Challenges, Innovations, and Future Outlook of Biologics Formulations

Although such biologics as monoclonal antibodies (mAbs), recombinant proteins, and nucleic acid-based therapies have revolutionized disease treatment across therapeutic domains, their utility remains constrained by a near-exclusive reliance on parenteral administration. Intravenous and subcutaneous administrations pose challenges for patient compliance, safety, and accessibility. Because of the limitations on parenteral routes of administration, the development of non-parenteral alternatives, such as oral, inhaled, transdermal, and intranasal formats, represents both a clinical imperative and a formidable scientific challenge.

An evaluation of the molecular and technical barriers to non-parenteral biologics delivery, as well as reviews of state-of-the-art advancements in formulation technologies and an assessment of current collaborative progress across the biopharmaceutical ecosystem, can shine light on where the biopharma industry stands today in terms of non-parental formulation market readiness. The latest developments led by contract manufacturers, biotechnology innovators, and academic partners will highlight the progress and outlook for emerging delivery systems poised to redefine patient-centric biologics administration (1–3).

How is the biologics delivery landscape evolving?

Despite the promise of mAbs, recombinant proteins, and nucleic acid-based therapies, more than 95% of biologics are still administered via injection or infusion. This dominant reliance on parenteral administration stems from the complex physiochemical properties of biologics, which are of large molecular weights and have structural fragility, as well as susceptibility to enzymatic degradation. These characteristics preclude simple oral dosing. However, reliance on repeated injectable dosing has been shown to result in reduced patient adherence, fear of needles, and added burden on healthcare systems (1–3).

The industry has thus turned its attention to alternative, less-invasive delivery modalities. Oral and inhaled biologics are attracting intensified R&D investment due to their broad patient acceptance, potential for home administration, and alignment with precision medicine initiatives. Market forecasts underscore this momentum. For instance, the oral biologics market is projected to expand at a compound annual growth rate (CAGR) of 35% between 2023 and 2028, while the inhalation contract development and manufacturing organization (CDMO) sector is expected to grow from $1.94 billion in 2023 to $2.7 billion by 2028, a 7.1% CAGR. In specific disease areas, such as asthma, biologic therapies are projected to reach $19.2 billion by 2031, signaling significant demand for innovations in pulmonary delivery (4,5).

What challenges present hurdles to non-parenteral biologics delivery?

Biologics are inherently more complex than small-molecule drugs owing to their large molecular weights, higher structural complexity, and sensitivity to pH, temperature, and proteolytic enzymes. Furthermore, the cost of biologics manufacturing places extreme importance on bioavailability, where even marginal losses during administration render a dosage form economically unviable (1,2,5,6).

Oral delivery of biologics faces route-specific obstacles, such as rapid degradation via enzymes in gastric and intestinal environments; impermeable epithelial and mucosal barriers, which prevent molecules larger than a few hundred Daltons (Da) from passing through (antibodies are typically >150 kDa); reduction of systemic bioavailability upon first-pass metabolism; and intestinal variability across patient populations, which further complicates pharmacokinetics (3). Clinical successes for oral biologics have been scarce, with oral peptide products (e.g., oral semaglutide) demonstrating feasibility but not yet scalability for large proteins or antibodies (7–8).

Although inhalation delivery offers direct access to systemic circulation through pulmonary vasculature, this route of administration suffers from technical and clinical constraints. Historical failures of inhaled insulins (e.g., Pfizer’s Exubera) have highlighted flaws in device ergonomics, interpatient variability, and costs as major barriers to commercialization. In addition, biologics must be formulated to remain stable during aerosolization, storage, and pulmonary transport, which often presents a steep technical challenge (2,9).

Meanwhile, a transdermal delivery option is severely limited by the outermost layer of skin (stratum corneum), which blocks hydrophilic and high-molecular-weight compounds. Advanced approaches, such as microneedle arrays, iontophoresis, and microporation, show promise but are so far limited to peptides or low-dose biologics (10).

What cutting-edge formulation and delivery technologies are in the works?

Particle engineering and inhalation platforms. Lonza is advancing particle engineering strategies to modulate pharmacokinetics and bioavailability in spray-dried powders. Collaborations with Iconovo have yielded intranasal biologics targeting obesity, leveraging the ICOone Nasal device to optimize dose delivery (11). Similarly, Lonza’s collaboration with Ethris is aimed at applying spray-drying techniques to stabilize messenger RNA (mRNA)-based vaccines at room temperature, reducing cold chain dependency while maintaining mRNA integrity (12).

In addition, CrystecPharma, in partnership with Intertek, is leveraging its modified supercritical anti-solvent (mSAS) technology to precipitate biologics into stable dry particles. Their fast-track dry powder inhaler platform accelerates development from laboratory design to good manufacturing practice and offers a robust approach for inhaled protein and peptide therapies (13).

Advanced oral delivery systems. Lonza is also pursuing smart capsules, designed for site-specific targeting within the gastrointestinal tract. These smart capsules employ mechanical and electronic components that enable release in the stomach or intestine. Bi-layer capsule technologies further allow compartmentalized release profiles tailored to molecule-specific pharmacology (14).

Meanwhile, Catalent Pharma Solutions is exploring lipid-based formulations (LBFs), building on established small-molecule solubilization methods to enhance macromolecular absorption. One promising line of research focuses on transiently modulating intestinal tight junctions to facilitate the uptake of high molecular weight biologics, a potentially transformative approach for oral mAbs (15–16).

US Specialty Formulations (USSF) has advanced QYNDR, a drinkable, protein-based oral/mucosal vaccine that demonstrated safety in Phase I COVID-19 clinical trials in 2023. Such approaches bypass the gastrointestinal degradation barrier by targeting mucosal tissue for immune activation, representing an alternative strategy for non-parenteral vaccination (17,18).

Other emerging routes. Transdermal microneedle patches, jet injectors, and sonophoresis platforms are also under evaluation for delivering smaller biologics, such as peptide vaccines. While dose limitations restrict broader application, such technologies could complement inhaled and oral products in specific contexts, particularly for pediatric or resource-limited populations (1,10).

Market dynamics and future outlook

Short-term innovations. The urgency of the COVID-19 pandemic catalyzed progress in non-parenteral biologics, particularly inhaled and intranasal vaccines. Self-administered inhalable or nebulized mRNA/lipid nanoparticle formulations targeting pulmonary diseases are anticipated in the near-term. These formats may be especially impactful for respiratory-targeted therapies, enabling localized lung delivery with systemic immune benefits (19).

Long-term challenges. Despite substantial momentum, effective oral or inhaled mAbs remain elusive. Addressing dose limitations, ensuring molecular integrity through complex biological barriers, and establishing reproducible absorption profiles remain key barriers. Moreover, large-scale clinical validation and long-term safety data will be essential before such platforms achieve widespread commercialization (2,3,7,8).

Strategic considerations. The diversity of biologics under development suggests that no single non-parenteral strategy will dominate. Instead, modalities will be tailored: oral delivery for chronic, systemic diseases; inhalation or intranasal delivery for respiratory or mucosal immunity; and transdermal approaches for lower-dose applications. The overarching driver will continue to be the pursuit of patient-centric care—convenient, non-invasive, and accessible therapeutics that reduce healthcare burdens while improving treatment adherence (1,2).

References

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2. Chauhan, V. M.; Zhang, H.; Dalby, P. A.; Aylott, J. W. Advancements in the Co-Formulation of Biologic Therapeutics. J. Controlled Release 2020, 327, 397–405. DOI: 10.1016/j.jconrel.2020.08.013
3. Muralidhara,B. K.; Wong, M. Critical Considerations in the Formulation Development of Parenteral Biologic Drugs. Drug Discovery Today 2020, 25 (3), 574–581. DOI: 10.1016/j.drudis.2019.12.011
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8. Kalra, S.; Das, S.; Zargar, A. H. A Review of Oral Semaglutide Available Evidence: A New Era of Management of Diabetes with Peptide in a Pill Form. Indian J. Endocrinol. Metab. 2022, 26 (2), 98–105. DOI: 10.4103/ijem.ijem_522_21 
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12. Ethris. Ethris and Lonza Collaborate to Develop Spray-Dried mRNA Vaccines for Respiratory Disease Prevention. Press Release. Feb. 11, 2025.
13. Intertek. Intertek Partners with CrystecPharma to Advance Formulation Science and Accelerate Development Timelines for Dry Powder Inhaler Products. Press Release. Dec. 11, 2024.
14. Lonza. Lonza Launches Tailored Offering for Smart Capsules Companies Developing Oral Delivery Solutions for Biologic Drugs. Press Release. Dec. 3, 2024.
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16. Meissonnier, J. Lipid-Based Delivery Systems—New Approaches for Macromolecule Oral Delivery, Abuse Deterrence & Bioavailability Enhancement. Drug Development & Delivery. April 2015.
17. USSF. US Specialty Formulations Completes Phase I of Clinical Trials for the QYNDR Vaccine. Press Release. Sept. 7, 2023.
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19. Global Genes. How Inhaled mRNA May Help Rare Disease Patients Breathe Easier. globalgenes.org, Jan. 25, 2024.

About the author

Feliza Mirasol is the science editor at BioPharm International®.

Article details

BioPharm International®/ Pharmaceutical Technology®/ Pharmaceutical Technology® Europe
Trends in Formulation eBook
October 2025
Pages: 6–10

Citation

When referring to this article, please cite it as Mirasol, F. Challenges, Innovations, and Future Outlook of Biologics Formulations. BioPharm International®/ Pharmaceutical Technology®/ Pharmaceutical Technology® Europe Trends in Formulation eBook 2025 October.