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

Cynthia A. Challener

Antibodies floating. 3D illustration | Image Credit: © Steven - stock.adobe.com

Successful biomanufacturing processes not only provide the desired product in high yield and purity, they provide consistent results whether implemented in the lab or the production plant. For many monoclonal antibody (mAb) products, processes must consistently perform at scales ranging from hundreds of milliliters to thousands of liters. Lack of scalability can result in significant project delays and added cost due to the need for further optimization. Developing scalable processes from the outset is therefore the most effective approach to ensuring the smooth advancement of mAb projects through development to commercialization.

The main technical challenges faced during the scaling of upstream mAb processes include variations in cell densities, cell viabilities, and product concentration, as well as potential offsets in product quality attributes, according to a spokesperson from Boehringer Ingelheim. These attributes can be impacted by the bioreactor design, process parameters such as temperature and oxygen transfer, media composition, supplement and feed strategies, and numerous other factors. Obtaining process understanding is therefore essential to establishing robust, scalable processes.

“Addressing these scale-up considerations in upstream mAb process development ultimately comes down to the timeline, budget, and priority of the developer,” says Leslie Wolfe, site head and vice-president (VP) of process development at KBI Biopharma. She notes that it is imperative to fully understand what knowledge exists and what is needed as part of the scope to help support effective process design. Because time and cost are often the most important drivers during early phase development, there may be a necessary trade-off in the form of reduced process knowledge and understanding of the design space. “One potential consequence,” observes Lorenz Hasler, VP of global manufacturing, science, and technology at KBI Biopharma, “may be reduced knowledge of key inputs to process design regarding quality attributes and process performance and underestimation of considerations as they relate to commercial manufacturing equipment.”

Benefits of established platform processes

An important consideration for mammalian upstream processes for mAb production, notes Hasler, is that the potentially critical respective key scale-up factors are comparable between processes. “Process knowledge and expertise can therefore be leveraged between processes. Because potential key parameters and equipment limitations can be taken into consideration upfront, potential scale-up issues can be reduced,” he explains. Risk analysis tools, Hasler adds, can then be used to screen and understand other potential process variables specific to the mAb candidate and thereby mitigate potential process risk at scale.

The best approach to ensuring scalability of mAb production is to use a platform process rather than focusing on individual project variations, observes the spokesperson from Boehringer Ingelheim. Taking this approach, it is possible to manage challenges to scalability using standard equipment (bioreactors).

Wolfe agrees that working with an established and scalable platform is key to mitigating the risks associated with scaling up. She notes that such a platform is typically developed through iterative application, which helps in establishing critical process knowledge.

“This knowledge and understanding form the foundation for establishing a process control and monitoring strategy tailored to each unit operation, leading to a potentially robust and reliable scale-up approach,” says Hasler. Platform processes may also speed up development activities because process development, and facility-fit assessments can leverage process knowledge and understanding, he adds. These platforms also help balance the timeline-versus-process-knowledge conundrum for programs with aggressive development timelines.

Relying on platform processes to ensure scalability must be pursued with some caution, however. “Conditions and predictions to perform a process at scale or commercial process for any new drug substance or drug product still need to be demonstrated at laboratory or pilot scale,” Hasler states. Additional information may also be needed to support the requirements of specific mAb-based candidates. When necessary, for instance, Boehringer Ingelheim uses computational fluid dynamics and process modeling, including detailed equipment characterization, to ensure smooth scale-up.

To ensure scalability for upstream mAb processes, designing an efficient process complemented with an effective process control approach is critical and should be tackled during early process development, according to Hasler.

For Boehringer Ingelheim, a critical aspect of its scalability approach for mAb processes is the selection of a robust clone during early development. The chosen clone, says the company’s spokesperson, should not only fit the platform, but also exhibit robustness in relation to classical scaling parameters.

Even when a platform process is employed, Hasler recommends generating process knowledge for a specific mAb candidate using design-of-experiment studies, which help in defining the relationships and multivariate interactions between various process parameters and resulting outputs. He notes that it is also crucial to develop compelling analytical methods to support these small-scale studies. Demonstrating scalability of upstream mAb processes at an intermediate scale is beneficial as well, according to Wolfe, as doing so helps to de-risk scale-up to manufacturing.

Finally, Hasler comments that for mAbs with expedited approval designations, the shortened development timelines may lead to a reduced approach to process design and, therefore, reduced process knowledge and understanding. To balance the potentially reduced process development activities, he suggests that a detailed gap identification and subsequent risk evaluation may support potential scale-up considerations and success.

Consistent scale-up through platform approach

Platform processes not only streamline the development of scalable processes, they also make it possible to use a consistent approach to scale-up across all mAb-related projects. That is the case at Boehringer Ingelheim. “We do not test different scale-up strategies for our projects, as our scale-up strategy is not influenced by the specific product being expressed. Whether the product is a standard IgG1 [immunoglobulin G1] antibody or a trispecific molecule, the scale-up strategy generally remains the same,” says the spokesperson from Boehringer Ingelheim.

While general scale-up strategies also apply to more complex or advanced antibody-based therapeutics, Wolfe observes that appropriate risk assessments should be conducted and considered with more complex therapeutic targets to ensure sufficient knowledge is available. “Using this approach ensures the target product quality profile is achieved from the defined process,” she concludes.

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

®
Vol. 48, No. 8
August 2024
Pages: 18–20

When referring to this article, please cite it as Challener, C.A. Considering Process Scaling for Monoclonal Antibodies During Early Phase Development. 

Articles

Platform processes and effective risk assessments help overcome time and cost challenges.

Considering Process Scaling for Monoclonal Antibodies During Early Phase Development

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The biologic drug segment has both expanded rapidly and evolved technologically over the past three decades. Many biopharmaceutical drugs have also reached blockbuster status. Some have already lost patent protection, and many more will during the next decade. All will face competition from biosimilars, which are increasingly accepted by doctors and patients. Biobetters—improved versions of the originator biologic offering advantages such as enhanced efficacy and safety, reduced side effects, and more attractive administration options and dosing frequencies—provide an alternative to biosimilars with greater potential for differentiation in the market. Increased understanding of disease pathologies and more advanced capabilities in the design, engineering, and manufacturing of biologics are leading to growth of the biobetters market, which is predicted to expand at a compound annual growth rate of approximately 8% over the next five years (1,2)

Manufacturing and product performance improvements

Drug developers pursue biobetters to improve the treatment of diseases, overcome the limitations of existing drugs, and better meet the needs of patients, contends Ulrike Herbrand, scientific director, global in vitro bioassays with Charles River Laboratories. “Biobetters are novel drugs that represent an improvement on the original drug and have advantages over the original drug,” she says.

Better treatment options are achieved through improved properties. Examples, according to Herbrand, include a longer half-life, higher stability and selectivity, increased specificity, reduced toxicity and immunogenicity, and/or a different route of administration. “All these factors are related to better efficacy, safety, or patient-friendliness,” she remarks.

Those improved properties can be realized by leveraging innovations in production technology, Herbrand says. “Greater understanding of human biology has enabled identification of opportunities to improve the molecular structure of originator molecules. Advances in cell-line engineering, cell culture processes, and process analytical technologies, meanwhile, enable better control of process parameters and thus more precise control of post-translational modifications and other important quality attributes,” she explains. Similarly, advances in formulation science make it possible to improve upon the formulation of the original therapeutic drug.

There is also an important market driver for the development of biobetters. “Unlike biosimilars,” Herbrand states, “biobetters are considered new drugs and therefore benefit from market exclusivity rights, even if they have similarities to existing therapeutics.”

Common chemical modifications include revising the glycosylation profile with the intention of improving the stability, pharmacokinetics, and immunogenicity of the originator biomolecule, according to Herbrand. PEGylation (attachment of polyethylene glycol to proteins) and sialylation (covalent addition of sialic acid to the terminal end of glycoproteins) are also well-known to improve the half-life, reduce immunogenicity, and enhance solubility, she adds.

Another important strategy is to modify the amino acid sequence of the protein. “Such changes can achieve enhanced efficacy and/or reduced side effects as well allow for engineering of the protein structure so it exhibits improved folding properties, which lead to both better stability and function,” Herbrand comments.

If the originator biomolecule is derived from proteins not of human origin, another chemical modification that is often employed is humanization to make the drug substance more like human proteins, according to Herbrand. This change reduces the risk of immune reactions.

Beyond changing the amino acid sequence, more significant structural modifications are often employed in biobetter development to enhance in-vivo performance. One of the most common structural changes, says Herbrand, is optimization of the binding site to improve its interactions with the target receptor and thus overall function.

As an example, Herbrand points to engineering of the complementarity-determining regions (CDRs) of antibodies. “These are the variable regions of an antibody that directly interact with the target antigen. Rational engineering of CDRs can improve binding affinity and specificity, which can lead to better therapeutic outcomes,” she observes. It is also possible to introduce charged amino acids (so-called charged mutations) near the edges of CDRs to enhance solubility and reduce aggregation. The latter can also be reduced/prevented by introducing other mutations to generate aggregation-resistant domain antibodies, Herbrand adds.

Increasingly, computation approaches are used for structure-based optimization during biobetter development. For instance, predictive computational strategies support the assessment of developability risks early in the lead candidate discovery phase, according to Herbrand. Computational modeling also helps identify key residues involved in binding to optimize binding affinity and predict solubility and stability properties and the potential risk of aggregation.

Biobetters can offer advantages other than those related to their quality, stability, safety, and therapeutic efficacy. A key goal of drug developers today is to provide medicines that take into consideration the specific needs of the target patient population so they are easy and convenient to use. As a result, a key aspect of biobetter development includes modification of the formulations of originator drugs to allow for greater patient-centricity.

“Changes in a formulation to support another route of administration, such as allowing the switch from intravenous to subcutaneous delivery, can make the patient experience more convenient and lead to healthcare savings,” notes Herbrand. “Higher concentration formulations, for instance, lead to a reduced application volume and thereby allow for administration via auto-injection devices, which is crucial for patients with chronic diseases (e.g., asthma, diabetes, colitis, or arthritis) who are dependent on regular drug administration,” she adds.

Formulation changes also involve using excipients that enhance drug stability, solubility, and bioavailability, Herbrand comments.

Protein engineering, including site-directed mutagenesis, molecular dynamics, PEGylation, sialylation, and bioconjugation, remains a foundational technology for biobetter development, with advances occurring in many of these areas, according to Herbrand. “Application of nanotechnology to drug design and development is a newer addition to the portfolio of engineering capabilities, with examples including formation of drug products as encapsulated or immobilized nanoparticles to improve pharmacokinetics,” she says.

One development area of particular interest to Herbrand is antibody-drug conjugate (ADC) biobetters. ADCs combine the tumor-targeting properties of antibodies and the cytotoxic potency of chemotherapeutics with the goal of delivering destructive compounds specifically to cancer cells while minimizing damage to healthy tissue. On the innovator side, Herbrand notes that manufacturers are currently working to identify new targets and/or payload mechanisms of action (MoAs).

ADC biobetter development, meanwhile, is focused on ADCs that leverage established target/payload MoA combinations but incorporate novel delivery components to achieve a best-in-class profile. “Non-specific and insufficient payload delivery remains a challenge with approved ADCs. Issues include premature payload release, poor tumor penetration, variable drug-to-antibody ratios, and aggregation,” Herbrand explains. Next-generation ADC technology aims to improve these aspects (3).

Always a balance between costs and benefits

Biobetters are designed to be an upgrade from existing therapeutics with structural or chemical changes that lead to improved efficacy and safety, lower side effects, and other advantages. “These improvements must lead to measurable benefits for patient and healthcare systems to justify the necessary developmental efforts and costs and to support regulatory approval,” states Herbrand.

As a result, the choice to pursue biobetter development depends on both safety and cost-benefit considerations, according to Herbrand. “Intensive research is needed to optimize therapeutic products, but it is not always the case that attempts to change and optimize an originator biomolecule will lead to better results. The efficacy or safety may not be sufficiently improved, and without superior performance there is no point in advancing such projects. It is also possible the cost-benefit ratio will not be clearly in favor of the biobetter, leading healthcare systems and patients to prefer the originator product or a biosimilar,” she explains.

The benefits, therefore, must be carefully weighed against the resources invested in biobetter development, Herbrand concludes.

Grand View Research. Biobetters Market Size, Share & Trends Analysis Report By Drug Class, by Application, by Route of Administration, by Distribution Channel, by Region, and Segment Forecasts, 2023–2030. 

https://www.grandviewresearch.com/industry-analysis/biobetters-market-report

Mordor Intelligence. Biobetters Market Size & Share Analysis–Growth Trends & Forecasts (2024–2029). 

https://www.mordorintelligence.com/industry-reports/biobetters-market

Sasso, J. M.; Tenchov, R.; Bird, R.; Iyer, K.A.;, Ralhan, K.;, Rodriguez, Y.;, and Zhou, Q.A. The Evolving Landscape of Antibody-Drug Conjugates: In Depth Analysis of Recent Research Progress. 

 34 (11), 1951–2000. DOI: 10.1021/acs.bioconjchem.3c00374

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Vol. 48, No. 7
July 2024
Pages: 14–15, 19

When referring to this article, please cite it as Challener, C. Biobetter Development. 

Weighing development costs/resources and performance benefits is essential.

Biobetter Development

AI-Enhanced Medicine Pill Concept for Future Healthcare. Pill symbolizing integration of artificial intelligence in the development of future healthcare and advanced treatments | Image Credit: ©PSCL RDL- stock.adobe.com

Artificial intelligence (AI) and machine learning (ML) in the biopharmaceutical industry have been widely applied across drug discovery and clinical development efforts. These technologies also have potential to impact many other aspects of drug development and manufacturing. Their use in formulation development has been growing in recent years due to the potential for AI/ML to streamline and accelerate this process, particularly for challenging drug substances such as those that suffer from poor solubility and bioavailability (1).

The traditional approach to formulation development involves extensive, time-consuming, and costly physical experimentation and screening, both in vitro and in vivo, to identify optimal formulations. Leveraging AI/ML algorithms allows for identification of formulations with the greatest likelihood of success, reducing the time and resources needed for physical evaluation. These technologies can also uncover new materials with attractive excipient properties and new formulation approaches not previously considered (2).

One example of an AI-based prediction tool designed specifically to aid formulation design is the freely available web-based platform, FormulationAI (3).

Formulations play a critical role in stabilizing APIs, enabling patient administration, and potentially mitigating toxic side effects while enhancing drug efficacy. “Regrettably,” observes Christine Allen, a professor within the Leslie Dan Faculty of Pharmacy at the University of Toronto and CEO of Intrepid Labs, a biotech start-up that utilizes AI/ML and robotics to accelerate formulation development, “the significant potential of formulations is often underestimated and, consequently, given lower priority in drug development, despite their ability to directly improve safety and efficacy.” She notes that approximately 80% of drugs fail in clinical development due to safety concerns and lack of efficacy, areas where better-formulated drugs might succeed.

Poor solubility/bioavailability present many development challenges

Between 70–90% of new chemical entities (NCEs) have solubility issues, according to Allen. A formulation that excels in enhancing solubility and bioavailability but falls short in safety, efficacy, or patient acceptability does not fulfill its therapeutic potential, adds Sanjay Konagurthu, senior director of science and innovation within Thermo Fisher Scientific’s Pharma Services business.

“One of the greatest challenges, therefore, is for developers to meticulously balance these considerations, creating formulations that not only improve drug delivery but also meet the broader criteria necessary for successful patient outcomes,” Konagurthu contends.

Speed is another ongoing challenge in the journey from molecule to medicine. “While maintaining safety and efficacy, scientists are always looking for a faster way to overcome hurdles like poor solubility and bioavailability and the trial-and-error formulation development process to get therapies into the hands of patients as soon as possible,” explains Konagurthu.

Difficulties arise, Allen adds, because current formulation methods are often slow and resource-intensive, which can hinder the rapid development and optimization of drug formulations that are crucial for overcoming solubility challenges.

In fact, Konagurthu comments, because poor API solubility typically corresponds with lower bioavailability and thus impacts the efficacy of the drug product, it can create a negative ripple effect from discovery to clinical trials. He points to several factors, from molecular properties to the characteristics of the excipients and formulations, as determining the solubility and bioavailability of an API. “For this reason, identification of the most effective combinations of drug and excipients is a complex and resource intensive process that requires rigorous experimentation, data collection and analysis,” he says.

Historically, scientists have looked to resolve poor API solubility through trial-and-error testing, which often results in longer development timelines. “With pharmaceutical companies focused on getting life-saving therapies to patients as quickly as possible, there is an urgent need for streamlined workflows that allow scientists to efficiently find the best way to improve a drug’s bioavailability,” Konagurthu concludes.

Predictive capabilities offer many benefits

Advanced predictive algorithms can help overcome this important challenge. “AI/ML offers low-cost predictions of properties such as solubility, dissolution rate, and stability,” Allen says. “Importantly, advanced AI approaches, such as those employed at Intrepid Labs, no longer rely on data-hungry ML models. In addition, combining technologies such as autonomous preparation and real-time sensing further enhances data-driven processes,” she adds.

In addition to predicting the most effective combinations of solubility enhancement technologies and excipients for drug development, Konagurthu believes use of AI/ML in this type of application can help scientists better understand the complex behavior of molecules, improve the speed of API discovery, and increase the accuracy of formulation development. “Ultimately, because these new technologies are able to generate high-quality data and insights for use throughout the drug discovery and development process, using them can have a significantly positive impact on budgets, timelines, and resources,” he states.

Another advantage of using AI/ML in formulation development is the ability to leverage wide-ranging datasets depending on the prediction target, route of administration, and so on. To address poor solubility, for instance, Allen notes that the apparent solubility or dissolution rate for amorphous solid dispersions (ASDs) can be predicted using ML models trained on datasets containing the composition of the ASD formulations, molecular descriptors, or other representations of the API(s) and polymers, and additional information on the method used to make the formulations, such as the processing parameters and attributes of the solution used for solubility or dissolution testing.

In many cases, computational chemistry methods including quantum mechanics (QM) and molecular dynamics (MD), quantitative structure-activity relationship models, and aspects of ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis are being applied to create customized formulation predictions as well, according to Konagurthu. To address poor solubility specifically, he adds that many solutions use proprietary algorithms to create predictive models based on specific properties of the substances. These tools are then used to generate predictive models for solubility and bioavailability enhancement; accelerated stability models for shelf-life and packaging determination; materials science, compaction simulation, and process models; and ADME/PK (pharmacokinetic) models to predict the effects of API physicochemical properties and pharmacokinetics.

For example, Konagurthu observes that techniques like QM/MD offer modeling capabilities that provide deep insights into physicochemical properties and molecular-level interactions, enabling structural mechanism exploration, free-energy evaluation, and spectroscopic characterization. “Using these insights in combination with AI/ML approaches has proven to be accurate and more efficient than trial-and-error experimentation,” he adds.

Application in formulation development is increasing

Over the past two decades, there has been a substantial increase in literature focused on the role of computational chemistry in the pharmaceutical industry, which highlights the capabilities of AI/ML in formulation development, according to Konagurthu. “The literature suggests an uptick in adoption and gives the scientific community proof points of how these new technologies address long-standing industry challenges of solving poor API solubility and bioavailability,” he notes.

One way to infer the level of adoption of AI/ML, Konagurthu says, is to look at the increase in regulatory submissions that involve these methods. Since 2021, FDA has received more than 100 submissions for drug and biologic applications using AI/ML components, spanning the drug development landscape from molecule to medicine (4). This surge in interest prompted FDA to create specialized regulatory groups that serve as both resources and facilitators of innovation for the pharmaceutical industry, he notes.

Specifically considering the development of formulations for poorly soluble/bioavailable APIs, Allen observes that the use of AI/ML is less advanced than it is for other areas of drug development, but it is growing.

To further the use of AI/ML solutions for formulation development, there are many hurdles to clear. As is the case with any data-driven application, large quantities of relevant, high-quality data are needed to create and train AI/ML models for formulation development. “Alternative ML approaches that require less data should also be evaluated. To see real success in this area, however, there is a need to embrace integration of AI/ML platforms within existing pharmaceutical frameworks,” comments Allen.

Other challenges noted by Konagurthu include model interpretability, intellectual-property concerns, cost of implementation, workforce training, and the need for regulators to develop and establish standards that not only help to maintain the integrity of these computational methods, but also help governing bodies evaluate submissions that use AI/ML in drug development.

These hurdles can be overcome, according to Allen, by building more interdisciplinary teams combining AI/ML expertise with pharmaceutical knowledge and increasing investment in AI/ML capabilities and training within the pharmaceutical sector​​. “Concerted efforts in data management, regulatory engagement, technology integration, and training will ensure that the benefits of AI and ML can be fully realized in pharmaceutical formulation development,” Konagurthu agrees.

Drug developers can also better leverage AI/ML platforms by identifying and working with a strategic contract development and manufacturing organization (CDMO) with deep experience and a strong track record of managing challenges posed by new technology adoption, according to Konagurthu. “For scientists who are looking to address poor API solubility and bioavailability, it can be extremely beneficial to collaborate with a CDMO specializing in computational drug development. CDMO partners are committed to staying at the forefront of pharmaceutical innovation and are adopting new technologies focused on speed, scalability, and innovation as a part of their end-to-end offerings,” he says.

Such partnerships can be highly effective in supporting pharmaceutical companies across the clinical supply chain, helping to ensure the faster delivery of high-quality therapeutics to patients, Konagurthu contends. He also emphasizes that widespread collaboration between pharmaceutical companies, CDMOs, and regulators on next-generation technologies could have many positive benefits for the pharmaceutical industry and the patients it serves.

AI/ML poised to have a significant impact

Both Allen and Konagurthu expect to see valuable short- and long-term benefits realized due to the use of AI/ML technologies to enable formulation development for APIs with poor solubility and bioavailability. For instance, working with colleagues at the University of Toronto, Allen has demonstrated that ML algorithms can be used to predict experimental drug release from long-acting injectable formulations and help guide their design (5).

“Using AI/ML technologies to address solubility and bioavailability challenges is a significant shift for the pharmaceutical industry. These technologies offer a more streamlined, accurate, and cost-effective path forward for drug development in general. For poorly soluble APIs in particular, they are enabling optimization of the selection of solubility enhancement technologies and excipients and paving the way for a more efficient and sustainable process,” states Konagurthu.

In the short term, Allen expects the enhanced predictive capabilities afforded by AI/ML platforms will lead to more efficient formulation processes. Longer-term, she anticipates that as drug formulation datasets reach critical mass and formulation scientists become more well-versed in AI/ML, ongoing advances in these technologies will continue to unlock new potential in formulation science, requiring continuous adaptation and learning within the industry. “There is tremendous potential for AI/ML to enable the accelerated discovery of new drug formulations and innovative drug delivery technologies,” she comments.

In fact, Konagurthu believes that AI/ML technologies “are poised to further accelerate the journey from molecule to medicine—leading us to a healthier society.” He adds that “as the industry continues to evolve, embracing these technological advancements will be key to overcoming long-standing challenges in drug development and unlocking new possibilities in the quest for more effective and accessible treatments.”

Jiang, J.; Ma, X.; Ouyang, D.; and Williams III, R.O. Emerging Artificial Intelligence (AI) Technologies Used in the Development of Solid Dosage Forms. 

Allen, C. Machine Learning Directed Drug Formulation Development. 

Dong, J.; Wu, Z.; Xu, H.; and Ouyangt, D. FormulationAI: A Novel Web-based Platform for Drug Formulation Design Driven by Artificial Intelligence. 

FDA. Artificial Intelligence and Machine Learning (AI/ML) for Drug Development. March 18, 2024. 

https://www.fda.gov/science-research/science-and-research-special-topics/artificial-intelligence-and-machine-learning-aiml-drug-development

Richards,K. U of T Scientists Use AI to Fast-track Drug Formulation Development. Press Release. Jan. 11, 2023. 

https://www.utoronto.ca/news/u-t-scientists-use-ai-fast-track-drug-formulation-development

®
Vol. 48, No. 6
June 2024
Pages: 14–17

When referring to this article, please cite it has Challener, C.A. Using Advanced Algorithms to Solve Formulation Challenges. 

Artificial intelligence and machine learning can help overcome poor solubility and bioavailability.

Using Advanced Algorithms to Solve Formulation Challenges

Young woman giving pill to her daughter at table | Image Credit: ©Pixel-Shot - stock.adobe.com

Taking patient needs and expectations into consideration when designing and developing new drugs has become increasingly important as evidence mounts that more convenient and easier-to-take products increase medication compliance. To be effective, drug therapies require patient adherence. For oral dosage drugs, particularly liquids, dispersible powders (granules), orally disintegrating tablets or films, chewable tablets, and minitablets, taste-masking can be critical for increasing patient compliance, as these dosage forms result in exposure of taste buds to the APIs, which can be an unpleasant experience, according to Liliana Miinea, technology manager, Pharmaceutical Excipients, at Lubrizol Life Science.

Leveraging taste-masking technologies and solutions that impart an attractive appearance help overcome such issues. It is a complex task, however, that requires consideration of numerous variables including patient profiles, drug product characteristics, and regulatory rules, among others, observes Nasrin Mahmoudi, Sr., lead applications scientist at IFF Pharma Solutions. As such, expertise in these formulation technologies is essential to implementing a patient-centered approach to drug development and ultimately improved therapy outcomes.

Important factors influencing patient compliance

With respect to factors influencing patient compliance, most experts agree that taste and appearance are two of the most important. For oral administration, they may only fall below ease of swallowing and dosing frequency, says Steve Amoussou-Guenou, technical development manager Europe at Roquette.

In addition to palatability and swallowability, other attributes that help ensure patients follow medication regimens as recommended and without delays, skips, or increasing/lowering the dose include acceptable aroma/smell and product packaging, adds Mahmoudi. “In 2006, the [European Medicines Agency] (EMA) reported that taste, smell, and texture were all integral factors in determining a medication’s acceptability for patients,” she says (1).

Excipients that can be used to taste-mask bitter APIs are referred to as bitter blockers. These compounds inhibit the molecular pathway that ultimately results in a bitter taste in the mouth on the cellular level (1). Compounds that block bitter receptors could potentially be used as excipients and replace other more complex taste-masking technologies.

Bitter tastes are detected by G-protein coupled receptors (GPCRs), predominantly those in the taste 2 receptor family (TAS2R), which comprises approximately 25 GPCRs (1). Molecules that preferentially bind to these receptors can prevent the detection of bitter tastes. However, genetics has a role to play in how each person perceives bitterness. In fact, more than 150 single-nucleotide polymorphisms have been found in TAS2R coding regions, all of which can influence the sensitivity of an individual to bitter tastes.

Another challenge is the need to identify which taste receptor(s) are targeted by a given API, as the bitter blocker must target the same receptor(s) to be effective (1). Often multiple receptors are involved, and therefore, a single bitter blocker will need to bind to most of them to truly block, rather than simply reduce, the perceived bitterness of an API.

1. Andrews, D.; Salunke, S.; Cram, A.; et al. Bitter-Blockers as a Taste Masking Strategy: A Systematic Review Towards Their Utility in Pharmaceuticals. 

“The importance of taste masking can be attributed to the fact that many APIs can be unpleasant or even impossible to consume without an effective taste-masking strategy—literally the spoonful of sugar that helps the medicine go down,” Amoussou-Guenou says.

Appearance, meanwhile, can be viewed by patients as an indication of quality. In certain markets such as Japan, Amoussou-Guenou notes, even a slight visual defect such as black specs or color heterogeneity will immediately cause concern. A consistent appearance is therefore vital for securing patient trust, as well as their attention. Some drug companies also use a unique visual appearance as a marketing tool and/or to help consumers identify their medications, limit cross contamination, and avoid potential toxicity.

Taking a patient-centric approach to formulation design

The most effective strategy for developing patient-centric formulations and achieving higher levels of medication adherence is to adopt a patient-centric design approach from the outset, Mahmoudi contends.

“Understanding how patient needs and preferences are influenced by variables such as age, overall health, disease states, and physical condition can help to design a patient-centric drug product suitable for a target patient population,” she explains.

For oral formulations, Mahmoudi says, tablet size, shape, smell, taste, and mouthfeel—or, for liquid dosages forms, rheology and volume as well as smell and taste—all impact a drug’s overall acceptability because they all impact swallowability.

To identify the needs of the target population, formulators rely on experience, sensory analysis, and marketing studies, according to Amoussou-Guenou. “[These] data are used alongside other factors like the dosage form type and advice of marketing teams to inform decisions around the drug product’s appearance and desired properties, as well as the most effective taste-masking technique to employ,” she comments.

The dosage form can also be an important dictator of taste-masking requirements. Orally disintegrating tablets (ODTs) and films (ODFs) are good examples, according to Amoussou-Guenou. “These dosage forms are specifically designed to dissolve in the mouth, and their buccal dissolution profile makes taste masking an especially important consideration,” he explains. In these applications, Amoussou-Guenou says producers typically opt for the functional excipient route, rather than coatings, though complexing the API is a viable secondary measure. Multipurpose, co-processed excipients that impart multiple attributes to ODT/ODF formulations are often preferred, as they can support rapid disintegration as well as a pleasant mouthfeel and flavor.

Several different approaches to taste-masking provide formulators with options depending on the various factors in play. The main determinant is the extent and type of the unpleasant taste or smell of the drug, whether it is bitter, sour, or an irritant, according to Mahmoudi. An API’s aqueous solubility also plays an important role in selecting a taste-masking technique because it can be more challenging to cover the poor taste of highly water-soluble drug substances. It is also often easier to taste-mask low dose formulations. In addition, the particle size and shape and the texture of the API, as well as the target release profile, should be considered when selecting a taste-masking method, Mahmoudi says.

The API can be chemically modified into a salt or pro-drug form to reduce its bitterness, according to Amoussou-Guenou. This technique is limited, however, to drug substances with suitable functional properties. More commonly, excipients with a sweetening effect are added to hide the bitter/unpleasant taste of the API. Molecular complexation with compounds such as cyclodextrins can also mask the taste of the API while the drug resides in the mouth. Finally, application of a barrier coating that remains intact while in the mouth but degrades once exposed to the acidic conditions in the stomach is another widely used approach.

“If an API is only bland or mildly off-putting, formulators can simply add acids, flavorants, or sweeteners to combat the bitterness. Excipients with a naturally sweet flavor, like mannitol, are common here, as they combine good tabletability with effective taste-masking characteristics,” Amoussou-Guenou notes.Coatings are preferred if the API has a strong bitter taste that cannot be sufficiently masked with the addition of excipients to the formulation.

Formulations can also combine taste-masking techniques in the case of particularly unpleasant-tasting APIs. When formulating ODTs for example, Amoussou-Guenou observes that the API can first be complexed with cyclodextrins, hiding the bitter compounds from the patient’s taste buds. Then the complexed API can be combined with a high-performance mannitol to lend reduced friability and a better overall tablet consistency, as well as a cool, almost minty taste that makes the disintegrating tablet a pleasure to take.

With respect to polymer coating technologies used for taste masking, Mahmoudi notes there are several hydrophobic or hydrophilic polymers and lipidic compounds available that can be used as coating materials. She highlights ethyl cellulose as a hydrophobic polymer with a pH-independent release. Mahmoudi also notes that the coating level will be determined by the bitterness level of the API and the dosage form properties and can be adjusted to not only provide taste masking, but also control the API release profile.

Miinea emphasizes how taste-masking technologies are continuously evolving to align with the progress in novel oral dosage forms that address the needs for patients with difficulty in swallowing. She points to polymethacrylates as being increasingly used as barrier coatings to taste-mask bitter APIs. Miinea specifically notes that crosslinked polyacrylic acid polymers (carbomers) having structures similar to weak cation exchange resins may form complexes with weakly basic drugs. “The resultant complexes are insoluble in saliva and mask the bitter taste of the API. When they reach the stomach and are exposed to its low-pH environment, they ionize and release the API without impacting its bioavailability. These polymers may also provide additional functionality, including reduced ‘throat catch,’ or the burning sensation associated with some APIs, including ibuprofen,” she remarks.

Meeting the needs of specific patient populations

Patient-centric formulation requires consideration of the close connections between user needs, dosage form design, and taste-masking technologies, because each patient population has its own discrete preferences and priorities, making some delivery methods more-or-less suitable, Amoussou-Guenou observes. In turn, he notes that just as the choice of delivery method stems from patients’ needs, taste-masking technologies are influenced by a drug’s format and target application.

In particular, Amoussou-Guenou notes that for groups with specialized needs such as pediatric, geriatric, and psychiatric patients, it may be necessary for drug developers to “think outside the pill box” to ensure taste-masking methods remain effective. For instance, some medications prescribed to children are not manufactured in pediatric dosage levels. For tablets, breakage in half or smaller units is therefore required. Barrier coatings used for taste masking will not be effective in this case due to exposure of the tablet core. Formulators therefore need to consider all potential patient populations when selecting a taste-masking technology for a given drug substance.

Taste masking is, in fact, extremely important for pediatric medications because it can significantly improve adherence in this population, according to Mahmoudi. It can also be more challenging, because the specific age, growth level and physiological development, underlying diseases, and regional/geographical preferences must all be considered during formulation development, including selection of the optimum taste-masking approach. As an example, Mahmoudi observes that market research suggests there are ‘favorite’ flavors that vary from country to country and indication to indication.

In the European Union, for instance, cherry and strawberry flavors are most preferred in pediatric medications for pain and infectious diseases, while lemon, peppermint, and orange are recommended for indigestion remedies (1). In the United States, meanwhile, children prefer grape, bubble gum, and cherry flavors (2).Maintaining a balance is essential

While developing palatable, pleasant-looking dosage forms is the key to improved patient compliance, it is necessary to not make drug products appear to be anything but medicines. “As an industry, we must make sure not to make drugs too appealing,” contends Amoussou-Guenou. “Drugs are just that in the end,” he continues, “and no matter how innocuous they look or taste, overconsumption can lead to serious complications. This consideration is especially important in dosage forms aimed at children,” states Amoussou-Guenou. “Producers must walk a formulation tightrope; not too bitter or bland that kids refuse their medicines, but not too craveable that they start to see potent drugs as candies,” he concludes.

A few opportunities for further development

There are two groups for which advances in taste-masking technologies could benefit. The first is infants and young children that require liquid medications or small particles that can be dosed with milk or soft food. Complicating their development is the need to meet different flavor preferences for different pediatric populations and different types of medications. The best approach, therefore, according to Mahmoudi, is to develop liquid, suspension, or ODT formulations with a neutral flavor or in a variety of flavors to be acceptable by children in different regions. Multiparticulate systems, including those based on pellets and mini-tablets, says Mahmoudi, are one approach that allows the flexibility needed for pediatric formulations.

The second group highlighted by Amoussou-Guenou is surprisingly patients who do not require any special considerations. “It may seem counterintuitive, but this group receives the least consideration when it comes to taste-masking. Of course, strategies for improving medicine accessibility for vulnerable populations are both important and necessary. However, as drug developers rightly become more sensitive to the needs of specific groups, they equally should not forget the fundamentals of making every day medicines more palatable, swallowable, and so on,” he states.

On a positive note, Amoussou-Guenou points to advances in the nutraceuticals segment, such as fun formats like functional gummies with attractive fruity flavors, that potentially have applicability for drug products as well. He also highlights steady improvements to the taste of established delivery methods like effervescent tablets. “These developments underscore the potential gains the pharmaceutical industry could realize by considering a more crowd-pleasing approach to taste masking,” he concludes.

EMA Committee for Medicinal Products for Human Use. Reflection Paper: Formulations of Choice for the Paediatric Population. European Medicines Agency, London, UK, 2006.

Mennella, J. A.; Roberts, K. M.; Mathew, P. S.; and Reed, D. R. Children’s Perceptions about Medicines: Individual Differences and Taste. 

When referring to this article, please cite it as Challener, C.A. Using Taste-Masking and Appearance to Address Patient-Specific Needs.

The use of appropriate taste-masking and appearance technologies can facilitate patient compliance.

Using Taste-Masking and Appearance to Address Patient-Specific Needs

glass frozen ampoule with a virus vaccine on the texture of cold ice top view, background with backlight on the theme of pharmaceutical drugs from viral diseases.| ©Александр Беспалый - stock.adobe.com

Messenger RNA (mRNA) molecules are inherently unstable and readily degrade when exposed to ubiquitous enzymes such as RNase and undergo pH-dependent hydrolysis of phosphorus-oxygen bonds when exposed to water. That instability creates challenges for manufacture, formulation, storage, and transport of mRNA-based vaccines and therapeutics. While encapsulation of mRNA drug substances in lipid nanoparticles (LNPs) enhances their stability (and facilitates their delivery into cells), mRNA-LNP products still typically require low-temperature storage and present distribution challenges in areas where cold-chain management is limited.

Increasing mRNA Product Stability with Lyophilization

One solution for overcoming mRNA instability is lyophilization, or freeze-drying, which is used in the manufacture of many biologic and small-molecule drugs that exhibit instability in aqueous solutions. Lyophilization involves the removal of frozen water (ice crystals) via sublimation under vacuum at low temperature to ideally produce a solid cake that typically can be stored at room temperature for extended periods. The challenge with mRNA-LNP products is to find the right lyophilization conditions that do not harm the product particles (change their size and polydispersity, among other attributes) and produce a solid with desirable properties.

While there was insufficient time during development of the mRNA-LNP COVID-19 vaccines to identify an effective lyophilization process, several companies have since then developed effective lyophilization solutions. Pfizer/BioNTech and Moderna are two well-known firms with candidates in the clinic. But it was the small biopharma company Arcturus Therapeutics, in collaboration with CSL, that received the first marketing approval of a lyophilized mRNA-LNP product. Its self-amplifying mRNA COVID-19 vaccine ARCT-154 was approved by Japan’s Ministry of Health, Labor, and Welfare (MHLW) in November 2023 (1).

The main challenge: maintaining integrity

While lyophilization is an important means of addressing stability issues associated with mRNA therapeutics, allowing the transport and storage of these products without the need for ultracold chain infrastructure, there have been challenges to effectively harnessing the benefits of lyophilization for these products, according to Vincenza Pironti, strategic marketing director at Recipharm.

The sensitivity of large, highly charged mRNA molecules, even when encapsulated in LNPs, to oxygen, light, heat, and temperature must be taken into consideration, contends Joseph E. Payne, president and CEO of Arcturus Therapeutics. The temperature transfer during lyophilization and the use of a vacuum places a strain on the LNPs. “It is necessary to develop a subtle and sophisticated method that does not perturb or discombobulate the nanoparticles during both freeze-drying and reconstitution,” he says.

Doing so, Payne adds, requires a considerable amount of resources and years of innovation, and typically involves the use of the right combination of buffers and excipients to stabilize the mRNA-LNPs during dehydration and rehydration.

These challenges, Pironti says, include ensuring the lyophilization process is effective at optimizing product stability and protecting the integrity of the LNPs. “In practice this means there needs to be a good final cake within the vial that can be readily reconstituted when it is time to administer without detrimental effects to the formulation,” she explains.

That can be particularly difficult to achieve for low-dosage formulations such as mRNA-based therapies due to the ratio of ingredients to dose volume, observes Pironti. “What is needed in these cases is the use of appropriate cryoprotectants or bulking agents within the formulation, which must be compatible with the formulation and the vial and ensure the stability of final drug product,” she observes. She also notes that comprehensive analytical testing of both the formulation and the LNPs well ahead of commercialization can help identify the right lyophilization methods to support product stability and shelf-life once the therapy is in commercial use.

Equally important, according to Christian Dohmen, executive director, technology development & CMC with Ethris, is to ensure that the LNPs are fully intact after reconstitution. There are many factors that contribute to product deterioration of lyophilized mRNA/LNPs, including particle size, mRNA integrity, and encapsulation efficiency. “If left unaddressed, the combined effect of these factors leads to deterioration of the product and decreased biological activity as well as undesired immune recognition (e.g., due to formation of aggregates), ultimately leading to reduced therapeutic potency,” he explains. In addition, he comments that aggregation of LNPs during the reconstitution process after lyophilization is another challenge for lyophilized mRNA products.

Pironti recommends using long freeze-drying cycles to prevent any damage to the LNPs within the formulation that could undermine performance and stability. Ethris has, Dohmen says, optimized its product design and lyophilization process to account for these factors and improve the potency of the resulting product as well as a reconstitution process that prevents aggregation from occurring.

Developing freeze-drying processes requires patience and deep product and process understanding.

Multi-unit pellet systems (MUPS) and intelligently encapsulated mini-tablet systems (EMTS) have unique combinations of advantages compared to conventional oral formulations. The drug release from MUPS and EMTS can be modified by combining pellets or mini tablets with different polymer coatings to achieve the desired profile, allowing modulation of controlled and sustained release. Reduced dose dumping allows for more consistent drug release, lowers risk of gastrointestinal irritations, improves bioavailability, and causes less variation in drug absorption between individuals, which results in improved efficacy with reduced side effects. These strategies also work well with fixed-dose combination (FDC) formulations, allowing controlled release of multiple drug substances, even those that are incompatible with one another, at different rates. MUPS and EMTS even have potential to enable oral formulation of biologics and the formulation of personalized medicines with tailored dosing.

Granules, pellets, and mini tablets (diameter less than three millimeters) are subunits of oral solid dosage forms. They are mixed with excipients and then enclosed within hard gelatin capsules or compressed into tablets. MUPS comprise pellets consolidated into tablets, while EMTS comprise mini tablets encased in capsules. Orodispersible matrices can be used to address swallowing issues. Modification of release profiles is accomplished by coating the individual pellets or mini tablets with functional polymers or other materials. Coatings can also prevent different interactions between incompatible drug substances and provide taste-masking. Dosages are easily adjusted by changing the number of subunits contained in each tablet or capsule.

Therapies on the market formulated as MUPS or EMTS include drugs for problems of the gastrointestinal tract—including gastroesophageal reflux disease, gastric acid-related disorders, and peptic ulcers, high blood pressure, diabetes, and diseases that benefit from targeted delivery strategies, such as ulcerative colitis and gastric, intestinal, duodenal and colon cancers, according to Rao Voleti, senior principal scientist for drug products and pharma services at Thermo Fisher Scientific.

Most of the MUPS/EMTS that treat diseases and conditions related to excessive stomach acid production are based on proton pump inhibitors (PPIs), adds Joao Marcos Assis, global technical marketing manager at BASF Pharma Solutions. He also notes that certain psychiatric conditions, such as depression and anxiety disorders, can be treated with controlled-release MUPS formulations of antidepressant and anxiolytic medications, which provide more stable blood levels of the drug substances for improved symptom management.

Pain management medications and treatments for hormonal disorders and some respiratory conditions (such as asthma, chronic and obstructive pulmonary disease) can also benefit from the sustained-release properties of MUPS/EMTS, according to Assis.

Finally, MUPS and EMTS, observes Voleti, are extremely effective dosage forms for patients with swallowing difficulties (dysphagia) across a variety of therapeutic areas, including cardiovascular, neurological, metabolic disorders, oncology, and more.

A growing percentage of APIs in the development pipeline suffer from poor bioavailability, as well as other issues such as instability, narrow therapeutic ranges, and/or the need for specific release patterns. MUPS and EMTS formulations can help facilitate the delivery of these challenging APIs.

Instability, such as in the case of PPIs when exposed to acidic pH levels, can be overcome because of the protective coatings provided to the pellet or mini-tablet subunits within the formulation. “This approach helps enhance the overall shelf life of the formulation, ensuring the drugs remain stable and effective over time,” says Voleti. Similarly, he adds that multiple APIs can be combined in a single drug product even if they have the potential to interact chemically with one another, because the protective coatings prevent such interactions.

For APIs with narrow therapeutic indices, the ability to modulate release profiles ensures that the concentration of a drug substance is maintained within the desired therapeutic range (above the minimum effective concentration and below the toxic concentration) for a longer duration, ensuring a more effective treatment outcome, Assis comments. That translates to increased efficacy and enhanced safety, which can be difficult to achieve otherwise. MUPS/EMTS also allow for reduction of the high dosing frequencies often required for medications with narrow therapeutic windows, which can contribute to improved patient compliance, Assis adds.

Other drug types for which formulation as MUPS/EMTS leverage sustained release profiles include highly potent therapies and drugs with a short durations of action, according to Assis. The former require precise dosing and careful control of drug concentration, which can be achieved using a drug reservoir system like those found in MUPS/EMTS formulations. For the latter, Assis comments, a drug reservoir system may prolong the therapeutic effect by releasing the drug substance gradually.

In addition to making it possible to incorporate multiple APIs that have the potential to interact with one another, MUPS/EMTS formulations can also accommodate APIs with different solubility profiles, allowing for the formulation of drugs that may have varying bioavailability profiles, Voleti says. MUPS and EMTS are also useful when different release rates are required to meet specific pharmacokinetic profiles. In fact, Voleti notes that combining drugs with variable absorption rates in a single formulation can help achieve a predictable pharmacokinetic profile. Reducing the number of different drugs patients must take can also help boost medication compliance.

Given that MUPS/EMTS contain subunits that must be manufactured and then further processed into the final drug product, their development and production is more complex than those for basic tablets and capsules. Indeed, Voleti points to several technologies that may be used for the development of MUPS/EMTS, including extrusion-spheronization, hot-melt extrusion, spray drying plus compression, mini-tablet compression, drug layering, multi-layer coating, taste-masking, multi-population encapsulation, and others. “The development and commercialization of MUPS and EMTS formulations face several significant challenges for which strategic approaches are required,” he states.

Particular issues that must be addressed, according to Voleti, include ensuring the shelf life and stability of MUPS formulations; maintaining drug-excipient compatibility; preventing moisture ingress, oxidative degradation, and component interactions; achieving particle and functional coating uniformity; navigating and avoiding intellectual property infringement; and adhering to regulatory requirements.

Assis also emphasizes the fact that producing uniform pellets of consistent size, shape, and drug content can be challenging, and coating pellets to provide the desired controlled or delayed-release profiles—as well as doing so in a consistent manner can be complex. “Ensuring an even and consistent coating thickness and uniform coating distribution across all pellets is crucial for consistent drug release and [to] reduce batch-to-batch variability,” he says. That requires determination of optimal coating process parameters, which can be a lengthy effort.

Maintaining the integrity of the coating in subsequent processing steps, such as tableting and encapsulation, is also crucial, because coating damage or breakage can alter the release characteristics. “Since most MUPS comprise pellets with functional coatings, maintaining film elasticity and flexibility is crucial for retaining the intended functionality, and therefore overcoming challenges related to blending and tableting coated pellets is essential to prevent film breakage and segregation issues,” Assis contends.

All of these challenges can be magnified when scaling from the lab to commercial production, Assis adds.

Finally, Voleti points out that there is one key limitation of MUPS and EMTS formulations. “Large doses cannot be accommodated in these forms and may require multiple units for administration, which can impact patient acceptability and compliance,” he explains.

Beyond the challenges to MUPS/ENTS development outlined above, the need to consider several different factors when designing these formulations adds further complexity. The dose; desired release profile(s), including duration of action, lag times in release, and others; physicochemical properties of the APIs involved; the desired shape and size of the particles, which can impact properties processability, uniformity, and release; the manufacturing and filling processes; and the selection of optimum/appropriate coating technologies are examples highlighted by both Voleti and Assis.

The choice of pellets or mini-tablets must also be considered, Assis notes. Mini-tablets are produced using tablet presses with specific punches, which avoids the need for large investments in equipment. Their production involves few processes; they generally require less coating material than pellets; and they have a greater capacity to incorporate active ingredients, according to Assis.

However, due to the size of the punches, the drug and excipient mixture must have high compressibility to mitigate high compression forces, as well as excellent flow to avoid weight and dosage variations, Assis observes. The larger size of mini-tablets also means it can be difficult to incorporate them into tablets, and thus hard gelatin capsules are typically preferred.

Other factors noted by Assis as important to consider during development of MUPS/EMTS formulations include the attributes and proportions of other tablet ingredients and whether taste-masking will be needed. Cushioning excipients in particular, he says, can impact tablet compression, while differences in the particle sizes of these excipients and coated pellets can lead to segregation risks and dose uniformity concerns. “Selecting appropriate diluents (major components of cushioning excipients) and other additives is relevant for successful formulation development of MUPS, especially those containing functional coated pellets,” Assis concludes.

Excipients, in fact, play a crucial role in determining the performance of MUPS/EMTS formulations. In addition to coating materials and cushioning agents, they can include diluents and fillers, binders, surfactants, solubilizers, and stabilizers. “By incorporating these excipients into the formulation, developers can enhance functionality and performance, ensuring optimal drug delivery and stability,” Voleti contends.

It is important to keep in mind, emphasizes Assis, that MUPS and mini tablets require highly compressible and flowable excipients to maintain the film integrity of pellets, reducing compression force and table weight variability.

Diluents and fillers, such as microcrystalline cellulose (MCC), sugar, starch, mannitol, and lactose, are frequently employed to increase the bulk volume of the formulation, while binders such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyvinyl pyrrolidone are commonly used to improve the cohesion and compressibility of the formulation, according to Voleti.

MCC, observes Assis, is a versatile diluent known for its compressibility, lubrication properties, and low moisture content that is widely used in MUPS, primarily because it presents excellent compressibility properties due to its high plasticity, allowing for easy formation of tablets with high hardness and low friability. “MCC also offers good binding capabilities, yet can help in the disintegration of tablets, ensuring rapid drug release and absorption,” he notes.

Crospovidone (cross-linked polyvinylpyrrolidone) is another excipient highlighted by Assis that has both disintegrant and binding properties, both of which are dependent on particle size. “Smaller crospovidone particles with high surface areas provide high compressibility, improving tablet hardness. Thus, super-fine crospovidone (Type B) is recommended for orodispersible tablets (ODTs),” he says.

Mannitol, meanwhile, is the diluent of choice for ODTs, according to Assis. This sugar alcohol offers high stability, fair compressibility, low hygroscopicity, and pleasant taste. It can act as a bulking agent and contribute to rapid tablet disintegration. Due to its poor binding ability, though, it generally must be used with other functional excipients such as binders and disintegrants.

Of binder options, Assis comments that hydroxypropyl cellulose can be used in tableting as a dry and wet binder at low concentrations (2 to 6 weight/weight %), but at higher concentrations can impact tablet disintegration. Copovidone can be used up to 10 weight/weight % and offers excellent dry binding properties, high plasticity, and low hygroscopicity, according to Assis. “Finer versions with high surface areas and high binding capacities are ideal for MUPS because much less material (1 to 5%) is required,” he comments.

An important trend regarding excipients using MUPS/EMTS formulations is increasing application of coprocessed excipients, which combine two or more excipients without changing their chemical composition but with improvement of physical properties. In addition to improved performance characteristics, coprocessed excipients often provide better processability along with time and cost savings.

“Coprocessed excipients are ideal for MUPS/EMTS formulations because they often exhibit better flow characteristics compared to individual excipients, leading to improved uniformity, reduced risk of segregation during compressing, and enhanced compressibility, allowing for easier tablet formation and better tablet hardness, which results in improved mechanical strength at low compression forces for reduced risk of pellet breakage and tool damage,” explains Assis.

Common coatings include ethyl cellulose, acrylic polymers, hydrophilic polymers, and lipid-based materials, with different grades employed to achieve different modified drug release characteristics, taste-masking, and protective properties, Voleti observes.

Examples of acrylic polymers noted by Assis include methacrylic acid-ethyl acrylate co-polymer (1:1) for film coating to create of enteric pellets, min-tablets, tablets, capsules, granules, and crystals and diethylaminoethyl-methacrylate and methyl methacrylate copolymer for taste-masking. He also highlights polyvinyl acetate plus povidone (polyvinylpyrrolidone) 30, which is available as an aqueous dispersion, for sustained-release formulations. In many coating formulations, Assis also emphasizes the importance of using appropriate plasticizers at the right concentrations for a given polymeric material to maintain flexibility during processing and thus prevent coating damage.

Finally, Voleti cautions that some excipients are to be avoided. They include those with known toxicity and safety concerns, those that are incompatible with the specific API of interest or the chosen manufacturing process, and those known to cause sensitivities for individuals in the target patient population.

In silico solutions accelerate development

Computer algorithms designed to aid formulators in the identification of optimum excipient combinations and concentrations, as well as formats for specific drug substances, are helping to reduce the number of physical experiments that must be conducted, saving time, money, and resources. “By leveraging in silico solutions, researchers and developers can streamline the formulation development process, making it more efficient and effective in creating optimal MUPS and/or EMTS formulations as well as reducing development time and conserving valuable API,” Voleti says.

Tools for accelerating the development of optimal MUPS/EMTS formulations include both computational modeling techniques enabled by artificial intelligence (AI) and machine learning (ML) that help in the design and optimization process, Voleti comments. More specifically, the behavior of excipients, processing parameters, and formulation variables can be predicted computationally, enabling the formulation design to be fine-tuned for optimal performance.

In addition, in silico techniques can be used to simulate drug-release kinetics from MUPS/EMTS, taking into account factors such as composition, environmental conditions, and predicted release profiles, according to Voleti. He points to tools such as GastroPlus (Simulations Plus), which considers the absorption, distribution, metabolism, and excretion characteristics of APIs and formulations, and the AI/ML predictive platform Quadrant 2 (Thermo Fisher Scientific) as valuable for predicting and overcoming solubility and bioavailability challenges.

Accelerated stability and assessment programs, meanwhile, provide the capability to predict stability and degradation pathways and select suitable formulation components and packaging configurations to enhance stability, Voleti observes. Compaction simulation modeling is also used to predict compression/compaction characteristics, ensuring scalability and process reproducibility, which helps to optimize the manufacturing process and shorten tech-transfer times, Voleti adds.

Comprehensive development strategy essential

Given the complexity of MUPS/EMTS formulations and the numerous challenges to realizing effective and optimal products, a strategic approach to their development is essential. Assis recommends a multi-pronged approach that leverages comprehensive pre-formulation characterization, quality-by-design and design-of-experiment (DoE) principles, robust manufacturing processes, coating optimization, and the use of advanced analytical techniques.

“Thorough pre-formulation characterization of the API and excipients is needed to understand their physicochemical properties, compatibility, and potential interactions, while a DoE approach enables systematic evaluation of formulation and process parameters and their impact on pellet/mini-tablet properties and performance in an efficient and targeted manner. That information can be used to implement appropriate process controls and quality assurance measures to minimize batch-to-batch variability and ensure reproducibility,” Assis explains.

Coating optimization is equally important, according to Assis, because it ensures a robust process that results in uniform coating distribution and proper adhesion, which are essential to achieving consistent drug release profiles. Finally, he notes that use of analytical techniques such as near-infrared reflectance and Raman spectroscopy and scanning electron microscopy provides valuable insights into formulation performance and aids in troubleshooting and optimization.

A comprehensive development strategy for MUPS/EMTS formulations should also encompass, says Voleti, the adoption of appropriate scale-up principles to ensure consistent performance and maintain product quality when scaling to commercial production; performance of stability studies to evaluate the chemical, physical, and microbial stability of the formulations; investigation of the intellectual-property landscape to identify potential infringement issues; a robust regulatory strategy that considers regional requirements, intended markets, and product classifications; and implementation of a patient-centric design strategy that includes a thorough literature review and evaluation of formulation excipients, coating materials, polymers, and formulation approaches.

Indeed, patient centricity has become an increasingly important aspect of drug development, as regulatory authorities seek to decrease medication nonadherence through introduction of drug products that consider patient concerns about ease of use, convenience, dosing frequency, and other factors.

MUPS and EMTS are by design patient-centric, says Voleti, as they offer flexibility in developing tailored release profiles to meet specific patient requirements when they are developed as modified-release dosage forms. “These formulations are adaptable to various patient groups, including pediatric, geriatric, and general populations. The flexibility of dosing, taste-masking, and improved palatability attributes all contribute to enhancing patient adherence to their medication regimen[s],” he explains.

Other advantages that MUPS/EMTS formulations offer include increased ease of swallowing and the ability to provide combination therapies through fixed-dose combinations that leverage synergistic effects and minimize the pill burden associated with long-term treatments. They can also be used for oral formulations with special applications, such as gastro-retentive and mucoadhesive therapies, and are readily adapted for alternative routes of administration such as rectal or vaginal, according to Voleti.

Advanced oral dosage forms allow for modulation of controlled- and sustained-release profiles.