Driving the Data-Rich Future of OSDs

Data-rich, data-led, data-driven — these terms increasingly define modern oral solid dose development.

As pipelines shift toward highly potent and structurally complex molecules, developers face growing pressure to better understand and control formulation and manufacturing variables that directly impact product performance. That requires far deeper process insight, generating large volumes of analytical, formulation and manufacturing data throughout development.

Process analytical technology (PAT), continuous manufacturing and real-time monitoring are helping companies move from reactive development toward more integrated and controllable manufacturing strategies. Increasingly, regulatory success also depends on the ability to demonstrate robust process understanding and data-backed control strategies.

At the same time, poorly soluble and low-permeability molecules continue to present major development hurdles. In this industry roundtable, experts identified enabling technologies such as amorphous solid dispersions (ASDs), hot-melt extrusion, lipid-based systems and advanced excipients as critical tools for improving solubility, bioavailability, scalability and overall product performance.

In the roundtable below, industry leaders discuss what it will take to navigate this next phase of OSD innovation.

Sharon Nowak

Global Business Development Manager, Coperion Health and Nutrition

Ph.D.

Uwe Hanenberg

Head of Product Development, Oral Solid Dose, Recipharm

Ph.D.

Nathan Dormer

Senior Director, Drug Product Development and Site Leader, Adare Pharma Solutions

David O'Connell

Director, Scientific and Technical Affairs, PCI Pharma Services

Ph.D.

Dom Hebrault

Associate Director, Crystallization Development & SFS, Veranova

What formulation strategies are being used to overcome solubility and permeability challenges in OSD development?

Uwe Hanenberg: One of the biggest formulation challenges today is that many new drug candidates have poor solubility or permeability. As a result, formulation scientists increasingly rely on enabling technologies that modify how the API behaves in the gastrointestinal environment. The most widely used approaches include amorphous solid dispersions, produced through technologies such as spray drying, hot-melt extrusion or newer high-energy fusion processes. These systems convert the crystalline drug into an amorphous form, improving dissolution and enabling higher bioavailability for poorly soluble molecules.

Additionally, alternative stabilization strategies are emerging. Co-amorphous systems, for example, use small-molecule co-formers such as amino acids rather than polymers to stabilize the amorphous drug, which can allow higher drug loading and more compact dosage forms. Beyond these approaches, formulation scientists are also exploring in situ nanoparticle formation, permeability-enhancing excipients and microenvironmental pH modulation to improve absorption of difficult molecules. Looking further ahead, digital tools are beginning to play a role in digital formulation design, with AI-driven models helping predict excipient interactions and screen stabilizing polymers more efficiently during early development.

Dom Hebrault: Overcoming solubility and permeability limitations in OSD development increasingly requires a science-led, integrated formulation strategy. Veranova has seen strong success combining early physicochemical characterization with enabling technologies such as amorphous solid dispersions, lipid based formulations, and targeted excipient selection. Early excipient compatibility and surfactant screening allow formulation scientists to tailor the microenvironment around poorly soluble APIs. Importantly, these approaches are paired with early stability and performance assessments to ensure gains in exposure do not compromise manufacturability or long-term stability, improving the likelihood of clinical and commercial success.

Nathan Dormer: Long-standing alternatives to overcome bioavailability challenges such as amorphous solid dispersions, particle size reduction, cyclodextrins and molecular carriers, lipid-based formulation technologies, and various nanocarriers/micelles continue to innovate. These approaches show the most consistent bioavailability improvements by enhancing solubility, maintaining supersaturation, and accelerating dissolution. Hot melt extrusion effectively enables ASDs and co-crystals, further boosting absorption. We are, however, seeing an increasing number of novel excipients that are improving solubility and miscibility through traditional formulation approaches.

David O’Connell: Poorly soluble crystalline APIs remain a central challenge in OSD development. At the most fundamental level, solubility can be improved through particle size reduction. Micronization, and increasingly sub-micron processing, increases specific surface area and enhances dissolution without altering the API’s solid state.

Beyond size reduction, classical excipient strategies focus on improving wettability. Surfactants such as sodium lauryl sulphate or polysorbates can enhance wetting and support dissolution performance in conventional formulations. More advanced approaches aim to maintain the API in an amorphous state, where solubility is significantly higher. Lipid-based systems and polymers with appropriate hydrophilic–lipophilic balance (HLB) values can stabilise amorphous dispersions.

Processing technologies such as hot melt extrusion and hot melt granulation enable APIs to be dispersed within molten carriers, preventing recrystallisation upon cooling. Spray-dried dispersions similarly use polymers (e.g. HPMC-AS) to stabilize APIs in an amorphous form following solvent evaporation. Finally, nanosuspension and nanomilling technologies combine particle size reduction with stabilizing excipients to enhance both dissolution rate and permeability.

In practice, successful strategies increasingly integrate particle engineering, functional excipients, and processing technologies to optimize bioavailability.

Sharon Nowak: Today’s complex OSD formulations including higher drug loading and poorly soluble APIs are indeed presenting challenges to manufacture of OSDs. However, innovative technologies such as hot-melt granulation in a twin-screw extruder have proven to overcome these challenges. Due to the versatile individual process sections of the extruder, and the use of specific polymers in the formulation, the crystalline structure is changed to amorphous and therefore guarantees better solubility and dissolution behavior.

In addition, manufacturers of excipients have made several improvements in excipient properties to address some of the challenges in manufacturing these difficult formulations. For example, excipients like HPMCAS (hydroxypropyl methylcellulose acetate succinate) or polyvinylpyrrolidon (PVP) can stabilize amorphous forms and control the release of the API.

In addition, for advanced manufacturing techniques like continuous processing, traditional OSD excipients are specifically being reformulated to aid in flowability throughout the continuous process. The development of coexcipients or preblended excipient/API compounds such as silicone dioxide and difficult flowing APIs are also aiding in the feeding of these ingredients to the continuous process, thus making it more efficient.

What are the primary scientific and technical barriers when transitioning a biopharma product or peptide formulation from liquid to stable OSD?

Hanenberg: The first challenge is enzymatic degradation in the gastrointestinal tract. Peptides and proteins are rapidly broken down by proteolytic enzymes such as pepsin, trypsin and chymotrypsin, meaning only small amounts of intact drug typically reach the absorption site.

A second major barrier is poor intestinal permeability. Because these molecules are relatively large and hydrophilic, they do not readily cross the intestinal epithelium. As a result, oral bioavailability for peptides can be extremely low, often below one percent. Approaches such as permeation enhancers, protective carriers and lipid or nanoparticle systems are being explored to improve transport across the epithelial barrier.

Stability also presents a significant challenge. Biologics are sensitive to temperature, moisture, pH changes and shear stress, meaning processes such as spray drying or lyophilization must be carefully designed to preserve molecular structure and avoid aggregation or degradation during storage. Manufacturing and dosing constraints can also become limiting, as the low oral bioavailability of peptides often requires higher doses than injectable formulations.

Addressing these challenges requires a strong understanding of both the underlying biology and formulation science in order to design delivery systems that protect the molecule while enabling reliable absorption.

Nowak: When using homogenization or emulsification techniques, exceptional care must be taken during the processing stages to ensure that denaturing the API does not occur, whether from heat, high shear, or particle size reduction. It is also important, if the product is to be introduced through the gastrointestinal tract that coatings be used so the actives in the API are not damaged before the proteins are absorbed — this can be done through hot melt extrusion techniques or utilizing special coatings.

How are drugmakers adapting continuous manufacturing to improve consistency and scalability?

Dormer: Using PAT — such as NIR, Raman and real-time modeling — increases consistency, enables rapid adjustments, and supports real-time drug product release. These automated strategies improve efficiency, scalability, and quality control across OSD production, in addition to being beneficial for HPAPI or high value therapeutics where right the first time is critical.

Nowak: It should be noted that both batch and continuous technologies are used by CDMOs, and considerable developments in process techniques have been made to improve changeover times and efficiency, which are of major interest in the contract manufacturing space.

For batch technologies, flexible granulation and drying components have been developed which support efficient scale-up from development through pilot and production scale. Fluid bed processing systems, for example, allow two granulation methods, drying and pellet coating within the same machine. In addition, PAT systems are increasingly integrated into granulation lines to measure inline parameters such as humidity, enabling improved process control and more accurate determination of batch endpoints.

Continuous manufacturing solutions also continue to grow with CDMOs due to their efficiencies, quick scale-up and ability to bring products to market quicker. Equipment manufacturers have also been working closely with CDMOs to develop lines that are quickly interchangeable and modular. Mobile skids as well as specialty modular design loss in weight feeders are specifically designed for quick removal and product changeover, all with containment, safety and time in mind.

In continuous work, PAT has also developed extensively. A variety of instruments such as probes for particle size measurement, homogeneity measurements via NIR, and measurement devices online for moisture are being used in both batch and continuous operations to not only improve product quality, but also to help model development and predict outcomes of future formulations.

Hebrault: Manufacturers are increasingly adopting continuous manufacturing and PAT, such as online spectroscopy, video microscopy and laser-based inline particle measurements, to improve control, consistency and scalability. Veranova views PAT as a critical enabler for transitioning from batch-based development to data-rich, adaptive manufacturing. Real- time monitoring of critical quality attributes such as particle size, particle size distribution, form, and morphology allows rapid process adjustments and reduces variability. When integrated with continuous platforms, PAT supports faster scale up, reduced cycle times, and more robust control strategies, ultimately enhancing product quality and supply reliability.

O’Connell: Continuous manufacturing offers clear advantages in consistency and scalability, but adoption within CDMOs remains commercially complex. The capital investment is significant, and platforms differ (e.g. integrated continuous lines versus modular systems). Once a CDMO commits to a specific technology, it risks limiting flexibility if customer preferences diverge. For this reason, successful implementation often depends on strategic partnerships, particularly with larger pharma companies that have robust pipelines and long-term demand to justify co-investment.

From a technical standpoint, scalability is one of continuous manufacturing’s strongest advantages. Output is increased through runtime rather than scale-up, reducing traditional batch-related variability. However, this relies on deep process understanding developed during an intensive experimental phase. PATs are central to this model. NIR spectroscopy can monitor blend uniformity in real time in direct compression systems, while moisture, temperature, and solvent removal can be continuously tracked in granulation processes. This real-time release approach enhances consistency and reduces reliance on end-product testing.

That said, establishing validated operating ranges and robust chemometric models requires substantial upfront development.

What are the biggest regulatory hurdles when introducing novel OSD technologies into global markets?

Hanenberg: The biggest hurdle is usually not that regulators object to technologies such as ASDs or multi-particulate systems. The challenge is demonstrating a clear understanding of the product’s quality attributes, in vivo performance and life cycle controls in a way that satisfies regulators across regions and supports approval and later changes.

For ASDs, one of the key hurdles is proving long-term physical stability and reproducible performance. As these systems are inherently metastable, developers must demonstrate robust drug–polymer miscibility, control recrystallisation risk and show that dissolution and supersaturation behavior remain consistent over shelf life and manufacturing changes.

Multi-particulate and modified-release systems introduce additional biopharmaceutic complexity. Regulators often expect a more comprehensive dataset to characterize release behavior, food effects and potential dose-dumping risks, alongside strong in vitro–in vivo understanding.

Another challenge is the use of novel or co-processed excipients. As these materials are typically evaluated within the context of a drug product, sponsors must provide convincing safety, quality and control data to support their use. Finally, global regulatory expectations remain only partially harmonized. Differences in bioequivalence requirements, waiver pathways and life cycle management expectations mean development strategies must also consider scale-up, post-approval changes and region-specific regulatory requirements from an early stage.

Dormer: Novel OSD technologies face major regulatory hurdles around ensuring amorphous stability, preventing recrystallization, achieving content uniformity, justifying alternative bioequivalence approaches, validating new excipients and processes, and meeting globally divergent CMC, dissolution, and control strategy expectations — all of which increase approval complexity.

Hebrault: When OSD programs are accelerated, the primary technical risks arise from incomplete understanding of API solid state behavior and formulation-process interactions. Poorly soluble compounds are particularly vulnerable to changes in polymorphic form, amorphous content, particle size distribution, and excipient-mediated mobility during processing. Rapid timelines can limit exposure to stress conditions such as compression, humidity, and thermal input, leading to unexpected dissolution or stability failures. At Veranova, we mitigate these risks through early solid state characterization, biorelevant dissolution testing, and parallel evaluation of enabling formulations, helping ensure robust clinical performance through scale up and manufacturing.

Nowak: The hurdles are the same for normal OSDs. But additionally, you must face and manage the poor stability of amorphous formulations, whereas excipients for stabilizing are necessary to be added to the formulation. This can influence and bring hurdles to stability and quality control. The analytical methods for those complex systems are often particularly challenging. It is important to note that for some novel technologies there are sometimes even no specific guidelines in place, which can present challenges to the formulators and manufacturers.

O’Connell: For technologies such as amorphous solid dispersions, spray-dried systems, or nanomilled APIs, the regulatory hurdle is often less about the process itself and more about the supporting data package. These approaches are no longer viewed as inherently novel; regulators have significant prior experience with them. However, they require a robust, technology-specific data set, including solid-state characterisation, stability (particularly recrystallisation risk), process controls, and a clear link between material attributes and clinical performance.

In practice, this means building an expanded regulatory dossier that demonstrates deep process understanding and long-term physical stability of the modified API, alongside the standard drug product submission requirements.

The greater challenge typically arises when introducing a novel excipient. In that case, regulators require comprehensive information on manufacturing, specifications, safety, and toxicology. A full excipient data package, often including detailed supplier documentation, becomes essential, and scrutiny is understandably higher. Overall, processing innovations are increasingly accepted; truly novel excipients remain the more significant regulatory hurdle in global submissions.

How do you see the global OSD segment evolving over the next 5-10 years?

Hebrault: Over the next decade, OSD delivery will increasingly rely on data-driven development, advanced enabling formulations, and model-enabled manufacturing. Veranova anticipates broader adoption of continuous manufacturing, expanded use of PAT, and greater reliance on predictive modeling to guide formulation and process decisions. Additionally, the growing complexity of small molecule APIs will continue to drive innovation in solubility enhancing technologies. CDMOs that combine deep formulation expertise with flexible manufacturing platforms will be best positioned to support faster development timelines and more resilient supply chains.

Nowak: Several of the techniques already listed will continue to grow in usage. The technologies include advanced manufacturing techniques such as hot melt extrusion, homogenization for lipid-based systems, nano particle development, and laser drilling of OSD forms.

In addition, the following trends are also becoming increasingly popular – to improve overall efficiency, improve process and personal safety and help with drug delivery to an aging population:

• The use of automated weigh dispensing for all components of the solid dosage form. The use of a highly accurate loss-in-weight feeder to dispense excipients and API components reduces manual labor, improves operator safety and quality, and reduces overall ingredient costs by minimizing losses.
• The use of easy to swallow/chew OSD forms such dissolvable tablets, powders and medicinal gummy technologies – all of these are crucial for an aging population with difficulties swallowing but also for children and adolescents.
• Finally, the use of personalized medicines and here especially the 3D-print of tablets will take an important role in OSDs. This paves the way for much smaller compact continuous blending, dispensing systems with introduction to the 3D printers.

Hanenberg: Over the next five to ten years, the OSD market is expected to continue evolving, but the market will increasingly split between high-volume commodity tablets and more complex, technology-driven oral products. Complex generics and modified-release formulations are likely to be major drivers of development activity. They offer opportunities for differentiation and present higher technical and regulatory barriers to entry compared with conventional immediate-release products.

Enabling formulation technologies are expected to become increasingly important as the industry continues to work with more poorly soluble and structurally complex drug candidates. Approaches such as amorphous solid dispersions, lipid-based systems and multi-particulate formulations are already playing a significant role in enabling oral delivery of these molecules.

Manufacturing innovation will also influence how the OSD segment develops. Technologies such as continuous manufacturing, process analytical tools and digital process control have the potential to improve process consistency, scalability and manufacturing efficiency. Outsourcing to specialized CDMOs is also expected to increase, particularly for technically complex OSD platforms such as modified-release formulations, hot-melt extrusion, spray drying and multi-particulate systems.

Overall, OSD will remain the dominant dosage form, but future growth is likely to be driven increasingly by more complex and technology-enabled formulations, including high-potency products, which are expected to see continued growth of around 6% annually, rather than simple commodity tablets.

O’Connell: Over the next 5-10 years, the global OSD segment will remain highly relevant, even as therapies become more targeted and complex. While biologics and injectables continue to grow, oral solid dosage forms retain clear advantages in patient compliance, cost of goods, and ease of administration. For many patients, oral delivery remains preferable to injections, particularly as companies explore oral alternatives in areas currently dominated by injectables, such as GLP-1 therapies.

At the same time, new chemical entities are becoming increasingly precise, often targeting specific genetic or protein pathways. This precision is driving lower dose strengths and significantly reduced occupational exposure limits. As a result, we will likely see continued growth in ultra-high potency OSD manufacturing, requiring advanced containment strategies, automation, and potentially greater use of robotics to protect operators. Complex generics and modified-release formulations will also expand, as companies seek lifecycle extension strategies and differentiated delivery profiles. As patents expire, demand for technically sophisticated generics will increase.

Overall, the future of OSD lies in greater potency, greater specificity, and greater technical complexity, but its fundamental advantages in accessibility and scalability will ensure it remains central to global pharmaceutical development.