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

Cynthia A. Challener

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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. 

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

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

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

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

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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.

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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.

®
Vol. 48, No. 4
April 2024
Pages: 18–22

When referring to this article, please cite it as Challener, C.A. Development of Mini-Tablet and Multi-Unit Pellet Systems. 

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

Development of Mini-Tablet and Multi-Unit Pellet Systems

3d illustration proteins with lymphocytes , t cells or cancer cells | Image credit: ©Design Cells - stock.adobe.com

Gamma-delta (γδ) T cells make up on average 4–5% of T cells found in human peripheral blood (1). Two different types predominate; one that is largely found in organs and tissues, and another found in blood. Unlike regular T cells, γδ-T cells function independent of the major histocompatibility complex (MHC) and recognize a wide variety of ligand molecules using multiple T-cell (TCR), innate (e.g., NKG2D), toll-like, and Fc (CD16) receptors. As a result, they are involved in immune responses against both pathogens and tumor cells, while also playing a role in homeostasis, wound healing, and aging.

Both autologous and allogeneic γδ T-cell immunotherapies are in development to treat a range of cancers. Stimulation and activation of the T cells prior to administration is common. While approaches are being pursued that use unmodified γδ T-cells because of their independent ability to identify cancer cells, many candidates in preclinical and clinical development also seek to boost their killing capability via genetic engineering and/or using a two-pronged strategy for increasing the susceptibility of the target cancer cells. Solutions include the use of combinations with chemotherapeutics or antibodies and active tumor modification with gene therapy.

According to William Ho, director, president, CEO, and co-founder of IN8bio, γδ T cells have the potential to address many challenges towards targeting different tumors, and when combined with chemotherapy or other therapies, that potential is magnified. This type of strategy, could, he believes, “make cell therapies a more central feature of the cancer armamentarium and provide potentially more lasting treatments.”

Several advantages vs. other cell therapies

Chimeric antigen receptor (CAR) T-cell therapies have been a fantastic advance in cancer treatment options, says Jeff Boyle, CSO of American Gene Technologies and spinout Addimmune. They are limited, however, by the need to have a differentiated antigen on the cell surface and “take all the breaks off of regular T cells,” which often results in off-target toxicity issues, he adds.

Gamma-delta T cells are not antigen-specific in the same manner, Boyle continues. “They recognize molecules via more of a pattern-recognition type of response that is not peptide-based and tend to be focused on entities arising from infection with fungi and bacteria, or carbohydrate entities,” he observes. That is an advantage because, Boyle explains, many of the same pathways upregulated during fungal and bacterial infections get upregulated in cancer as well. In addition, the broad targeting ability means γδ T-cell immunotherapies could possibly be generic, their MHC independence means there is greater potential for allogeneic therapies with reduced concerns of graft-versus host disease (GvHD) or host-versus-graft (HvG) rejection, and their different mechanism of action suggests they could have safer profiles.

More specifically, according to Ho, γδ T cells are “primordial innate anticancer cells that bridge the innate and adaptive branches of the immune system and present a formidable multi-tiered weapons package to directly recognize and immediately respond to a broad range of cancer-associated stress antigens with direct killing and release of inflammatory cytokines. In addition, γδ T cells can kill or amplify indirect killing mechanisms such as antibody-dependent cellular cytotoxicity through both CD16 and CD3 pathways, which sets up the potential for therapeutic synergy with cancer-target antibodies or bispecific engagers,” he observes.

Normal alpha-beta (αβ) T cells emerge following the initial innate immune response and recognize threat-specific peptides unique to the cancer, but the number and heterogeneity of tumor associated-antigens (TAAs) increases rapidly as the tumor grows and ultimately exceeds their ability to respond, says Ho. With their redundant stress-signaling pathway, γδ-T cells can overcome the complexity of tumor heterogeneity, he notes. Like natural killer (NK) cells, Ho adds, γδ-T cells can kill tumor cells very effectively, but because they are T cells, they can create an adaptive or memory response and are more persistent than NK cells. Furthermore, he points out that because normal cells do not express stress antigens, many of the toxicities of αβ T-cell therapies like cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) or neurotoxicity, and GvHD may be avoided.

Patient-specific, autologous cell therapies have manufacturing and logistics challenges, but do not present concerns of potentially lethal GvHD. Off-the-shelf, allogeneic versions are potentially easier to produce more cost-effectively, would be immediately available, and because they come from healthy donors should be more robust from an activity- or tumor-killing standpoint, Ho comments. With allogeneically delivered αβ-T cells, however, potential lethal immune toxicities such as GvHD must be overcome through significant genetic editing.

The γδ T-cell, MHC-independent mechanism of action may obviate those risks, says Ho. He adds that γδ T-cell therapies have traditionally been known not to initiate GvHD. “Our data has not yet demonstrated a concerning safety signal with either of the autologous or allogeneic delivered products IN8bio is developing, including not having observed any CRS or ICANS to date,” he contends.

There are two important challenges to developing effective γδ T-cell therapies. They derive from the broad-natured activity of γδ-T cells, which is both a strength and a weakness, as they tend not to be as potent as desired at killing tumor cells, according to Boyle. Their killing capability is therefore often increased by increasing the activity of the γδ-T cells, and boosting the susceptibility of tumor cells to attack by these enhanced cells.

Ideally, Boyle observes, stimulation of the γδ-T cells occurs 

 prior to administration, which is then achieved in conjunction with another therapeutic agent of some kind (small molecule, antibody, gene therapy), that targets some of the tumor cells, the effect of which then spreads throughout the tumor.

Many different types of therapies based on cell types that occur naturally in the body are under development today. Designing optimum immunotherapies based on complex living cells that represent only a fraction of the highly complex immune system has limitations, however (1,2). Researchers do not yet fully understand the operations of different cells, making precise engineering a challenge. Undesirable cellular activities can result in off-target effects, for instance. The differences in patient cells due to genetic and environmental factors can, meanwhile, greatly impact the effectiveness of living cell therapies.

An alternative approach involves bottom-up construction of synthetic cells, such as “cell-like lipid-based compartments in the form of giant unilamellar vesicles,” in a step-by-step manner that allows for incorporation of defined functional capabilities and attributes (2). Such synthetic cells would thus be much simpler and perform only specific functions, potentially with greater potency and without concern of unwanted side effects.

To date most synthetic cells have been used in a laboratory setting for research applications, but some have been designed as potential drug-delivery systems and others that produce drug substances are being investigated as

treatments, including their implantation into tumors as anticancer therapies, their use to promote neuronal development, and a means to deliver insulin 

One recent paper reports the creation of immune-inspired synthetic cells (iiSCs) “that display an antigen-directed target specific cytotoxicity against cancerous cells” by incorporating aspects of NK, T, and B cells and adding a polyethylene glycol coating to prevent interactions with non-target cells (2). As a specific example, the researchers then immobilized immunoglobulins targeting leukemia cells onto the synthetic cells. While the system was built only to demonstrate the technology, the researchers believe that versions designed for 

application should be possible to make without too much difficulty given the charge-mediated assembly process employed (2).

Indeed, some believe that synthetic cells might prove to be optimal for the development and production of therapies for individuals or small patient populations, including on-demand, personalized cancer vaccines and drugs to treat rare infections (1). The ability to construct synthetic cells that are stable at room temperature would also facilitate eliminating the need for cold-chain management through their storage, transport, and delivery.

Regulatory clarity is still needed for treatments based on synthetic cells, however (1). While the guidelines for engineered cell therapies, such as CAR T-cell therapies, are applicable to some degree, synthetic cells are different and have unique aspects that will require specific guidance. To realize that goal will require close collaboration between developers of synthetic cell therapies and regulatory bodies such as the US Food and Drug Administration (1). Long-term security risks associated with development of synthetic cell therapies must also be considered and addressed (1).

1. Sampson, K.; Sorenson,C.; and Adamala, K. The FDA Needs to Get Ready to Evaluate Synthetic Cells, the Next Generation of Therapeutics. 

https://www.statnews.com/2022/07/26/fda-develop-framework-evaluate-synthetic-cells/

2. Bücher et al. Bottom-up Assembly of Target-specific Cytotoxic Synthetic Cells. 

The rarity of γδ-T cells in the immune milieu creates a third important challenge to developing γδ-T-cell therapies, notes Ho. Because they encompass approximately 5% of the total lymphocyte, or white-blood-cell population, obtaining sufficient cells to formulate multiple doses requires significant cell expansion.

Fortunately, though, the ability to grow γδ-T cells in large numbers is easier than growing standard effector T cells, according to Boyle. “Standard T cells once activated immediately begin upregulating all systems and processes, and it is necessary to shut those down in order to maintain effectiveness after longer periods of expansion. That is not an issue with γδ-T cells, which means it is much less difficult to maintain effectiveness during expansion compared to other types of T cells,” he explains.

Developing allogeneic and autologous treatments at IN8bio

IN8bio is a clinical-stage company with two active programs in glioblastoma (GBM) and hematologic malignancies. The GBM program has progressed to a Phase II study, and the company is completing its Phase I study in hematologic malignancies. “Our philosophy is to create a cancer therapy that achieves durability, tolerability, and addresses tumor heterogeneity to achieve the goal of our mission ... Cancer Zero, or the safe elimination of all cancer cells in every patient battling the disease,” Ho remarks.

That mission is being implemented, according to Ho, by coordinating γδ T-cell therapy with other therapies available to patients to ensure that cancer cells are attacked when they are at their lowest in numbers and are the most vulnerable. “With their unique status as cells that sit at the nexus of the adaptive and innate immune systems, γδ T cells address the critical concerns limiting the utility of cell therapies in solid tumors (i.e., durability, addressing tumor heterogeneity, and safety) and have demonstrated less potential for immune toxicities like CRS or ICANS than traditional αβ T-cell therapies,” he comments.

Specifically, IN8bio has developed proprietary technologies for the expansion, activation, and genetic engineering of γδ-T cells. The company has created γδ-T cells that are chemotherapy-resistant for treatment of solid tumors using autologous cells and plans on doing the same with allogeneic cells, according to Ho. For leukemia patients, it has optimized methods for expanding and activating γδ T cells 

 from allogeneic donors without additional modification. IN8bio is also working to create non-signaling CAR-T (nsCAR) therapies out of γδ T cells that allow them to distinguish between tumor cells and healthy tissue, thus avoiding many of the on-target, but off-tumor toxicities reported with αβ CAR T-cell therapies.

Another area of development for IN8bio is the creation of induced pluripotent stem cell (iPSC)-derived γδ T cells to allow the potential production of cell banks with multiple billions of cells, Ho says. Finally, the company is also investigating opportunities for combining γδ T cells with other novel therapies to maximize their potential as immunotherapies.

“IN8bio has unique expertise based on the seminal work of our CSO, Dr. Lawrence Lamb, who has studied γδ T cells for nearly three decades. His research has led to our unique capability in isolating, expanding, and activating these cells to maximize their efficacy, as well as modifying them into the variety of modalities possible with γδ T cells,” Ho says. He adds that through optimization efforts, the company has reduced the manufacturing time and cost and limited manufacturing failures for its autologous products.

One specific clinical program mentioned by Ho is IN8bio’s Vd2+ γδ T-cell program. He notes that this particular type of γδ T cell is prone to exhaustion or death during the expansion and engineering process. “Their production at scale requires some finesse, and thus we are the only group to date that has brought genetically modified Vd2+ γδ-T cells to patients in the clinic through the FDA,” he comments. The company also intends to demonstrate the utility and risk: benefit ratio of both its autologous and allogeneic γδ T-cell therapies in its Phase II INB-400 trial.

Leveraging gene therapy at American Gene Technologies

The γδ T-cell therapy program at American Gene Technologies has been reduced in scope for the past 18 months as the company has focused on developing solutions for human immunodeficiency virus (HIV) infections. The company recently announced the spinout of its HIV-related assets to a new company (Addimmune). Once the spinout is completed, American Gene Technologies will be continuing with a different executive team and renewing its focus on γδ T-cell therapy.

American Gene Technology’s approach involves activation of a large number of highly purified γδ T cells 

 combined with administration of a gene therapy designed to make the target tumor cells hyper-sensitive to the γδ-T cells. “

 tumor targeting using a gene therapy makes it possible to add molecular mechanisms within the tumor that make is susceptible to the specific type of γδ-T cells that we are administering,” Boyle explains.

Gene therapy as a combination treatment was selected, Boyle says, because it creates the opportunity to make one type of γδ T-cell therapy broadly applicable to many different tumor targets. “We can lock down the expansion and activation of the γδ T cells and then use those cells for different cancer treatments by changing the tumor-targeting ability of the gene therapy,” he notes.

In addition, gene therapy provides molecular control of expression within the tumor through selection of different knockdowns, according to Boyle. Use of a small-molecule as an adjunct treatment is problematic, he believes, because these treatments are delivered systemically, which increases the chances for off-target effects. Antibodies as adjuncts, however, are more promising from Boyd’s perspective, particularly as antibody-based technologies continue to advance.

1. Ling Ma; Yanmin Feng; and Zishan Zhou. A Close Look at Current γδ T-cell Immunotherapy. 

®
Vol. 48, No. 3
March 2024
Pages: 16-18

When referring to this article, please cite it as Challener, C. A. Development of Gamma-Delta T-Cell Therapies. 

Activation and expansion are essential for success in both autologous and allogeneic therapies.

Development of Gamma-Delta T-Cell Therapies

FDA, as well as other regulatory agencies around the world, have for many years been encouraging drug makers to switch from batch to continuous processing due to the many benefits this manufacturing technology offers. FDA has approved several small-molecule drugs, including novel products that were initially developed leveraging continuous processing and existing products for which some part of their production was switched from batch to continuous operation. The COVID-19 pandemic highlighted the need for such manufacturing solutions that can afford higher quality products more reliably and efficiently. Continuous manufacturing is attractive because it provides both cost and quality benefits, and is in fact in alignment with FDA’s initiatives focused on designing quality into processes from the outset, rather than relying predominantly on confirmational testing at the end of a production run.

Many advantages of continuous manufacturing

Continuous processing offers many advantages over batch production, including improved quality, lower costs, greater sustainability, more flexibility, and the ability to produce novel chemicals not accessible in batch mode (1–3). Higher drug-substance and/or drug-product quality results because continuous processes operate at an optimal steady state with minimal byproduct formation or processing failures, respectively. That results in fewer lost “batches,” greater confidence in product performance, improved manufacturing efficiency, and assurance of supply for patients.

For drug substances, flow chemistry performed in microreactors enables the implementation of highly exothermic reactions and the use of hazardous materials that might not be possible in batch mode. Higher purities and yields mean reduced purification needs for greater efficiency and lower cost.

For both drug substances and drug products, shorter processes with fewer steps are often possible, leading to shorter processing times. Smaller footprints and elimination of the need for intermediate hold and storage tanks also contribute to reduced costs. Continuous processing also affords the flexibility to increase or decrease production to meet changing market demands, increasing supply-chain security. Scale-up (or scale-down) can be achieved by running the process for a longer (shorter) time on the same equipment, eliminating any need
for additional process optimization in larger bioreactors.

Continuous manufacturing also supports a quality-by-design (QbD) approach to process development and leverages process analytical technology (PAT) for real-time quality monitoring.

As of late 2021, FDA had approved 10 continuous manufacturing applications, most for small-molecule drug products. The first approval was made in 2015. In 2020, however, the agency approved the first application for continuous production of an API and the first continuous process for a biologic (2).

Process development understanding and control at the heart of QbD and continuous manufacturing

Successful development and implementation of a continuous manufacturing process requires deep understanding of the process, most notably how changing process conditions impact product quality. Establishing the optimal steady state at which a continuous process should be run cannot be achieved without in-depth process knowledge. Real-time monitoring is then essential to ensure the optimal process conditions are maintained.

The QbD approach similarly requires deep process and product understanding (4,5). This knowledge is used to first establish a quality target product profile (QTPP) that will ensure safety and efficacy for the final drug product. Critical quality attributes (CQAs), or specific characteristics of the drug product and drug substance that impact product quality, are then identified during process development. Design-of-experiment (DoE) studies and process modeling can then be leveraged to determine which specific critical process parameters (CPPs) impact the CQAs. A control strategy is then established to ensure
those CPPs remain within acceptable limits, leading to the development of a highly robust process.

The reliance on process understanding links the QbD approach closely with continuous manufacturing (6). One is a quality strategy, the other a manufacturing method. When pursued simultaneously, continuous manufacturing, in fact, can lead to greater process understanding and ultimately process control, and thus more robust processes. It has been suggested that continuous manufacturing “can be seen as a practical application of the QbD principles, providing a mechanism to achieve the QbD goal of consistently producing high-quality products” (6).

Control strategies for continuous drug substance and drug product manufacturing

One of the challenges with continuous processing approaches in which multiple operations are linked together, such as flow chemistry for API synthesis with purification via filtration and crystallization and then continuous tableting, is the fact that any changes in process conditions in upstream unit operations may impact the performance of linked downstream unit operations.

That is one reason a QbD approach to process development can be highly beneficial. It enables the development of robust processes with well-defined design spaces that account for potential feed characteristics from upstream and potential impacts downstream combined with carefully established control strategies that ensure appropriate CPPs are maintained (4). The greatest benefits of such a process development strategy can be gained by using feedforward and feedback controls based on real-time data collected using PAT tools. Furthermore, because the same equipment can be used from early development to commercial production, typically once a control strategy based on CPPs is implemented and shown to be effective, it can be leveraged across all development stages.

During process development, the specific control strategy to be implemented should be determined by conducting a risk assessment (4). Strategies can be based on manual collection of process data all the way through automatic adjustment of feeds based on real-time data gathered using PAT tools. It is also possible for continuous processes to include the ability to divert material for a given time in the event it is found using real-time analysis to be nonconforming.

Verification of control is realized by testing the developed process with varied feeds and confirming process behavior (4). Proper performance of in-process analytics and control methods must also be demonstrated. Control ranges should be justified. Once a process has reached commercial stage, it is then necessary to perform periodic assessments to confirm continued effectiveness of the control strategy despite any variations in process equipment, raw materials, or environmental factors (7).

Regulatory support for emerging technologies

FDA has been a leader in championing the modernization of pharmaceutical manufacturing to enhance efficiency, quality, and safety. Its efforts began back in 2002 with launch of its Pharmaceutical cGMPs for the 21st Century: A Risk Based Approach initiative (8). The European Medicines Agency (EMA) and Japan Agency for Medical Research and
Development (AMED) have joined in more recently, also encouraging the use of emerging technologies.

To further encourage adoption of new manufacturing technologies, FDA in 2004 published PAT–A framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, guidance encouraging the use of a QbD approach and PAT (9). In its 2011 Strategic Plan for Regulatory Science, FDA called for research to identify better technologies that enable continuous manufacturing (10).

In 2017, the agency reiterated its support for continuous processing in Advancement of Emerging Technology Applications to Modernize Pharmaceutical Manufacturing Base, guidance issued by FDA’s Emerging Technology Team (ETT) (11). FDA then addressed quality issues for continuous manufacturing in the 2019 draft guidance, Quality Considerations for Continuous Manufacturing (12).

Overall, FDA consistently stresses the alignment of QbD with continuous manufacturing and emphasizes the fact that continuous processes can be developed and implemented with the existing regulatory framework (7) and using a data-driven approach (12). In addition, success can be best assured by leveraging well-established data models constructed using multivariate data analysis and real-time process monitoring technologies during process development and when implementing continuous processes to aid with process control, reduce variability, and improve product quality and consistency (13).

The concept of quality by control (QbC) has been proposed in recent years as a means for taking QbD even further (3). In this approach, active feedback control is used for process design and development, which can for certain processes accelerate identification of optimal CPPs using much less expensive materials.

2023 Final ICH Q13 guidance on small- and large-molecule continuous processing

The most recent regulatory guidance for continuous drug manufacturing was finalized in March 2023. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q13 Continuous Manufacturing of Drug Substances and Drug Products (14) “describes scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of continuous manufacturing” for both small- and large-molecule drugs and builds on existing ICH quality guidances (15).

The document was developed through collaboration of FDA, EMA, and other international regulatory bodies with pharmaceutical companies and industry trade groups. In the section of pharmaceutical development, the ICH Q13 guidance specifically refers to the need for application of QbD principles and the importance of establishing deep process understanding and effective process control strategies and the appropriate use of mathematical modeling (6). The importance of effective control strategies is reiterated in sections on manufacturing and control strategy implementation, which also emphasize the need to use a science- and risk-based approach for the development and implementation of continuous processes.

The ICH Q13 guidance can, according to some, be viewed as a “comprehensive framework for the implementation of continuous manufacturing processes” that not only provides regulatory clarity on the subject, but also emphasizes the adoption of a lifecycle approach to process validation; integrates QbD and risk-management approaches for improved quality and consistency; highlights the potential for increased sustainability; encourages innovation and modernization; and creates opportunities for increased manufacturing flexibility and efficiency (6).

To date, approved products that are manufactured using continuous processes leverage hybrid approaches in which one or two unit operations have been implemented in a continuous fashion. The ultimate goal will be to achieve fully integrated continuous manufacturing solutions in which, for small molecules, raw materials undergo conversion via flow chemistry into APIs that are then directly purified (e.g., continuous crystallization) in a continuous fashion, with the purified material then directly fed into a continuous drug-product production process, possibly involving blending with excipients, traditional extrusion, tableting, and coating, as well as hot-melt extrusion, spray-drying, and electrospinning for the formation of amorphous solid dispersions (3).

Such an end-to-end (E2E) or fully integrated continuous manufacturing process would provide even more benefits that have been observed with the continuous processes approved to date (3,7). The Novartis-MIT Center for Continuous Manufacturing (CCM) demonstrated the first end-to-end continuous process for production of aliskiren hemifumarate starting from advanced synthetic intermediates through tableting in 2012 (16). Compared to the traditional process, this solution took approximately one-sixth the time. A much smaller version of the reconfigurable flow chemistry unit was then developed and used to produce diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride, which were purified in batch mode to generate liquid dosage forms (17,18).

The success of this academic-commercial relationship recently spurred follow-on activity by this involving exploration of continuous manufacturing for mRNA products (19), which is heavily encourged by Peter Marks at FDA.

Based on this initial work, the company Continuus Pharmaceuticals was spun out of the CCM in 2012 to commercialize ICM solutions. The company has collaborated with Italian pharmaceutical equipment maker IMA to develop practical solutions. The first true end-to-end integrated continuous manufacturing system for production of small-molecule oral solid dosage forms was introduced by the company in 2019 (20). Today it offers a pilot-scale E2E system (21) for late-stage process development and early clinical manufacturing. In 2021, Continuus Pharmaceuticals won a $69-million grant from the US government to produce in the United States using a good manufacturing practice-certified, E2E continuous manufacturing facility three small-molecule drugs considered to be essential medicines (22).

Vezina, A. Quality by Design Procedure for Continuous Pharmaceutical Manufacturing: An Integrated Flowsheet Model Approach (2017). Electronic Theses and Dissertations. 5690. 

Zeta, L.; Johnson, J.; Roberts, D.; and Slater, S. FDA Leads Global Work on Continuous Manufacturing Approaches to Up Quality, Supply Chain Resilience. Hogan Lovell Engage, Press Release. August 23, 2021.

Domokos, A.; Nagy, B.; Szilágyi, B.; Marosi, G.; and Nagy, Z.K. Integrated Continuous Pharmaceutical Technologies—A Review. Org. Process Res. Dev. 2021, 25, 4, 721–739. 

Ishimoto, H., et al. Approach to Establishment of Control Strategy for Oral Solid Dosage Forms Using Continuous Manufacturing. Chemical and Pharmaceutical Bulletin, 2021 69 (2). 

Manser. B and Glenz, M. Quality by Design in Continuous Bioprocesses. Pall Corporation Technical Regulatory Topic, July 15, 2021.

Chandramouli, R. Embracing the Future: ICH Q13 Guideline on Continuous Manufacturing of Drug Substances and Drug Products. LinkedIn Pulse, June 8, 2023. 

https://www.linkedin.com/pulse/embracing-future-ich-q13-guideline-continuous-manufacturing-r

Wahlich, J. Review: Continuous Manufacturing of Small Molecule Solid Oral Dosage Forms. Pharmaceutics. 2021 Aug; 13(8): 1311. doi: 

FDA. Guidance for Industry: Pharmaceutical Current Good Manufacturing Practices for the 21st Century: A Risk-Based Approach (Rockville, MD, February 2003).

FDA. Guidance for Industry: PAT–A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (Rockville, MD, October 2004).

FDA. Strategic Plan for Regulatory Science (Rockville, MD, August 2011).

FDA. Guidance for Industry: Advancement of Emerging Technology Applications to Modernize Pharmaceutical Manufacturing Base (Rockville, MD, September 2017).

FDA. Draft Guidance for Industry: Quality Considerations for Continuous Manufacturing (Rockville, MD, February 2019).

Sartorius. Why the FDA Encourages Continuous Manufacturing Supported by Data Models. Sartorius Science Snippets Blog, May 11, 2021. 

ICH. Q13 Continuous Manufacturing of Drug Substances and Drug
Products Guidance for Industry, Level 1 Guidance (2023).

Continuous manufacturing and a quality-by-design development approach are a natural fit.