lipid adduct formation, directly affecting in vivo performance and potentially compromising tolerability.
If these operations are not optimized with the same rigor as formulation composition, variability can be introduced, obscuring or even altering the desirable biological outcomes that qualified the candidate selection. From a CMC perspective, downstream processing is a key step where reproducibility is preserved or deviations manifest. We encourage early innovators to consider clinically relevant downstream processes to avoid significantly delaying the development timeline.
Why are well-constructed CMC programs so crucial for positioning a therapeutic for successful advancement to the clinic?
ET: An early program may demonstrate compelling expression, knockdown, or editing in the target tissues or cell types of small in vivo studies, but if innovators cannot convey a scalable process development plan that demonstrates CQA control, regulatory confidence erodes, and IND timelines can be significantly delayed or derailed altogether.
A strong CMC strategy links formulation intent to manufacturing reality. It addresses whether a delivery system can be reproduced consistently, scaled while preserving efficacy, and comprehensively characterized to ensure reliable safety.
Where do you see the most significant opportunities for advanced drug delivery systems in today's market?
ET: The industry buzz around non-viral delivery technologies for in vivoCAR-T is particularly energizing for us, and we see significant opportunity for innovators to further advance the viability of these treatments. This specialized field is attractive because in vivo CAR-T can deliver therapeutic payloads that effectively treat a wide range of cancers and autoimmune diseases, while limiting off-target adverse effects. Meanwhile, compared with ex vivo cell therapy, in vivo CAR-T significantly reduces the number of hospital visits required, thereby reducing patient burden.
We're excited that more innovations in this space are on the way, such as new target-site-binding ligands that enable more favorable CQA control through surface conjugation and purification steps of the conjugated LNP manufacturing process, without compromising binding affinity or resulting efficacy.
Additionally, facilitating new routes of administration for non-viral therapies is poised for significant research and will benefit patients with central nervous system (CNS), kidney, respiratory, and many other conditions. Given our experience with lipid, polymeric, and ligand-conjugated nanoparticles, these efforts are of significant interest to the Phosphorex team, and we are well-positioned to serve as a key resource for the industry as these programs advance.
Target-Appropriate Biodistribution Success Requires Comprehensive Strategies Throughout the Development Lifecycle
Achieving target-appropriate biodistribution is not just a formulation challenge; it spans formulation science, process design, and CMC. As delivery technologies mature, therapeutics become increasingly complex, and regulatory stringency rises. IND filing success will increasingly depend on the careful balance and integration of these disciplines from discovery through filing.
Phosphorex helps biopharma and biotech companies engineer targeted delivery vehicles by integrating formulation development, process design, and CMC strategy into a streamlined, clinically viable approach. By designing delivery systems with scalability, reproducibility, and regulatory expectations in mind from the outset, we enable partners to maintain delivery performance in vivo and de-risk the development path from candidate selection to IND filing.