Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Cynthia A. Challener

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The global population is aging, and the prevalence of chronic illnesses is on the rise, meaning that bio/pharmaceutical companies are seeking out new therapeutic approaches that may not only provide relief from disease symptoms but may also offer a real cure. Emerging therapies, such as genetic medicines, cell therapies, multispecific antibodies, and other novel modalities, are providing viable therapeutic options to a whole host of disease areas. However, these therapeutic modalities are highly complex and present numerous challenges to their development across formulation, manufacturing, analysis, regulatory compliance, and other activities. While significant advances have been made in the past decade, new hurdles continue to emerge as drug companies seek to bring promising candidates through the clinic and to the market more rapidly and at lower cost.

Both small and large biopharmaceutical companies developing emerging therapies must overcome a wide range of hurdles as they seek to bring their candidates forward, regardless of the modality. One of the major challenges heavily emphasized by Kate Broderick, chief innovation officer at Maravai Life Sciences, is limited access to funding. “In the current environment, finding the funding essential for supporting projects from initial discovery to first-in-human trials is extremely difficult,” she states.

A big issue for Yochi Slonim, CEO and cofounder of Anima Biotech, is the current limited understanding of disease biology, which combined with traditional drug-discovery methods and existing datasets, leads to reinforcement of pre-existing hypotheses rather than mechanistic insights.

“Genes and proteins play a critical role in the onset and progression of disease, but the conventional drug-development approach still fails to account for the complex interplay at the molecular and cellular levels, which leads to poor translatability for emerging therapies,” agrees Asim Siddiqui, senior vice president and scientific fellow at Seer.

Slonim also highlights the fact that many key disease-driving proteins, including transcription factors, scaffolding proteins, and intrinsically disordered proteins, are well established in disease pathology but remain undruggable using conventional small-molecule or biologic approaches. Furthermore, he notes that while powerful, phenotypic screening is often unable to elucidate the mechanism of action (MoA) of promising compounds.

“For these reasons,” says Slonim, “researchers often lack a clear understanding of how compounds function within disease biology, and as a result many promising molecules fail to progress, even when they demonstrate strong initial effects.”

The complexity of development due to the involvement of cutting-edge technologies such as gene editing and cell engineering that require deep scientific expertise, precise control, and extensive validation—and, therefore, longer development timelines and increased costs—is another general challenge, according to Jeng Her, founder and CEO of AP Biosciences. The lack of translationally relevant preclinical models that accurately predict treatment response in humans is an additional important issue.

Material sourcing is also often a hurdle in the development of emerging therapies. Access to plasmid DNA is often cited as a limiting factor for many genetic medicines. Ensuring the necessary supply of excipients crucial for the stability and efficacy of novel formulations that meet stringent purity, regulatory compliance, and functional requirements remains a persistent bottleneck as well, according to Marie-Sophie Quittet, head of customer relationships for Adragos Pharma.

Development of cost-effective, robust, scalable processes that afford high yields of high-quality drug substances and drug products is a key challenge for most new modalities. “Many novel therapies require intricate processes that must be efficiently scaled while ensuring batch-to-batch consistency, particularly bispecific antibodies,” observes Her. Cell therapies and viral vector-based gene therapies are also complex and difficult to manufacture, causing very high manufacturing costs and patient access issues, according to Jens Vogel, president and COO at Mirai Bio.

Difficulties with integration of automation technologies and rapid analytics is an important contributor to this issue, says Mike Paglia, chief technology officer with ElevateBio BaseCamp. He also notes that the shift to platform processes can help address some manufacturing issues, but maintaining flexibility and adaptability is also essential in optimal processes developed to produce novel therapies.

. Many regulatory hurdles exist as well. Navigating regulatory landscapes is particularly challenging, as existing guidelines were primarily designed for small molecules and biologics rather than these newer, more complex modalities, according to Her.

“Pioneering new science requires forging a new regulatory path, which for both regulatory authorities and developers can be complex and time-consuming,” Broderick comments.

Striking a balance between the technical expectations of customers and regulatory constraints is a significant obstacle, Quittet adds. “Each innovation brings unique requirements and specifications that must be harmonized with the evolving regulatory guidelines to ensure safety and efficacy,” she says.

An example highlighted by Brian Pepin, CEO of Rune Labs, is the reliance of regulators on existing clinical assessment tools for clinical endpoint validation that were developed before digital technologies and artificial intelligence (AI)/machine learning (ML), which he believes do not offer the scalability or precision required to demonstrate the effectiveness of emerging therapies.

For novel modalities, summarizes Chris Learn, senior vice-president and head of Parexel International’s Cell and Gene Center of Excellence, regulatory guidance can be limiting, constantly evolving, and differ from one agency to another. He does emphasize, though, that while the uncertainty is challenging, it also presents opportunities for developers if they take the right approach.

 Many people today are also wary about the new technologies upon which emerging therapies are based. As an example, Rajiv Gangurde, vice-president, technical at Parexel points out that patients may hesitate to enroll in clinical trials that require an invasive, investigative procedure—particularly with irreversible, single-dose administrations. He adds that emerging therapies also face the challenges common to all new medicines associated with misinformation, its influence on public opinion, and its downstream effects.

Given the diversity of novel modalities advancing in the clinic today, it should not be surprising that some development challenges are uniquely associated with specific classes of compounds. For bispecific antibodies and bispecific antibody-drug conjugates (ADCs), target selection, engineering, and safety profile management present hurdles due to the fact these molecules engage two different targets simultaneously, according to Her. “Some of the difficulties lie in identifying target pairs that work synergistically without triggering unwanted immune activation or systemic toxicity, maintaining structural integrity and ensuring proper antigen engagement, and fine-tuning protein engineering to prevent mispairing and aggregation while optimizing batch consistency,” he says.

For nucleic acid-based candidates, the biggest challenge according to Broderick is finding manufacturers that can produce products in the desired form at the appropriate quality and yield in a specified timeframe. “A lot of companies claim they can do all of these things, but in actual practice producing these drugs is much more complex than most people think,” she observes.

Small molecules that modulate messenger RNA (mRNA) biology regulators without introducing synthetic mRNA are a new approach in the RNA field. They enable disease-specific control of mRNA expression and have the potential to treat conditions that previously have been considered undruggable, according to Slonim, but present a new set of challenges, such as identifying the precise regulatory mechanisms that control mRNA function in disease, ensuring target specificity, developing new screening methods for mRNA regulation, and understanding the complex functional impact of modulating mRNA pathways.

In the field of radiopharmaceuticals, Kathy Spencer-Pike, chief commercial officer for Nucleus RadioPharma, notes that one of the biggest challenges is talent acquisition and retention, because trained nuclear pharmacists, radio and analytical chemists, microbiologists, and radiation safety experts are often not easy to find in the exact locations and in the proper timelines. She also notes that due to the short half-lives of radiopharmaceuticals, they must be administered to patients within days or sometimes hours of production. “In addition to the special equipment and knowledge needed to handle radiopharmaceuticals, developers must have a foolproof plan leveraging a complex combination of production, quality control, proper handling, and transportation capabilities to bring these therapeutics and patients together,” Spencer-Pike contends.

Stability, solubility, and pharmacokinetic (PK) optimization are three important formulation challenges for emerging therapies, according to Her. Solubility and viscosity problems can be problematic in high-concentration formulations intended for subcutaneous administration, Her adds. “Innovative strategies for use of novel excipients, predictive modeling for sequence optimization, and advanced drug-delivery systems are needed to address many of these formulation issues,” he comments.

While lipid nanoparticles (LNPs) have proved useful for the delivery of the COVID-19 mRNA vaccines, they do suffer from several limitations with respect to unwanted side effects and delivery, largely to the liver. “The challenge,” says Broderick, “is to develop delivery systems that can, for instance, target the right muscles, the brain, or nerves to treat Huntington’s, Alzheimer’s, and multiple sclerosis, respectively. However, pioneering new opportunities requires proving new technologies are safe and effective and garnering regulatory acceptance, both of which can be challenging, arduous, and time-consuming,” she says.

Vogel agrees. “Delivering nucleic acid medicines involves multiple steps once the drugs are injected, each of which is impacted by the design of the delivery vehicle, the chemistry of the various components, the size and polydispersity of the particles, the placement of any shielding and targeting moieties, and the specific formulation in terms of the ratio of the different components used. Formulation optimization therefore needs to holistically take all parameters into account,” he notes.

Formulation challenges also arise for many emerging therapies due to the need for careful control of storage conditions, according to Quittet. Storage at ultra-low temperatures requires not only specialized equipment, but formulations designed to mitigate risks. That necessitates at the least, she says, selection of materials that align with the sensitivity of these therapies and the development of sensitive, robust, and sophisticated material testing protocols to ensure the compatibility and stability of products.

The complexity of novel modalities and their manufacturing processes create hurdles for all emerging therapies, particularly those with compositions that differ greatly from traditional small-molecule and biologic drugs. A key challenge in emerging therapies, contends Mercedes Segura, vice-president of process development with ElevateBio, is the need to develop robust and scalable manufacturing processes from the start, ensuring a smooth transition into GMP manufacturing while supporting commercial readiness in the future.

The issue, adds Paglia, is not only to develop processes that are rapid, robust, and potent, but that can be consistently reproduced and scaled in multiple locations/regions to ensure global commercial success. He emphasizes the value of advanced digital quality and control systems and the need to have an overarching quality and control system that allows for standardization across many manufacturing locations.

That issue ties into the question of whether to conduct process development work in-house or outsource. If the latter is selected, one challenge then becomes choosing the right contract service provider, which, according to Christiane Niederlaender, vice-president, technical with Parexel, “depends on the scope, complexity, and timeline for manufacturing an advanced therapy asset as well as the financial, geographical, and scaling considerations that a sponsor must reconcile often without the benefit of certainty or assurances.” She does agree that moving to a decentralized manufacturing model involving distributed production across multiple, geographically dispersed locations may result in reduced transportation costs and lead times, increased flexibility and responsiveness, and enhanced opportunities for customization, but does require robust and reproducible processes.

Manufacture of nanoparticles, says Quittet, requires meticulous processes to ensure sterilization while avoiding sedimentation during filling, which can be particularly difficult for gene-modified particles and ADCs. Similarly, the need to achieve extremely high purities for gene-editing therapies and the challenges associated with developing processes that can meet these expectations while also affording high yields in a cost-effective manner are highlighted by Broderick. Quittet also notes that development of efficient and industrially feasible scalable lyophilization cycles complicates manufacturing for many emerging therapies.

When it comes to adoptive cell therapies, Segura believes that “investing early in process development (PD) with experienced PD teams and leveraging their extensive processing and testing capabilities, optimized workflows, and manufacturing platforms for both cell products and gene-modifying components not only mitigates chemistry, manufacturing, and control (CMC) risks—such as process failures, costly comparability exercises, and scale-up challenges—but also paves the way for long-term success.”

The advent of personalized mRNA-based cancer vaccines, meanwhile, poses challenges related to downscaling rather than upscaling, according to Broderick. The same is true for autologous cell therapies, for which the biggest challenge is that one batch equals one patient, and manufacturing can only be scaled out, not up, observes Vogel.

These therapies, says John Tomtishen, Cellares’ senior vice-president and Integrated Development and Manufacturing Organization general manager, require highly skilled professionals to operate in large cleanroom facilities leveraging manual benchtop equipment to produce one therapy for a patient at a time. “Automation and integrated manufacturing approaches that can lower costs, accelerate timelines, and enable commercial-scale manufacturing are pivotal to transforming the cell therapy manufacturing paradigm,” he states.

While Vogel recognizes that allogenic cell therapies enable some scale-up, he also expects the continued need for partial human leukocyte antigen (HLA) matching to present supply-chain challenges. The solution, he believes, is to replace complex ex vivo engineering and manufacturing of cells with targeted engineering of cells in vivo.

Developing fit-for-purpose analytical assays for novel therapies is complicated by many factors ranging from regulatory uncertainty to material availability and assay performance issues. “The timeline for regulatory agencies to publish analytical development guidelines can be quite lengthy, and for many emerging therapies, including those for which preliminary guidance has been published, clarity is often lacking regarding many issues, including which assays are acceptable,” Broderick comments.

One example highlighted by Quittet is the lack of validated methods for nanoparticle suspensions intended for injectable use. For instance, endotoxin testing is challenging for solutions that are already turbid; although, alternative methods are being explored when the turbidity is manageable. “Establishing reliable analytical methods involves leveraging prior knowledge and adapting to product-specific and regulatory requirements, while developing novel approaches validated over time,” she says.

Material (i.e., drug substance, drug product) availability can be problematic as well. “Material must be produced to develop an assay, but material production in turn relies heavily on analysis, (e.g., methods to assess purity and yield). So, process and analytical development need to be coupled and appropriately balanced,” Niederlaender explains. He also notes that development activities require heavy investments in terms of time and resources, which can be difficult, particularly at the onset of a project.

Of particular concern for Tomtishen is the development of potency assays for novel therapeutic modalities. He points to assays for cell therapies as being particularly challenging due to the inherent variability of cell-based products, including patient-to-patient variability and complex MoAs.

Lack of comprehensive analytical guidance is just one challenge derived from regulatory uncertainty. A more overarching issue, according to Barbara Abissi, manager of regulatory affairs for Parexel, is the lack of regulatory frameworks in many countries, which makes it difficult to properly categorize and evaluate emerging therapies. “Different regulatory authorities often operate independently without effective communication, and the resultant lack of coordination can lead to inconsistent evaluations, requirements, and timelines without predictability. These regulatory challenges underscore the need for harmonized approaches and clear guidelines to ensure the safe and efficient development of emerging therapies while maintaining rigorous oversight,” she contends.

With so many different challenges to overcome, there is no one single strategy that developers can pursue to ensure successful advance of their promising drug candidates. In fact, while some strategies apply across different challenges, in many cases different approaches are needed to address each individual challenge.

The first step is to enhance understanding of biology and human health. Siddiqui points to the promise of integrating deep proteomic insights with genomic research, known as proteogenomics, for revealing the relationships between proteins and genetic information and pinpointing the underlying drivers of disease. “Integrated proteomic workflow technologies coupled with mass spectrometry offer enhanced protein coverage beyond the limitations of affinity-based methods for known proteins on a panel. With this approach, it is possible to conduct unbiased proteomic analyses to study the effects of emerging therapies, such as profiling xenotransplantation and immune dynamics or targeting cancer vulnerabilities with RNA-based treatments,” he says. Ultimately, Siddiqui believes that by better identifying how drug interactions affect the proteome, therapies can be designed that will dramatically improve patient outcomes.

The next step is collaborating with experienced service providers, both contract research and contract manufacturing and development organizations. “Engaging with such partners as early as possible in development allows process development and regulatory expectations to be aligned,” Quittet states. She adds that proactive collaboration ensures that manufacturing processes are robust and compliant and support the complex, often bespoke, needs of novel therapeutic modalities and can streamline the transition from development to commercialization.

Due to the unique manufacturing challenges posed by radiopharmaceuticals, in fact, Spencer-Pike believes that outsourcing to established service providers with expertise in handling radioactive materials and a comprehensive distribution network can be a viable option for developers of all sizes. “Smaller biotechs can find the flexibility helpful, while Big Pharma companies can use outside partners to mitigate the uncertainty and wasted capacity that can come with building too much of their own manufacturing infrastructure,” she comments.

Another general strategy being pursed to overcome manufacturing challenges is the development and implementation of platform processes. This approach has been highly effective for increasing the efficiency and productivity and reducing the cost of recombinant protein and monoclonal antibody production, and many emerging therapy developers are seeking to establish platform solutions for novel modalities with the same goals in mind.

Such efforts are being encouraged by FDA, which published draft guidance on its Platform Technology Designation Program for Drug Development in May 2024 (1). “Reviewing and adjudicating safety and efficacy profiles across dozens of new therapy submissions each year that are each produced with custom processes and technologies is extraordinarily challenging for regulators. By moving to platform approaches, both development and approval times are reduced,” Learn observes.

Indeed, such platform technologies can allow for standardized and modular approaches to manufacturing, formulation, and delivery, according to Her. Once a product has been approved that is developed and manufactured using such platform technologies, some requirements can be reduced and review can be achieved more quickly for future products developed and produced using the same technologies, Broderick says.

In the end, Tomtishen believes that use of platform technologies within drug development, particularly for complex and diverse emerging therapies, will have a profound impact on reducing time-to-market while also ensuring patient access to safe, efficacious, and high-quality drug products.

Leveraging AI and predictive modeling tools

Underlying many strategies for overcoming development challenges posed by novel modalities is the application of AI and other digital technologies, which today are being leveraged to improve drug discovery, lead selection and optimization, process development, and manufacturing in many different respects.

“Automation, modeling, and AI when combined are impacting various stages of advanced therapy development, from initial research to patient care,” says Gangurde. He points to advances in target identification/drug design, manufacturing optimization, quality control, patient stratification, and treatment optimization algorithms.

The power of AI, ML, and other predictive modeling tools, believes Vogel, is manifested in their capacity to analyze very large and complex datasets and find patterns amidst the noise. “This new ability to leverage high-throughput platforms to generate high-quantity and high-quality data sets, particularly of in vivo data, is accelerating and derisking the development of emerging therapies. By leveraging data lakes and advanced machine intelligence, we are enabling the rapid implementation of learnings into drug and cargo design. This is creating an immense opportunity to crack the code of delivery and pioneer cures for patients in need,” he concludes.

One key example for Slonim is the analysis with AI of proprietary deep data (large-scale experimental datasets generated directly from both healthy and diseased cells), which he notes is providing unique insights into disease mechanisms and thus supporting more effective drug discovery. He highlights visual biology as an important advance that integrates experimental biology with large-scale pathway visualization. “This approach generates millions of high-content images for a given disease, capturing hundreds of cellular pathways and uncovering mechanistic insights that traditional methods cannot access and allows for building of evolving AI models that further enhance disease understanding and target discovery,” he explains.

AI and predictive modeling tools are also being used to enhance process design, augment training, and allow for rapid reporting of key performance indicators and process data, which in turn support automation of routine activities, reduction of costs, and increased consistency, according to Paglia. “The ability to have data collection, analysis, and reporting fully automated allows for reduced operating expenses, which has a direct impact on product cost of goods and allows for more rapid release of a product for treatment,” he says.

Broderick is also excited about the potential for real-time data analysis in clinical trials, which she believes will “completely change the dynamics of drug discovery and development.”

Leveraging AI and moving from subjective and episodic assessments to objective, continuous real-world monitoring with digital biomarkers could accelerate regulatory approval and improve clinical decision-making, Pepin agrees. AI models are also being used to match patients with the right therapies to optimize patient recruitment for clinical studies. The use of predictive algorithms to anticipate symptoms, such as off-times in Parkinson’s, can, furthermore, enable proactive care adjustments, he says.

Caution around the application of AI and other advanced technologies is warranted, though. “For these efforts to be meaningful, notable acceleration and efficiencies gained will have to be demonstrably shown in terms of research advancements, personalized treatment, and improved clinical outcomes,” Learn cautions.

Draft Guidance for Industry: Platform Technology Designation Program for Drug Development 

Cynthia A. Challener, PhD, is a contributing editor to 

®
Vol. 49, No. 3
April 2025
Pages: 10–15

When referring to this article, please cite it as Challener, C.A. Navigating the Complexities of Emerging Therapy Development. 

Articles

Advancement of emerging therapies faces hurdles across all aspects and phases of drug development and manufacturing.


Navigating the Complexities of Emerging Therapy Development

Nano particle molecule. Nano medicine and nanotechnology biotechnology concept. Organic or inorganic polymeric sphere, capsule, quantum. | Image Credit: ©Irina - stock.adobe.com

Drug solubility directly impacts bioavailability and absorption levels, and thus efficacy and safety.Improving the solubility properties of drug substances is therefore important for achieving optimal drug performance. Many different formulation strategies can be used to enhance solubility and bioavailability and provide consistent absorption rates that support optimal drug levels. One of the most affective approaches is use of nanoscale delivery systems for which the size, surface properties, and other attributes can be carefully controlled to support not only enhanced bioavailability, but targeted delivery and controlled release of APIs, as well as both diagnostic and therapeutic functionality (1).

Review of recent FDA approvals of small-molecule drugs indicates an increase in the percentage of novel drug products leveraging innovative mechanisms of action (2,3). Many of these molecules, according to Christian Jones, chief commercial officer at Nanoform, represent increasing structural diversity, complexity, and lipophilicity, with many insoluble in aqueous media.

In fact, with more than 90% of new drug candidates under investigation classified as poorly soluble, achieving optimal bioavailability remains a significant challenge in pharmaceutical development, adds Harsh Shah, a senior scientist with BASF Pharma Solutions. In oral formulations, poorly soluble APIs can result in high pill burdens due to the need for patients to take multiple or larger doses to achieve the desired therapeutic effect. Similarly, in parenteral formulations, poor solubility can lead to increased particle sizes, causing pain and discomfort at the injection site. Both contribute to reduced medication compliance.

Enabling technologies are therefore needed to improve dissolution and solubility in intestinal fluids, Jones says. Due to the diversity of API structures and physicochemical properties, however, no ‘one-size-fits-all’ solutions are available. “Nanoscale technologies are one area of investigation with the potential to bring previously undruggable drug candidates to the market and to reduce preclinical and clinical attrition,” Jones observes.

Nano drug delivery systems have, in fact, emerged at the forefront of advanced solubility enhancement technologies for improving drug dissolution, absorption, and overall therapeutic performance, according to Shah. Not only does nanosizing increase dissolution rates, reduce aggregation, and improve bioavailability, it achieves these enhanced properties without the need to form salts or other types of complexes, adds Nitin Swarnakar, North American application labs manager with BASF Pharma Solutions. Nanoscale systems are also often more stable and can be designed to enable controlled API release, and they can increase the performance of other approaches to solubility enhancement, such as amorphous solid dispersions (ASDs).

Drug products are considered to involve the application of nanotechnology, according to FDA, if one external dimension or an internal or surface structure is in the nanoscale range (approximately 1–100 nm) or a material or end product is engineered to exhibit properties or phenomena, including physical or chemical properties or biological effects, that are attributable to its dimension(s), even if those dimensions fall outside the nanoscale range up to 1 μm (1000 nm) (4).

Nanoform differentiates between two broad applications of nanoscale technologies: API particle-size reduction (e.g., nanomilling [5] and nanoforming [6]) and solubilization of APIs in excipient nanostructures (nanoemulsions, lipid nanosystems, polymeric nanoparticles, inorganic nanocarriers, etc.) (7). API particle size reduction improves dissolution rates and, at the lower end of the nano range, apparent solubility, ultimately boosting the fraction of the dose absorbed from of the intestinal tract, Jones explains. Within the second application, various mechanisms are at work. “Nanocarriers can keep the API in the amorphous state and improve solubility. Lipid systems might enhance solubilization into bile salt micelles or even enhance lymphatic absorption, whereas polymeric or magnetic nanoparticles might target specific tissues,” he says.

Lipid-based delivery systems, including liposomes and solid lipid nanoparticles (LNPs, particularly for messenger RNA delivery), nanocrystals, nanoemulsions, iron-polymer complexes, and micelles represent the most widely investigated nano-based drug-delivery systems (8). Others include inorganic, polymeric, hybrid, and biologic (exosomes, virus-like particles) nanoparticles.

Of particular interest are self-nanoemulsifying drug delivery systems (SNEDDS), notes Swarnakar. SNEDDS formulations typically consist of a mixture of lipids, surfactants, and cosolvents that can self-emulsify upon gentle agitation, forming stable nanoemulsions with high surface areas, improved drug dissolution properties, and enhanced permeability across biological membranes, resulting in improved drug absorption and bioavailability.

“Polymeric nanoparticles, micelles, and lipid-based nanoparticles have shown tremendous potential in improving the delivery and efficacy of drugs, particularly in the field of cancer therapy,” Swarnakar observes. Careful formulation is essential in designing these systems, though, as abrupt precipitation of the API or carrier in plasma upon administration by the parenteral route can lead to serious side effects. “Appropriate selection of functional lipids, polymers, and surfactants is crucial to ensuring the success of these drug-delivery systems,” he contends.

Nanoscale delivery optimal for the most challenging APIs

Nanotechnology is often applied to drug substances that present high solubility challenges. “Nanoscale delivery systems have emerged as a key strategy for enhancing the bioavailability of BCS [Biopharmaceutics Classification System] Class II and IV drugs, which suffer from poor aqueous solubility and incomplete gastrointestinal absorption,” notes Swarnakar.

Compounds with high lipophilicity or hydrophobicity (indicated by high logP values) usually benefit from lipid solubilization and nanoemulsifying drug-delivery systems, comments Jones. “‘Simple’ solubilization technologies can be insufficient for BCS class 4 compounds exhibiting both poor permeability and solubility (such as proteolysis targeting chimera molecules) and compounds for which solubility can be enhanced through alternative absorption mechanisms such as paracellular transport and lymphatic absorption,” he observes.

Drug substances that experience rapid and extensive metabolization can also benefit from nanoscale delivery approaches. “Avoiding first-pass gut-wall and liver metabolization by using cleverly designed nanoformulations could yield better therapies for these types of molecules,” Jones explains. He adds that for both BCS Class IV and heavily metabolized APIs, administration routes other than oral that are enabled by nanotechnology can and should also be considered.

LNPs, meanwhile, have been clearly shown to protect biologic payloads (particularly mRNA) from enzymatic degradation and enhance systemic delivery (9). Many types of nanoscale carriers have also been used in cancer treatments to enable targeted drug delivery while minimizing systemic toxicity, according to Swarnakar.

Nanoscale delivery technologies are more frequently applied to certain therapeutic areas where they address critical challenges in drug solubility, stability, targeted delivery, and bioavailability, according to Shah. Based on the approved indications for marketed drugs, application of nanoscale technology has been significant in the oncology space, followed by infectious diseases, pain management therapy, and others (8,10).

For instance, many kinase inhibitors used in cancer therapy exhibit poor solubility (11). “These compounds need enabling technologies, even more so if patient-centric treatment regimens are to be developed,” Jones remarks.

Another driver of interest in nanoscale delivery solutions noted by Jones is the shift from daily oral medications to subcutaneous long acting injectable (LAI) formulations, such as in the case of treatments for psychiatric diseases and viral infections (12,13). “In a subcutaneous matrix, an API’s release rate is governed by particle dissolution. Considering the poor solubility of most of these APIs, nanoparticle-based LAI formulations are becoming more common because they allow for tunability of the API release window/profile,” he explains.

It is important, adds Shah, to highlight the crucial role that surfactants and functional lipids play in the successful development of formulations utilizing nanoscale delivery technologies. “These excipients not only aid in solubilizing the drug, but also improve the safety and bioavailability of the therapeutic agent. By carefully selecting and optimizing these components, therefore, researchers can enhance the performance and efficacy of nanodrugs,” he states.

Due to the nature of most nanoscale solutions, they are ideal for use in combination with other delivery technologies. Combination or hybrid approaches, according to Jones, can often provide synergistic or symbiotic effects on apparent solubility, absorption, and in certain cases, even permeability.

SNEDDs are a prime example. Another is the use of nanoparticles with bound/adsorbed cyclodextrins. Amorphous solid dispersions, traditionally not categorized as a nanotech approach, can also fall into this category, Jones observes, because upon dissolution in the gastrointestinal tract, the API from a solid dispersion can form drug-rich nanoscale domains before being dissolved into bile salt micelles. Use of permeation enhancers, such as in nanocarriers with bile salts for enhanced intestinal absorption of BCS Class IV drugs, and the attachment of ligands to nanoparticles, such as mRNA-LNP vaccines with PEGylated lipids for improved stability and cellular uptake, are other hybrid approaches of note, says Swarnakar. BASF has also integrated SNEDDs and ASD technologies to improve the physical stability, solubilization, and absorption of the model drug ritonavir.

“By combining nanoscale solutions with other delivery technologies, it is possible to significantly enhance solubility, stability, absorption, and targeted delivery, making these approaches powerful tools in modern drug development,” Swarnakar states.

Jones concludes that, “Drawing hard boundaries around enabling technologies is usually needless.”

Although nanoscale delivery technologies clearly enhance solubility and bioavailability for many types of drug substances and formulated drug products, developing them is not easy. Several challenges across raw material sourcing, manufacturing, formulation, quality control, and regulatory approval must be overcome in the process, according to Shah.

One of the primary obstacles in developing nanoscale delivery solutions for poorly soluble APIs is ensuring the quality and purity of the excipients used in these formulations. For instance, liposomal drug-delivery systems and solid LNPs rely on excipients of natural origin, making excipient purity a critical factor. “Variability in starting materials can lead to inconsistencies in batch manufacturing, ultimately affecting drug efficacy and safety. Endotoxins, meanwhile, pose a significant challenge in manufacturing processes due to their presence in bacterial sources,” Swarnakar observes. Thorough testing and control of elemental impurities, microbial content, and endotoxin burden is therefore essential for all parenteral excipients.

Ensuring formulation and process robustness can also be difficult but is crucial for minimizing batch-to-batch variability. “Maintaining critical quality attributes (CQAs) such as particle-size distribution, surface charge, and stability throughout the product’s shelf life requires a comprehensive understanding of formulation science and process parameters,” Shah says. He adds that degradation pathways must be well-characterized to ensure long-term stability and therapeutic performance.

Another important issue noted by Jones is the need for economical production scaling, as without a robust production process, no nanotechnology can reach clinical and market maturity.“Joint efforts of experienced engineering and formulation teams and well-grounded science are needed to overcome the challenges of efficient scale-up,” he contends. To that end, Nanoform developed a proprietary nanoforming technology that has been shown to be effective at producing several tons of API nanoparticles per year.

Even choosing appropriate packaging can present hurdles. “Ensuring the compatibility of a formulation with container materials to prevent leaching of components is particularly important if solubilizers are used in the formulation,” Swarnakar explains. BASF is working on research projects to target chemistries that help reduce compatibility issues. For instance, he notes that recent studies show that the company’s biosurfactants ensure the physical stability of proteins by covering their interactions with interfaces (air-water) and vial surfaces (e.g., glass or polydimethylsiloxane), as well as with themselves.

The regulatory aspects of nanoformulations can also present challenges. While regulatory approval of orally administered “simple” nanoformulations (e.g., nanomilled or nanoformed APIs) is straightforward, Jones notes that for nanocarriers that might linger in the body (e.g., inorganic nanosystems), early consultation with regulatory bodies is highly recommended to avoid caveats at later stages of development.

Despite these challenges, Shah emphasizes that advances in formulation technologies, process optimization approaches, and regulatory standardization are making nanoscale drug delivery more viable. Strategic collaborations between industry, academia, and regulatory agencies are also playing a crucial role in accelerating the development and approval of nanomedicines for poorly soluble APIs.

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Cynthia A. Challener, PhD, is a contributing editor for 

®
Vol. 49, No. 3
April 2025
Pages:16–19

When referring to this article, please cite it as Challener, C.A. Enhancing Solubility and Bioavailability with Nanotechnology. 

Advanced solutions are improving drug dissolution, absorption, and overall therapeutic performance.

Enhancing Solubility and Bioavailability with Nanotechnology

Magnified View of Lipid Nanoparticles | Image Credit: ©Aniwat - stock.adobe.com

Addressing the challenges posed by the limited bioavailability of many small-molecule APIs and the instability and inability of nucleic acids to pass through cell membranes has become an important goal within drug development. Most efforts have focused on finding delivery systems that enhance stability and solubility, facilitate cellular entry, and ideally allow effective targeting of specific cells, tissues, and/or organs. Nanoparticle systems, with their small size, high surface areas, and adjustable functionality have attracted significant attention (1).

Most prominent systems to date have been lipid nanoparticles (LNPs), which have been shown to be effective for the delivery of RNA and DNA. LNPs have their own limitations, however, which is driving interest in the development of other nanoparticle delivery systems, including both inorganic and organic alternatives. Three organic options with real potential include exosomes, polymeric nanoparticles, and DNA-based nanoscale frameworks.

While LNPs are currently the go-to solution for delivery of nucleic acids, there is significant room for higher-performing alternatives, as LNPs face several limitations that impact their effectiveness as drug-delivery systems, according to Grant Boldt, chief operating officer at CPTx and gxstrands.

These issues include poor stability, a limited loading capacity for drug substances, manufacturing process scale-up challenges, and the small number of approved lipid excipients available for LNP formulation, notes Tom Tice, senior director global strategic and technical marketing for parenteral drug delivery with Evonik Health Care.

LNP instability is of particular concern. “LNPs can potentially be unstable during storage, leading to drug leakage,” Boldt observes. They are also subject to rapid clearance from circulation, reducing their bioavailability.

In addition, LNPs suffer from challenging extrahepatic delivery, says Davide Zocco, head of exosomes development at Lonza. Specifically, intravenously injected LNPs are mostly absorbed by the liver, with limited exposure to other tissues. “While new lipid chemistries have been developed to facilitate extrahepatic delivery, no (successful) clinical data have been reported yet,” he says. Furthermore, achieving effective endosomal escape and intracellular delivery remains a significant challenge, limiting the successful release of therapeutic cargo into target cells, Boldt adds.

Other challenges highlighted by Zocco include limited activation of mucosal immunity required for successful intranasal administration of vaccines, risk of unwanted immunogenic reactions, and limited evidence of the ability of LNPs to deliver other drug substances such as proteins.

The advantages of nanoscale delivery systems have led to significant efforts to identify other forms of nanoparticles without the limitations associated with LNPs. FDA guidance (2) considers nanomaterials, such as nanoparticles, as materials with dimensions within the nanoscale range of approximately 1nm to 100nm or outside the nanoscale range (up to < 1000 nm) if they exhibit properties or phenomena that are attributable to their dimensions, Tice observes. Alternative inorganic and organic solutions are under investigation. Leading inorganic nanoparticle technologies include those based on gold, iron oxide, and mesoporous silica nanoparticles, as well as quantum dots.

Organic options include extracellular vesicles such as exosomes; polymeric nanoparticles such as dendrimers, polyplexes, and polymersomes; DNA nanostructures; self-assembling peptides; and virus-like particles (VLPs).

While polymeric and inorganic NPs are synthetic, exosomes are produced by cells, and their molecular composition varies depending on the cell source, according to Zocco. Their potential as delivery vehicles is, adds Tice, primarily based on their ability to mimic important cellular interactions and signaling. Exosomes also, notes Boldt, leverage their natural origin and tissue tropism for targeted and biocompatible delivery. DNA origami and other DNA nanostructures, meanwhile, provide precise structural control, programmability, and multifunctionality for advanced therapeutic payloads, Boldt says.

Polymeric nanoparticles are, says Tice, among the leading organic technologies with demonstrated utility in the clinic. Most notable are those based on polymers already used as excipients in drug formulations, particularly bioabsorbable, biocompatible poly(lactide-co-glycolide) polymers (LG polymers), and poly(ethylene glycol) (PEG)/LG polymer copolymers (diblock polymers). Typically, polymeric nanoparticles are designed for drug targeting and to be taken up by cells such as T-cells or the spleen for immunotherapy, Tice adds. In addition, they can provide immediate release or extended release of their active ingredients.

Dendrimers, with their highly branched architecture, enable efficient drug encapsulation and controlled release, Boldt comments. He also notes that self-assembling peptides are gaining attention for their ability to form stable and versatile nanostructures, and VLPs are of interest because they mimic the efficiency of viral delivery while avoiding infectious risks.

“These technologies offer unique and complementary properties, enabling tailored solutions for specific therapeutic applications and enhancing the potential for effective and targeted drug delivery,” Boldt concludes.

Exosomes, observes Zocco, are nanoparticles naturally produced by cells to maintain cell homeostasis (e.g., disposal of molecules) and communicate with other cells through material transfer or surface receptor-mediated signaling (kiss and run mechanism). “As a result,” he says, “they can be exploited to deliver drugs to specific tissues across biological barriers and, given their physiological role, with a lower risk of triggering adverse immune reactions as compared to other organic or inorganic nanoparticles.”

Development of exosomes as drug delivery vehicles does present some challenges, though. Given the high heterogeneity of exosomes, critical quality attributes (CQAs) of exosome-based drugs are not clearly defined, and companies need to proactively engage with regulatory bodies to define their path toward clinical development and commercialization, according to Zocco.

In addition, the development of analytical technologies to characterize exosome-based drugs is an ongoing effort (e.g., single-particle analysis), and as yet no single technology has been generally adopted to address CQAs. “As a consequence,” Zocco notes, “acceptance criteria ranges may change depending on the chosen technology. Furthermore, most analytical technologies have been developed for exosome characterization, with only a handful of them supporting qualified assays for quality control in good manufacturing practice (GMP) manufacturing.”

There is also a lack of expertise in, and scalable processes for, the scalable manufacture of exosomes, according to Zocco. This issue is further exacerbated by the fact that most developers establish their own exosome manufacturing processes using specific cell sources (and media), and no exosome manufacturing platform (and cell source) has been widely accepted yet.

Finally, unlike LNPs for which delivery of nucleic acids has been effectively demonstrated, loading of exosomes with this type of drug substance has proven challenging. “While surface linking with antiSense oligonucleotides and small-interfering RNAs has been demonstrated, luminal loading via electroporation or other means has been largely unsuccessful. Cell engineering strategies or alternative technologies for post-production loading are required to advance the field further,” Zocco concludes.

Despite the challenges, exosomes are still an exciting and innovative drug delivery system, Zocco believes. “While it’s likely that exosomes will not replace LNPs or other nanoparticles any time soon, they may provide a valid alternative to developers that are willing to solve the challenges and benefit from their natural ability to deliver molecules designed to improve health and treat disease,” he concludes.

Lonza’s EngX drug delivery system, which achieves surface and luminal loading of therapeutic molecules into exosomes via linkage to the expressed proteins prostaglandin F2 receptor inhibitor in the EWI (glutamine-tryptophan-isoleucine) immunoglobulin superfamily and brain-abundant membrane-attached signal protein 1 in the myristoylated alanine-rich C-kinase substrate protein family, respectively, is one example of an exosome technology being investigated in clinical trials. Other companies employ similar approaches with exosome shuttle proteins mediating active loading into exosomes, according to Zocco. “Using these systems, efficient loading of large proteins (e.g., gene-editing elements), nucleic acids (e.g., messenger RNA), and even viruses (e.g., adeno-associated viral vectors) has been demonstrated.”

Lipid nanoparticles can include liposomes (lipid vesicles that have at least one lipid bilayer with or without a PEG lipid) and lipid vesicles without a lipid bilayer and comprising multiple lipids, including a PEG lipid and an ionizable lipid designed to deliver messenger RNA. Compared to these LNPs, LG polymer nanoparticles, which have a wide range of tunable properties and performance qualities, can better meet the needs of today’s new modalities, according to Tice.

LG polymer tuning includes manipulation of polymer molecular weight, lactide/glycolide ratio for hydrophobicity tailoring, and end-group structures, says Tice. Nanoparticles made with PEG/LG polymers, meanwhile, have PEG molecules oriented on their surfaces to which various molecules can be attached to increase targeting properties and/or active ingredients.

Compared to LNPs, LG polymeric nanoparticles can support higher drug loading levels and release drugs over longer periods, Tice observes. In addition, they do not require self-assembly and can be produced using more controlled and scalable processes, such as emulsion-based continuous nanoencapsulation. They are also simpler than LNPs, requiring a single polymer excipient, and can be lyophilized and stored at refrigerator temperatures.

As with other technologies, there are some challenges to using polymeric nanoparticles for drug delivery. Tice highlights encapsulation of water-soluble drug substances with high encapsulation efficiencies as potentially presenting difficulties. However, the tunability of polymeric nanoparticles often makes it possible to overcome this issue by modifying the polymer properties and developing an appropriate and optimized manufacturing process. He also notes that optimal processes often help address any scaling challenges, with typical batch sizes for clinical trial materials ranging from 1 to 10 kg.

Ongoing research is also leading to further progress with polymeric systems designed to mimic the biological compatibility and complexity of therapeutic mechanisms of action, and particularly those that can serve as alternatives to lipid-based drug delivery systems, according to Tice. “The goal is to combine the biological performance advantages of lipid-based systems with the process and manufacturing advantages of polymer-based drug delivery systems,” he states.

One of the newest organic nanoparticle technologies in development involves the use of DNA-based nanostructures, which Boldt believes offer distinct advantages for drug delivery due to their highly programmable and customizable structures. “DNA-based nanoparticles are biocompatible, biodegradable, and allow precise control over size, shape, and ligand display, enabling targeted and efficient delivery,” he states.

As importantly, DNA-based nanoparticles can carry multiple therapeutic payloads and demonstrate improved cellular uptake and endosomal escape capabilities, according to Boldt. In fact, DNA nanostructures provide superior structural control and multifunctionality compared to other organic options, offering enhanced adaptability for complex therapeutic needs, he says. “Furthermore, compared to alternatives, they exhibit very low immunogenicity and can be easily modified chemically for targeting or payload attachment,” Boldt notes.

Boldt concludes that given their high biocompatibility, minimal toxicity, and biodegradability, DNA-based systems represent a promising platform for the delivery of advanced, personalized, and genetic medicines. In particular, CPTx believes DNA nanostructures are ideally positioned to serve as a versatile and effective next-generation solution in genetic medicines.

Given the nascent nature of this technology, DNA-based nanoparticle delivery systems not only offer exciting opportunities for innovation and progress, but also present many hurdles to commercial development that require specialized expertise in DNA manufacturing and manipulation as well as drug development in general.

For instance, Boldt notes that nuclease degradation in biological fluids and rapid clearance from circulation presents initial challenges that are being addressed with ongoing advancements in stabilization techniques and delivery strategies. Efforts underway to development enhanced cellular uptake and overcome endosomal entrapment are also proving to be promising. Potential immunogenicity issues, meanwhile, are being overcome through sophisticated design approaches, ensuring safer therapeutic use. Regulatory validation is also a necessary step, but one that represents an opportunity to establish robust standards that will facilitate broader adoption across the industry, according to Boldt.

“By overcoming these challenges, the immense potential of DNA-based nanoparticles as a transformative platform for drug delivery can be fully realized, opening doors to more precise, effective, and personalized medical treatments,” Boldt states.

CPTx is one of only a few companies at the forefront of DNA-nanoparticle-based drug development and working to realize its potential. The company is focused initially on the development of DNA nanostructures for targeted self-gene delivery to specific cell and tissue types. “Our innovative approach leverages the delivery of genes as single-stranded DNA (ssDNA) vectors, offering remarkably low immunogenicity and enabling the potential for repeat dosing—an exciting leap forward for applications like in vivo chimeric antigen receptor T-cell therapies,” Boldt explains.

Proprietary technologies needed to achieve successful scale-up and meet rigorous regulatory requirements for clinical and commercial therapies have already been established, according to Boldt. In particular, CPTx’s processes for production of ssDNA strands and nanoscale DNA frameworks for drug delivery applications allow for efficient, economically viable manufacturing at the large scales needed to meet the demands of several high-impact unmet medical needs. Advanced analytical methods have also been developed to ensure safety, efficacy, and compliance throughout the regulatory process and address the challenges associated with introduction of novel modalities.

Big expectations for nanoscale organic delivery technologies

In the near term, LNPs are expected to remain a preferred option for nanoparticle-based drug delivery. The unique properties of alternative systems, including exosomes, polymeric nanoparticles, and DNA-based nanoscale frameworks, offer the potential for improved performance over LNPs for many drug substances and therapeutic applications, including cancer, autoimmune and infectious diseases, inflammatory conditions, and genetic disorders (1).

Rumiana Tenchov. Nano-sized Drug Delivery Systems Can Treat Cancer, HIV, and More. Chemical Abstracts Service Insights, August 30, 2024.

Guidance for Industry: Drug Products, Including Biological Products, that Contain Nanomaterials

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Vol. 49, No 2
March 2025
Pages: 14–17

When referring to this article, please cite it as Challener, C.A. Organic Nanoparticle-Based Drug-Delivery Systems as Alternatives to Lipid Nanoparticles. 

Exosomes, polymeric nanoparticles, and DNA nanostructures offer many potential advantages.

Organic Nanoparticle-Based Drug-Delivery Systems as Alternatives to Lipid Nanoparticles

The careful design and development of formulated oral drug products are key to ensuring patient acceptability and compliance for achieving the desired clinical outcomes. Many APIs are extremely bitter or have other aversive attributes that can make developing palatable drug products challenging, notes Nazim Kanji, executive director of pediatric services with Quotient Sciences. Several factors can influence palatability, including the chemical structure of the drug substance and the finished medicinal product formulation, as well as the excipients used. “Undesirable taste is a common problem seen in medicines spanning all therapeutic areas, from antibiotics and painkillers to antihistamines and decongestants,” Kanji notes.

Taste masking of oral dosage forms is, therefore, an essential component of formulation development. A one-size-fits-all approach is not available, however, according to Ashish A. Joshi, pharma technical and business manager with BASF Pharma Solutions. Taste-masking strategies, he observes, must almost always be tailored to various aspects, such as the degree of inherent bitterness of the drug, the type of dosage form, the patient age-group, and whether the final formulation is in a solid or liquid form.

As the percentage of drug substances in development suffering from bitter tastes has increased and many new formulation and delivery strategies have been introduced to increase patient convenience and compliance, taste-masking technology has therefore evolved. In addition to more traditional approaches such as the use of barrier coatings, solid dispersions, and the addition of sweeteners and flavoring agents, formulators are leveraging newer strategies such as liposomes, various forms of complexation, co-crystal and pro-drug formation, emulsification, and microsphere and encapsulation technologies.

As part of developing palatable pediatric and patient-centric drug products such as solutions, suspensions, and orally disintegrating tablets (ODT), several recognized approaches can be taken to mitigate the poor taste of these APIs. “The most common approaches include using a combination of flavors and sweeteners to mask a bitter taste or barrier coatings to prevent the release of API from the drug product into the buccal cavity prior to the dose being swallowed,” comments Kanji.

Some advances in taste-masking technology are improving on these basic approaches. Researchers are, for instance, exploring methods to enhance both the perception and physicochemical stability of long-acting flavors through encapsulation and complexation techniques, according to Joao Marcos Assis, global technical marketing manager at BASF Pharma Solutions. Joshi adds that certain zinc salts have also demonstrated the ability to mask bitter taste effectively.

Improvements in pH-dependent barrier film coatings, meanwhile, have helped to overcome the coating inefficiencies for fine (small particle size) drug substances that require extended processing times due to their large surface areas. For these APIs, additional steps or approaches such as drug granulation to increase particle size or drug layering in inert pellets, can be used, Assis observes.

Lipids and insoluble polymers such as stearic acid, ethyl cellulose, and carnauba wax, when used in combination with surfactants, have also been shown to be promising as effective taste-masking approaches for drug particles. “These hydrophobic materials have low solubility in the mouth, contributing to improved taste-masking properties,” Joshi explains. He does caution, though, that it is important to be aware that use of lipid coatings may result in changes in a drug substance’s release profile, thus potentially impacting drug bioavailability.

Reverse-enteric polymers have become increasingly attractive as taste-masking polymers due to their pH-dependent solubility; they do not dissolve in the mouth at salivary pH, but once exposed to the acidic pH of the stomach, dissolve immediately to release the drug substance.

When these types of polymers are employed, the coating composition and level must be carefully balanced to prevent drug release during the residence time in the buccal cavity (e.g., up to 30 seconds for orally disintegrating tablets) while still allowing adequate drug release in the gastrointestinal tract to ensure that pharmacokinetic (PK) performance is not compromised, according to Kanji. “Realizing this balance can be a challenging prospect and may not be accurately predicted by in vitro dissolution testing,” he observes.

One example noted by Assis is a copolymer of methyl methacrylate (MMA) and diethylaminoethyl methacrylate (DEAEMA), which exhibits a lipophilic characteristic and does not dissolve at neutral to basic pH due to the amino functional group. “This lipophilic quality is very beneficial to the process [because] it reduces the required coating level for taste-masking purposes and provides moisture protection for sensitive drugs,” he observes. With these attributes, the drug substance becomes more suitable for liquid taste-masked formulations, where well-coated particles can be suspended in a neutral pH liquid, enabling the creation of a taste-masked suspension.

In the dry-powder form, water-insoluble matrices have been used effectively in melt-granulation processes, Joshi adds. During extrusion, the polymer covers the drug substance and forms a stable barrier layer once the granules are cooled. “The key advantage of this process is that it does not use any water or solvents and thus achieves efficient taste-masking of a moisture-sensitive drug substance while minimizing its possible degradation due to exposure to an aqueous or organic coating process,” he comments.

Another benefit to melt-granulation is the reduced process time compared to film coating, according to Assis. It can also be implemented as a continuous process, he notes. Reverse-enteric polymers in the dry state may also be suitable for the development of hot-melt extrusion formulations, allowing the production of taste-masked amorphous solid dispersions with improved solubility and taste, Assis remarks.

Using a mixture of water-soluble and insoluble polymers represents another newer strategy. “Tailoring the ratio of a polyvinyl acetate (PVAc)-based water-insoluble polymer and a water-soluble pore former such as a polyvinyl alcohol-polyethylene glycol (PVA-PEG) copolymer in a barrier coating allows efficient taste-masking to be achieved without significantly altering the release profile of the formulation,” Joshi explains.

The assessment and optimization of the polymer coating can be efficiently undertaken by integrating drug product formulation development and manufacturing with clinical testing activities, says Kanji. Quotient Sciences, for instance, uses a proprietary drug-development platform that enables drug products to be manufactured, released, and dosed in healthy subjects in a matter of days so that compositions can be optimized based on emerging clinical data. In addition to PK data, each formulation’s palatability attributes (e.g., bitterness, mouthfeel, grittiness, and aftertaste) can also be assessed as part of the same study, Kanji adds.

Following development of the taste-masked dosage form, confirmation of acceptability is achieved via palatability assessment of the drug product, thereby providing assurance that poor taste will not impact patient acceptability and compliance, Kanji concludes.

Lipid excipients are also being explored as encapsulating agents. One example highlighted by Joshi involves dispersing the drug substance in molten stearic acid or glycerol monostearate followed by atomization in a cold environment using a melt-congealing microencapsulation process. “This approach is particularly useful when the API is both extremely bitter and highly sensitive to moisture because it allows for effective taste-masking without the use of a typical aqueous barrier coating,” he contends.

Masking the taste of highly bitter drug substances in liquid dosage forms (solutions or suspensions) remains a significant challenge. Despite advances, effective taste masking can still be difficult when a drug substance has multiple taste and/or sensorial attributes (e.g., bitter, metallic, burning sensation), according to Kanji. This situation is particularly true for liquid formulations, which typically rely on the use of flavors and sweeteners for taste masking, he notes. Barrier coatings may also lose their effectiveness over the shelf-life of the product due to continuous exposure of the API to water, Joshi adds.

One new solution is to use micelle-forming surfactants, liposomes, or cyclodextrins to protect the drug substance. “For instance, in an aqueous environment,” Joshi comments, “certain surfactants and poloxamers form micelles that can entrap the drug substance, forming transient inclusion complexes, thus shielding it from the tastebuds and effectively masking its taste. This approach, he observes, also has potential for use in other dosage forms, such as gummies.

The use of water-in-oil (W/O) emulsions for taste masking of soluble APIs is another promising approach for liquid formulations, according to Assis. “In this case, the drug substance is effectively encapsulated within the water phase, which is surrounded by the continuous oil phase, preventing it from coming in direct contact with the taste buds and thus masking unpleasant tastes such as bitterness,” he says.

The water-soluble API is dissolved in the aqueous phase. The continuous phase comprises an oil with an acceptable taste profile, with medium-chain triglycerides (MCTs) being of particular interest, as well as surfactants with both low and high hydrophilic–lipophilic balances (HLBs) as the emulsifiers, Assis observes. He notes that polyoxyl 40 hydrogenated castor oil with a high HLB of approximately 14 to 16 is recommended for solutions and suspensions because, unlike other emulsifiers, it has a more pleasant taste. Additionally, glycerol monostearate type II (mono- and di-glycerides) is an excellent alternative as a co-emulsifier due its low HLB value of approximately 3.8.

The water phase is dispersed within the continuous oil phase, and the resulting O/W emulsion has the drug substance “hidden” within the emulsion droplets, which act as a barrier between the API and the taste receptors, Assis says. The oil phase surrounding the water droplets, meanwhile, prevents release of the drug substance while it is in the mouth; release occurs only once emulsification and absorption take place in the gastrointestinal tract.

Solutions for high drug-loading formulations

One important trend in oral dosage drugs is development of high-drug-loading formulations. “High-dose drugs in solids can be very tricky and demand better approaches to improve their taste profiles,” Joshi says. For instance, he notes, traditional barrier coatings can be challenging as long coating processing times are often required to achieve the desired level of masking.

One alternative is to use a dual-granulation coating approach to establish a barrier coating. “In this process,” explains Joshi, “the coating polymer not only covers the API and excipients, but also acts as a binder that enables formation of larger granules. The result is effective taste masking combined with improved flowability and compressibility of the drug product.” It is necessary, though, to use appropriate cushioning agents/plasticizers to maintain the integrity of the polymer following compression into a tablet. Certain methacrylic acid polymers can be effectively used in this application.

Development of additives for oral dosage drugs that block the receptors in the mouth that perceive bitterness has been a goal for many years. Taste buds elicit taste responses using G-protein coupled receptors (GPCR) or ion-channel receptors. Modulating their responses using compounds that block these receptors would be an effective means of eliminating the perception of specific tastes, according to Joshi.

This approach remains challenging, however. Such compounds need to be safe and provide transient and reversible modulation so that a patient’s taste perception is not affected for a long time after consuming the drug, Joshi says. In addition, there are at least 25 different, highly genetically diverse bitter taste receptors, and the drug substance-taste receptor pathway is not always known, Assis observes. Despite these challenges, a few specific compounds referred to as bitter blockers have been developed that interfere with the taste transduction process, at least to some degree, by inhibiting the taste cascade (interrupting the GPCR signal cascade), says Assis.

A few other approaches are also being explored. For instance, the API, which typically exists as a salt of some kind, can be converted into a more palatable compound, such as a prodrug, freebase, or different salt, according to Assis. It is necessary when using this strategy, however, to carefully consider the formulation development time and to assess any potential changes in pharmacokinetics.

Finally, complexing agents like ion-exchange resins and cyclodextrins can be used to prevent interaction of the API with bitter receptors. When using these approaches, Assis emphasizes the importance of considering factors such as the potential for drug-resin dissociation and the amount of cyclodextrin needed, respectively, as these factors may impact dosage size and costs. Cyclodextrin, for instance, can not only be very costly, but also may need to be used in a high quantity to ensure effective complexation with the drug substance at the molecular level.

Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology®.

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Vol. 49, No. 1
January/February 2025
Pages: 17–19

When referring to this article, please cite it as Challener, C.A. Evolving Approaches to Taste Masking. 

Increasing API and formulation complexity and new delivery strategies are driving innovations in taste-masking.

Evolving Approaches to Taste Masking 

Demand for biosimilars is predicted to be expanding at a compound annual growth rate of nearly 18% from $9.4 billion in 2023 to $66.9 billion in 2028 (1). This strong growth reflects both higher acceptance and adoption rates and increasing numbers of approvals in multiple regions. By mid-2024, 40 biosimilars had been approved by FDA in the United States, with 25 products launched to the market. While this growth is attracting new entrants, hurdles to developing cost-effective and competitive biosimilars remain. In addition to the need to clearly demonstrate biosimilarity to reference branded products, manufacturing complexity, including scaling challenges, must be overcome.

Developing a biosimilar starts with characterization of the reference product. That information is used to develop a cell line capable of producing the desired product with comparable post-translational modifications and other important product quality attributes. Process development and optimization, including upstream cell culture and downstream purification comes next. Comprehensive product characterization, formulation development, fill/finish, final product release, and packaging round out the activities.

Successful scaling of upstream, downstream, and fill/finish operations while ensuring high yields of high-quality product that is comparable to the reference molecule requires consideration of many factors. The best approach is to use a holistic strategy that takes these factors into account from the outset.

Biosimilars approved to date are largely recombinant proteins and monoclonal antibodies. The past decade has witnessed a rapid rise in approvals of more complex modalities, such as bi- and tri-specific antibodies, fusion proteins, antibody-drug conjugates, and cell and gene therapies. In a recent analysis, the Boston Consulting Group estimated that new modalities represented $168 billion in pipeline value in 2024, an increase of 14% from 2023 (2). Many products in these new drug classes will soon lose patent protection, according to Patrick Meyer, global head of business development and alliance management at Rentschler Biopharma.

“These modalities present greater challenges in development, manufacturing, and analytics compared to conventional antibodies. They often necessitate advanced cell-line development techniques, additional downstream processing steps, and sophisticated formulation and analytical methods,” Meyer says. This greater complexity means that developing scalable processes is often more difficult. Importantly, the different modalities often have specific manufacturing requirements and thus require tailored and customized development, optimization, and scaling solutions.

Meyer therefore anticipates the growing diversity of modalities will further drive the need for contract development and manufacturing organizations (CDMOs) with the willingness and flexibility to adapt to new modalities and markets.

Although it may not seem like a specific scaling challenge, Meyer argues that the need to demonstrate biosimilarity is indeed a scaling challenge because of the nature of biologics. “Ensuring biosimilarity is a multifaceted challenge because biological systems are inherently variable, and thus achieving comparability with the reference product requires addressing several important aspects throughout the development and approval process,” he observes. One crucial success factor in biosimilar process scaling, therefore, is maintaining cell growth and productivity without introducing variability when transitioning from small-scale to large-scale bioreactors.

Achieving product and process consistency from batch to batch and across scales is a notable challenge as well. Realizing this goal must start at the cell-line development stage, where all differences from the reference product must be minimized, according to Meyer. Development of highly controlled processes is then essential to ensure stringent product quality as processes move through development phases and scale-up to commercial production. “Application of advanced analytical techniques that enable comprehensive comparison of the biosimilar’s critical quality attributes (CQAs) to those of the reference product is key,” he says. Biosimilar developers therefore must have experience and expertise in the analysis of biologics and access to well-equipped, state-of-the-art analytical labs.

Successful scale-up of biosimilar manufacturing processes also requires access to a stable supply chain affording consistent supply of high-quality raw materials and up-to-date knowledge of regulatory requirements, Meyer notes. Process scaling must also be practically achievable with reasonable process economics without compromising product quality.

Fortunately, the biopharmaceutical industry is, although conservative, also highly innovative, with constant investment in new technologies geared to improving productivity and quality while reducing risk and cost. Biosimilar developers have benefited from many recent advances.

Notable examples highlighted by Meyer include single-use bioreactors, which reduce the risk of cross-contamination across all scales; process analytical technology, which allows for real-time monitoring and control of critical process for streamlined scale-up and consistent performance from lab to commercial production; and innovations in cell-line development such as clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing and high-throughput screening, which have led to more productive and robust cell lines that, in turn, support streamlined scaling.

Of course, introduction of new technologies inevitably brings new sets of challenges. For instance, new technologies cannot be integrated into complex biomanufacturing frameworks without a transition period, according to Meyer, which can include, among other things, reconfiguration of systems and processes and significant training of personnel.

The implementation of new technology also brings about new challenges regarding data management and security, Meyer comments. “As biopharmaceutical manufacturing becomes more automated and digitized, it is the responsibility of CDMOs to ensure the safe and compliant handling of client and product data,” he contends.

Overall, Meyer concludes, it is essential to balance the benefits and challenges of innovative technologies to realize the successful and sustainable scale-up of biosimilar manufacturing processes.

Adopt a holistic strategy and platform processes

Process consistency and robustness, analytical excellence, and regulatory compliance are essential in the scale-up of biosimilars.