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

Cynthia A. Challener

Pink-white and blue-white capsule pills with concept of precision medicine with nanotechnology, proteomics, and advanced artificial intelligence to enhance diagnostics and patient-specific solutions. | Image Credit: ©Artinun - stock.adobe.com

Patient adherence to medication is a challenge. Patients prefer the use of oral medicines over injectable ones for obvious reasons. Therefore, there is an ongoing need to develop personalized and patient-centric delivery solutions, including devices, for the administration of oral medicines that fit patient lifestyles and optimize the safe and effective use of oral medicines. Key attributes include improved taste and ease of swallowing, patient-friendly administration, flexible dosing, and reduced dosing frequencies.

More sophisticated and tailored solutions are emerging, including modified-, sustained-, extended, and controlled-release formulations; smart pills incorporating digital technologies for sensing and reporting; transdermal patches; and subcutaneous implants. New manufacturing methods are also being explored to enable more personalized and patient-centric dosage forms, such as 3D printing of oral solid dosage (OSD) drugs.

Personalized OSD forms aim to improve outcomes and adherence by tailoring medicines to each patient’s needs. “Standard tablets are easy to mass-produce but do not account for differences in age, weight, genetics, or disease progression,” says Bing Xun Tan, pharmaceutical application laboratory manager, Roquette Health & Pharma Solutions. “Customizing dose strength or form maximizes therapeutic efficacy while minimizing side effects, which is crucial for pediatric and geriatric patients,” he notes.

Personalized formulations support drug titration—such as loading and maintenance dosing—as well as body surface area- or weight-based adjustments, which are particularly important in oncology and pediatric care, according to Thierry Jomini, CEO and founder of AbbatiaLabs. In addition, he observes that personalized dosing facilitates safe medication tapering, giving patients a better chance to discontinue treatment optimally, and helps combat issues like antibiotic resistance and drug habituation. Finally, comments Jomini, solid oral forms offer superior stability compared to liquids, enabling global accessibility even in regions without refrigeration, thus ensuring reliable treatment delivery across diverse environments.

Advances like 3D printing, multiparticulate systems, and improved excipients such as pregelatinized starch or mannitol now enable bespoke formulations, according to Tan. Regulators, he adds, are also starting to play a role. FDA’s pediatric exclusivity provision (1), for instance, provides a financial incentive for pharmaceutical manufacturers to conduct and submit pediatric studies supporting the development of age-appropriate dosage forms that could also allow for dose titration. Similarly, in Europe, the Pediatric Use Marketing Authorization (PUMA) (2) incentivizes medicines developed exclusively for use in the pediatric population with data and market protection for product authorization.

“These drivers support the shift from ‘one-size-fits-all’ medicines towards precision approaches that make drug therapy safer, more effective, and better adapted to the patient,” Tan concludes.

Enhancing treatment efficacy through better adherence

The drivers for patient-centric formulation development are similar to those for personalized OSD drugs because both approaches focus on enhancing treatment efficacy and patient adherence by emphasizing individual preferences and needs, says Lydia Marinou, technical sales manager with Adragos Pharma.

As examples, Marinou points out that flexible dosing schedules and dosage forms that align with patients' lifestyles can significantly improve adherence rates, and the use of mobile health applications that gather patient feedback further supports this trajectory. “Successful case studies, such as patient-centric inhalers collecting real-time data, illustrate how understanding patient profiles and medication adherence can lead to more effective and satisfactory treatment outcomes,” she adds.

John van den Anker, chief scientific officer of AbbatiaLabs, agrees that the primary motivation for both personalized and patient-centric products is improved adherence to therapy. “Medications that are easier to administer—whether by patients themselves or by caregivers—significantly increase the likelihood of consistent treatment,” he notes. “Moreover,” he continues, “patient-centric products help reduce dosing errors, which are a leading cause of medication-related issues, particularly in settings requiring precise, bodyweight-based dosing such as pediatric care.”

Patient-centric design, according to Tan, focuses on making medicines easier to use—like easier-to-swallow tablets or chewables, taste-masked forms for children or older adults, or fast-melt options including orally disintegrating tablets (ODTs) for those with dysphagia. “By reducing behavioral and sensory barriers, these designs encourage correct use. Commercially, they appeal to patients, caregivers, and providers seeking better compliance,” he says.

In addition, Tan comments that as lifestyle medicines (like those for weight loss) grow in popularity, there is also a market-driven demand for more lifestyle-friendly, personalized formats. This trend, he observes, mirrors similar trends in nutraceuticals and cosmetics, where personalization is already a significant consumer demand.

Significant overlap between personalized and patient-centric OSD drugs

Consequently, there is a clear overlap between personalized and patient-centric oral solid dosage drugs, as both concepts prioritize ease of use and accuracy in drug administration, according to Jomini.

Tan, meanwhile, views personalized OSD drugs with doses and/or drug combinations customized for individuals as, effectively, a subset of the broader patient-centric approach. “While personalization focuses on pharmacological customization (right drug, right dose), patient-centric design ensures that the dosage form itself is acceptable, convenient, and adapted to the patient’s needs and preferences,” he explains. In practice, Tan notes that advances like 3D printing enable both at once: for example, a chewable, flavored tablet designed for a child that also delivers a precise weight-based dose.

Van den Anker contends that flexible dosing devices—such as POWDOSE from AbbatiaLabs—exemplify this convergence by enabling patients or caregivers to easily and reliably select the precise dose needed, typically in just a couple of simple steps. “These innovations support both individualized treatment regimens and user-friendly administration, making them essential tools for delivering truly tailored and accessible therapies,” van den Anker believes.

Overall, concludes Tan, “patient-centric design provides the usability framework, while personalization ensures pharmacological precision. Together, they represent a shift from viewing the patient as a passive recipient of standardized treatment to an active participant whose unique needs and circumstances shape the final product.”

Recent technology advances of note for van den Anker include flexible and user-friendly dosing solutions that allow precise, individualized dosing. He also highlights 3D printing as an emerging and powerful tool for creating customized drug formulations tailored to each patient’s needs; long-acting formulations, which contribute by reducing dosing frequency and improving adherence; and easy-to-swallow formats—such as multiparticulates and dissolvable tablets—that enhance patient comfort and usability, particularly for children and the elderly. “Together, these innovations are transforming the landscape of oral drug delivery toward more tailored and accessible care,” he states.

Manufacturing, scalability, and regulatory complexity challenges

Developing patient-centric and personalized OSD drugs is not a simple endeavor, however. There are several challenges along the way. The biggest hurdles, according to Tan, lie in manufacturing, scalability, and regulatory complexity.

One major barrier highlighted by Jomini is the need for the pharmaceutical industry to invest in new infrastructure, such as equipment for 3D printing individualized doses or systems for filling flexible dosing devices, which also require compatible multiparticulate formulations.

Technologies like 3D printing, adds Tan, are well suited to one-off or small-batch production, but because each tablet is printed layer-by-layer, this method is too slow and costly for large-scale deployment. In addition, he notes that supply chains must also adapt, particularly for excipients. “The sourcing of ready-to-use blends and functional excipients that streamline small-batch production has never been more important,” Tan states.

Furthermore, Tan emphasizes that highly individualized production demands new distribution models, specialized training, and flexible quality systems capable of ensuring consistency and safety for varied products. Regulations need updating as well. “Regulatory frameworks, while evolving, still generally assume mass production of standardized forms. Clear guidance on quality controls, validation, and data protection (especially when handling patient-specific data) is still developing,” Tan says.

Another challenge for van den Anker is the need for development of robust clinical evidence clearly demonstrating that precise dosing leads to better health outcomes. In addition, he observes that for many personalized and patient-centric OSD drugs, “payers must be willing to support potentially higher costs for these advanced therapies in recognition of their benefits in adherence and therapeutic effectiveness.”

Overall, according to Tan, “the crux is how to scale up personalization without compromising cost-effectiveness, safety, or regulatory compliance—challenges that will require not only technological solutions but also reimagined business and regulatory models.”

Regulatory considerations significantly impact the development of personalized and patient-centric OSD drugs, and agencies are adapting their frameworks to better accommodate innovations, Marinou says. She points to incorporation of quality-by-design principles to ensure safety and efficacy as an example.

Regulatory frameworks must continue to evolve, however, to address novel challenges while maintaining safety and quality, according to Tan. “New production methods require robust validation (especially for on-demand and small-scale manufacturing environments), as well as solid quality controls and assured compliance with good manufacturing practices. Handling patient-specific data also demands stringent privacy protections,” he explains.

The approval of patient-customized 3D-printed medicines and devices exemplifies the evolving landscape for Marinou (3–5). She emphasizes, though, that addressing compliance complexities and establishing robust pharmacovigilance systems remain critical for companies aiming to introduce personalized treatments that align with regulatory standards. “Navigating the complexities of compliance is essential,” she says, “particularly as the inclusion of real-world evidence, which allows companies to leverage patient data for adaptive regulatory pathways, becomes increasingly important.”

If delivery is achieved using specialized devices, there are additional regulatory considerations. Products that include a device component—such as a flexible dosing system—may be classified as combination products, which can introduce added regulatory complexity, especially for developers more accustomed to small-molecule drugs, says Jomini. “While this pathway is more common in biologics and injectables, it poses a challenge in the OSD space. Moreover, any medical claims, such as improved outcomes, must be substantiated by robust clinical evidence,” he observes. Despite these hurdles, Jomini does note that specialized regulatory expertise is available to support developers through this process.

Also on the positive side, Tan notes that many pharmaceutical regulatory agencies are already encouraging patient-focused approaches. In addition to the aforementioned pediatric development incentives, he highlights FDA’s Patient-Focused Drug Development initiative (6), which emphasizes incorporating patient perspectives and needs. “Together, these regulatory drivers support safer, more tailored therapies that meet the multifaceted needs of a diverse, global patient body,” Tan says.

Despite the many challenges, developers of OSD drugs are pursuing innovative solutions that support the creation of personalized and patient-centric products designed to increase medication adherence and provide better outcomes.

Tan notes that the ability of 3D printing to enable on-demand, patient-specific tablets with tailored doses and flavors has been demonstrated for pediatric use in hospital trials (7). “Hospital pharmacies are beginning to adopt 3D printers and precise dosing devices to create tailored oral forms at the point of care—such as child-friendly, flavored tablets with exact doses,” he notes.

Fast-melt tablets and dissolvable oral films improve administration for those with swallowing difficulties, while multiparticulate systems, such as pellets and minitablets, enable flexible drug-dose combinations that can reduce pill burden, according to Tan. He points to the OraFID (Sensidose, part of Navamedic ASA) prefilled dose dispenser as simplifying minitablet administration by allowing patients and caregivers to accurately dispense the required dose. “Minitablets and multiparticulates promise superior accuracy and dosing flexibility, allowing complex regimens to be delivered in single capsules or even sprinkles with specific release profiles,” he says.

Other advances highlighted by Tan include improvements to excipient offerings such as plant-based mannitol and other starch derivatives, which ultimately support better taste-masking, compressibility, and customized release profiles. “The industry’s growing understanding of the importance of these factors is driving the development of excipients designed specifically for patient-centric forms and advanced manufacturing, laying the groundwork for truly personalized, user-friendly oral medicines,” he says.

Innovative drug delivery systems, meanwhile, are transforming personalized medicine, according to Marinou. “Nanoscale carriers, such as dendrimers and liposomes, enhance drug solubility and targeting, allowing for treatments such as personalized cancer therapies that deliver chemotherapeutics directly to tumor cells. Layered tablets provide controlled release of multiple drugs, which is particularly useful for the management of chronic conditions, as seen in combination therapies for diabetes. Additionally, smart delivery systems, such as implantable devices that can adjust dosages based on real-time physiological data, represent the future of medication adherence and effectiveness, allowing for tailored treatments that adapt to individual patient dynamics,” she comments.

In the near future, van den Anker believes the development of oral formulations for traditionally injectable therapies, such as oral insulins and GLP-1 drugs for obesity and type 2 diabetes, will have significant potential to advance personalized and patient-centric OSD drugs. “These innovations could greatly improve patient comfort and adherence,” he states.

Longer-term, Tan believes artificial intelligence (AI)-driven formulation design and fully decentralized manufacturing will revolutionize production of personalized and patient-centric OSD drugs. “AI models can help predict optimal doses and formulations based on individual patient data, while advanced manufacturing units in pharmacies or clinics produce these custom forms on demand,” he observes. Tan also expects smart ingestible devices and biosensors will eventually provide the added benefit of real-time monitoring and responsive drug release, enabling dynamic personalization (8). “Once the lingering technological and regulatory barriers have been addressed, these developments could create an interconnected, on-demand systems delivering personalized oral therapies at scale within the next decade.”

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EMA. Paediatric-use Marketing Authorisations. Ema.europa.eu. Updated July 31, 2025. 

https://www.ema.europa.eu/en/human-regulatory-overview/marketing-authorisation/paediatric-medicines-marketing-authorisation/paediatric-use-marketing-authorisations

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Stoops; et al., Clinical Implementation of a Paediatric 3D-printed Combination of Sulfamethoxazole and Trimethoprim. 

Chai; et al., Utilizing an Ingestible Biosensor to Assess Real-Time Medication Adherence. 

 Dec;11(4):439-44. DOI: 10.1007/s13181-015-0494-8

Cynthia A. Challener, PhD is a contributing editor to

Articles

The development of personalized and patient-centric oral solid dosage (OSD) drugs aims to improve medication adherence and therapeutic outcomes by tailoring treatments to individual patient needs. Innovations such as 3D printing, smart pills, and flexible dosing devices are transforming drug delivery, making it more precise and user-friendly. However, challenges in manufacturing, scalability, and regulatory compliance persist. Regulatory frameworks are evolving to accommodate these innovations, emphasizing patient-focused approaches. Future advancements may include AI-driven formulation design and real-time monitoring systems, further enhancing personalized medicine.

New manufacturing methods are being explored, but challenges are still present in personalized medicine development.

Personalized and Patient-Centric Administration of Oral Medicines

Magnifier with pills on blue background | Image Credit: © Pixel-Shot - stock.adobe.com

Pharmacokinetic (PK)/pharmacodynamic (PD) modeling of small-molecule drug candidates provides information essential for selecting and progressing optimal drug candidates. Effective PK/PD modeling, however, requires specialized expertise, time, and resources that are not always readily available.

Use of advanced artificial intelligence (AI) and machine learning (ML) algorithms can ameliorate resource limitations while also enabling the identification of patterns not readily apparent to human analysts, thus streamlining development while providing more robust predictions of 

PK/PD modeling plays important role in drug development

Understanding the absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties of small-molecule drug candidates can inform the evaluation of small-molecule drug candidates through discovery and development efforts. Detailed information about these attributes can help weed out undesirable molecules and move forward candidates with a higher likelihood of success. In vitro and in vivo PK/PD screening studies are time-consuming and costly, however, with ADMET assessments often becoming a bottleneck in drug development programs (1).

In silico approaches for determination of ADMET properties have, therefore, become crucial to accelerating drug discovery and development efforts, allowing rapid evaluation of large numbers of compounds. “PK/PD modeling provides a quantitative framework that is essential for effective, data-driven drug development,” states Pauline Traynard, product manager for MonolixSuite at SimulationsPlus. “By integrating diverse data from laboratory experiments and clinical studies, these models allow us to understand the complex interplay between a drug’s concentration in the body and its therapeutic effect. This mechanistic insight is critical for optimizing dosing regimens, designing more efficient and informative clinical trials, and making crucial go/no-go decisions,” she explains.

Ultimately, Traynard observes, PK/PD modeling helps reduce late-stage attrition rates and supports a more streamlined, cost-effective, and successful path to regulatory approval and clinical use.

Increasing complexity creating challenges

Greater understanding of disease mechanisms and advances in rapid synthesis of compound libraries based on increasingly complex molecules, many which have limited solubility (and therefore bioavailability) under physiological conditions, has created several challenges to achieving effective PK/PD modeling.

“Emerging trends such as highly potent molecules with narrow therapeutic indices and complex drug delivery technologies (e.g., long-acting injectables or lipid nanoparticles) pose significant modeling challenges,” says Traynard. She also notes that many advanced drug candidates exhibit nonlinear kinetics, require specialized absorption models, or interact with biological barriers in non-intuitive ways.

An additional significant challenge, Traynard adds, arises during clinical development. “Understanding and predicting the high degree of variability in how different patients respond to a drug is difficult to decipher from the limited samples per patient typically collected during clinical trials,” she comments.

AI/ML algorithms overcome many modeling challenges

AI/ML algorithms are instrumental in overcoming many of these modern PK/PD challenges, according to Traynard, due to their superior ability to identify complex patterns in high-dimensional data where mechanistic understanding is still incomplete.

The most impactful applications for AI/ML-based PK/PD modeling are, Traynard observes, in early-stage discovery and the enhancement of mechanistic models. “In discovery, AI/ML-driven prediction of ADME and toxicity is invaluable for rapidly screening vast compound libraries to de-risk projects before significant investment is made,” she explains.

For instance, Traynard notes that AI/ML models can rapidly and accurately predict a full suite of ADME properties directly from a chemical structure, allowing scientists to screen and optimize thousands of candidates virtually and focus resources on the most promising ones. In clinical development, meanwhile, ML-based models can in early development be employed to analyze sparse patient data for efficient identification of factors contributing to variability in drug response, leading to more robust population PK models and better-informed dosing strategies, according to Traynard.

AI/ML techniques are particularly valuable for classes of APIs where traditional modeling methods face limitations due to underlying biological or chemical complexity. Traynard highlights compounds with poor solubility and permeability (Biopharmaceutics Classification System Class II/IV), where AI/ML can effectively model the intricate relationship between a drug’s formulation and its in vivo absorption to predict bioavailability. “It is also used for APIs with complex safety profiles or non-linear pharmacokinetics, as AI/ML is adept at integrating diverse biological data to identify safety signals, such as the potential for organ injury, that are difficult to predict with simpler models,” she says.

Significant benefits can also be obtained when using ML models in conjunction with in vitro-in vivo extrapolation and physiologically based pharmacokinetic (PBPK) modeling because integration of these approaches provides a more comprehensive picture of a drug’s ADMET profile (2). Augmentation of established PBPK and population PK/PD models with model structure learning and parameter estimation is, says Traynard, a second key application. As an example, such modified models are useful for identifying influential covariates or nonlinear relationships within clinical data.

A third important application of advance algorithms in PK/PD modeling is the automation of model development workflows, which Traynard believes can reduce time-intensive manual steps by implementing ML-guided model selection, fit optimization, and diagnostics.

The biggest challenge to enabling the widespread use of AI/ML algorithms to improve PK/PD modeling is the same issue facing the development of AI/ML models for all other applications in the biopharmaceutical industry: the need for large quantities of high-quality, reliable data. “Limited access to large, high-quality datasets needed to train reliable AI models is a major challenge to broader AI/ML adoption in PK/PD modeling, largely due to restrictions and experimental variability,” observes Traynard.

Another important concern noted by Traynard is the inherent “black box” nature of some algorithms, which may lack the transparency needed for regulatory or internal scientific confidence.

Hybrid approaches combining established mechanistic models like population PK/PD or PBPK with interpretable AI components are therefore gaining traction. “This strategy grounds the AI’s powerful pattern-recognition abilities in the context of known biology, making the results more interpretable, scientifically plausible, and trustworthy for both scientists and regulators,” Traynard comments.

Regulatory acceptance is crucial, of course, and there is growing interest from regulators in AI/ML’s potential for population simulation, dose selection, and decision support, according to Traynard, particularly when integrated into PBPK or exposure-response models used in regulatory filings.

“The core regulatory concerns,” observes Traynard, “are model transparency, validation, and managing bias to ensure that any AI/ML tool is fit-for-purpose.” As a result, she says, there is a strong emphasis on establishing “good machine learning practice” and developing explainable AI that allows regulators to understand the basis of a model’s predictions.

Going forward, Traynard believes the evolution of AI/ML in PK/PD modeling is likely to center on a deeper integration with mechanistic science, creating powerful hybrid systems that are both more predictive and explainable. “As these predictive models become more robust, we anticipate advances in automated clinical trial simulation and design, where AI could be used to forecast trial outcomes under different scenarios and optimize protocol parameters in silico before a single patient is enrolled,” she adds.

Looking further out, Traynard notes that leveraging AI to deliver truly personalized medicine represents an important frontier. “The ambition,” she explains, “is to use sophisticated algorithms to integrate vast, patient-specific datasets to enable more accurate personalized predictions of an individual’s unique response to a drug, paving the way for individual treatment optimization.”

Myung, Y.; de Sá. A.G.C.; and Ascher, D.B. Deep-PK: Deep Learning for Small Molecule Pharmacokinetic and Toxicity Prediction Open Access. 

 52 (W1), pp. W469–W475. DOI: 10.1093/nar/gkae254

Bassani, D.; Parrott, N. J.; Manevski, N.; and Zhang, J. D. Another String to your Bow: Machine Learning Prediction of the Pharmacokinetic Properties of Small Molecules.

 19(6), 683–698. DOI:10.1080/17460441.2024.2348157

Cynthia A. Challener, PhD, has been a freelance technical writer for more than 25 years and is a contributing editor to 

Pharmacokinetic/pharmacodynamic (PK/PD) modeling is crucial for drug development, providing insights into drug absorption, distribution, metabolism, elimination, and toxicity (ADMET). However, traditional PK/PD modeling faces challenges due to complex drug properties and patient variability. Advanced AI and ML algorithms offer solutions by identifying patterns in high-dimensional data, enhancing early-stage discovery, and improving mechanistic models. Despite their potential, AI/ML models require large, high-quality datasets and face transparency issues. Hybrid models combining AI with mechanistic approaches are gaining traction, promising more predictive and explainable outcomes.

Artificial intelligence and machine learning can help identify complex patterns.

Overcoming PK/PD Modeling Challenges

medicine and vision concept - woman closeup and eye diagram, future technologies | Image Credit: ©Julia - stock.adobe.com

Aging of the global population and the rise of chronic diseases, particularly diabetes, have contributed to an increase in the occurrence of eye diseases, such as glaucoma, keratitis, age-related macular degeneration (AMD), dry eye disorder (DED), and diabetic retinopathy (DR). Pharmaceutical companies have responded with growing investment in the research and development of novel eye treatments and drug delivery systems designed to address key challenges in ocular therapy. Current treatments range from traditional small-molecule and antibody-based drugs to cell and gene therapies and nanoparticle delivery solutions, along with various types of ocular implants and the use of drug-eluting contact lenses (1,2).

One area of focus has been the development of solutions for the sustained delivery of treatments, particularly to the posterior part of the eye. Many ocular therapies are formulated as eye drops that must be administered frequently to overcome the many physical and mechanistic barriers in the eye and ensure sufficient dosing. Sustained and targeted delivery products are helping reduce the dosing frequency by overcoming ocular barriers and increasing bioavailability.

Delivery of therapeutics to the anterior, or front of the eye, is generally simpler than delivery to the posterior part, because topical eye drops are an option. There are limitations to their effectiveness, however. “Drops do not maintain good bioavailability and are relatively quickly flushed out by nasolacrimal drainage,” explains Jeffrey S. Heier, chief scientific officer with Ocular Therapeutix. “While they are a convenient mode of delivery,” he adds, “they present challenges in terms of not only bioavailability, but limited duration of therapeutic effect, both of which contribute to inconsistent patient compliance and suboptimal outcomes.”

Treatments for glaucoma (high eye pressure), as well as infections and inflammation of the eye, are good examples. Glaucoma eye drops typically need to be administered at least once daily, and in many cases, multiple times a day. For some conditions, Heier observes, drops must be delivered on an hourly basis. “Such a dosing frequency is only sustainable for a short period of time. In fact, it is readily accepted that even with easy-to-administer options like eye drops that must be applied just once daily, adherence remains a major issue due to the frequency of this regimen,” he says.

Another option for treatment of the anterior segment of the eye is straightforward intracameral injections, according to Heier. This method of administration delivers ocular therapies directly into the anterior chamber of the eye, allowing for targeted delivery and resulting in enhanced bioavailability (3).

While treatments for infection, inflammation, high eye pressure, and neovascularization have been shown to be effective, this method of delivery is considered “off-label,” as FDA has not approved products specifically for this use, except two intracameral implants (see below). In addition, many patients are hesitant to receive eye injections.

Targeting the back of the eye presents unique challenges, not only in achieving therapeutic durability but also in navigating complex regulatory expectations, Heier comments. Indeed, delivery to the posterior segment is anatomically more complicated, especially when the durability of treatment is a primary objective.

“Although advances in intravitreal medicines have shown incremental increases in durability compared to prior standard of care, current retinal therapies rely on frequent intravitreal injections to maintain their effect,” observes Peter Jarrett, chief technical officer for Ocular Therapeutix.

For many patients, even therapies that require administration every three to four months can be challenging, as this type of regimen places a significant burden on patients and care partners, according to Jarrett. “To treat the full spectrum of patients with retinal disease or other conditions affecting the posterior segment, there is still a need for more durable treatments, and the development of longer-lasting treatments is such a critical focus,” he says.

New sustained-delivery therapies, however, must be proven to be as safe and effective as existing treatments that may require much more frequent administration. In addition, Jarrett notes that targeted delivery to the retina and posterior segment of the eye necessitates overcoming several blood-ocular barriers, including the blood-aqueous barrier and the blood-retina barrier.

“Historically,” Jarrett explains, “overcoming these physiological defenses has required delivering drugs at high concentrations. However, this approach often results in increased systemic exposure, which in turn can lead to a higher incidence of adverse events and toxicities. Striking the right balance between effective ocular delivery and systemic safety remains a focus in the development of retinal therapies.”

Potential for better treatments with greater convenience

While small steps taken to enhance ocular delivery have had positive impacts, there is still real potential for innovative solutions, particularly those leveraging sustained-release delivery technologies, to have dramatic effects on patient outcomes.

“While incremental improvements can be achieved through sophisticated formulations, such as enhancing solubility, prolonging ocular surface retention, or improving penetration through ocular barriers, these refinements often reach a ceiling in terms of clinical impact,” Heier remarks. “In contrast, transformative advances in treating chronic eye diseases are more directly realized through sustained-release delivery technologies, which bypass many of the pharmacokinetic limitations of topical or injectable drugs by providing continuous, controlled delivery of therapeutics directly to targeted intraocular tissues over extended periods,” he contends.

In addition, Jarrett emphasizes how important it is for developers to realize that results obtained in clinical trials often do not translate to the real world for treatments with dosing regimens patients have difficulty consistently maintaining as part of their daily lives. “A durable therapy that reduces treatment burden could offer not just convenience, but potentially better long-term outcomes for patients who would otherwise fall through the cracks of an intensive treatment schedule. Recognizing this balance between ideal clinical trial conditions and the real-world experience of patients is key to advancing more durable treatment options,” he states.

Nanoscale drug-delivery systems are recognized to achieve enhanced bioavailability and targeted and sustained delivery of many types of therapeutics addressing a wide variety of conditions, including eye diseases (2). Examples of different types of nanoparticles used for ocular drug delivery include nanomicelles, liposomes, polymeric nanospheres, and peptide-based nanoparticles (2).

Nanomicelles in preclinical testing have been shown to experience good uptake by corneal cells and when administered topically to achieve sustained delivery of drugs to treat DED, neovascular AMD, inflammation, and other eye disorders (1). Biocompatible lipid nanoparticles can deliver drugs with both hydrophobic and hydrophilic properties for extended periods. In one animal model of glaucoma, large unilamellar liposomes achieved sustained delivery of latanoprost, a common drug used to reduce eye pressure, for up to five days (4).

Peptide-based nanoscale delivery systems are particularly attractive because they are not only biocompatible, but can be used to target specific cell receptors, disrupt endosomal membranes, and carry drug payloads to the nucleus (1). Of the two main types of systems (elastin-like polypeptides and silk fibroin polymers), the former have been investigated for sustained release of drug substances from contact lenses due to their ability to remain adhered to their surfaces.

Researchers continue to investigate the potential of nanoscale materials for the formulation of extended-release ocular therapeutics, with efforts focused on increased drug-loading capacity, ocular residence time, and release periods while reducing potential toxicities (1).

Drug-eluting contact lenses and canalicular plugs

Given the limitations and issues associated with the use of eye drops and intracameral injections for treatment of conditions in the anterior segment of the eye, other options for delivery are looking to leverage the accessibility of this portion of the eye, according to Heier. Examples include drug-eluting contact lenses and canalicular plugs.

As indicated previously, sustained, topical delivery of ocular therapies to the anterior of the eye is possible using contact lenses loaded with active drug substances, such as peptide-based nanoparticles carrying drug payloads. It is even possible to improve drug loading by incorporating non-covalent binding sites into the lenses when they are manufactured (1). Delivering drugs using contact lenses is attractive because this approach is non-invasive and can potentially support increased drug uptake compared to topical applications (eye drops, creams, ointments). ACUVUE Theravision contact lenses (Johnson & Johnson Vision Care), which provide sustained delivery of ketotifen for the treatment of itchy eyes, are the first FDA-approved drug-eluting contact lens product (5).

Canalicular plugs belong to a class of treatments known as punctal plugs, which are inserts designed to slow or block the outflow of tears from the eye (6). Punctal plugs can be temporary, semi-permanent (resorbable), or permanent (synthetic, usually silicone), and some are able to provide sustained release of drug substances. They are most widely used to treat DED and have been shown over three decades to be generally safe and effective; although, they can fall out, become partially displaced, or lead to watery eyes.

Recent developments have helped address many of these issues. One example is a canalicular gel device (Lacrifill, Nordic Pharma) introduced in June 2024 (7). The chemically crosslinked particulate hyaluronic acid (HA) hydrogel device is designed to completely fill the canaliculus regardless of its size in different patients, preventing dislodgement and the buildup of stagnant tears and mucus that can result in infection. It is meant to be used for up to six months and can be easily removed by applying a sterile solution.

Significant advances have also been made over the past two decades in ocular implant technology for sustained release of drugs that treat a number of eye diseases. Implants can be biodegradable, although some are not (8). The former can suffer from the rapid release of remaining active drug substance upon degradation, while the latter require surgical removal when the drug substance is fully released.

Bioerodable implants are thus receiving more attention. These products are slowly solubilized upon exposure to biological fluids, leading to slow release of the drug and absorption of the implant material into the eye, avoiding a final “burst” release (8). The rate of dissolution can also be controlled by modifying the chemical composition of the polymer used in the implant. Theoretically, these devices could provide sustained release of therapeutics for months to years.

Jarrett highlights the use of degradable or erodible matrix materials for the sustained delivery of small-molecule drugs. “The choice of drug and implant material are extremely important in designing such a sustained-release system,” he says. “Challenges include drug potency, safety, control of drug release rate, local and systemic drug concentrations, implant biocompatibility and bioresorption, implant size and placement position, and the injection technology utilized,” Jarrett denotes.

As an example, Jarrett points to bioresorbable hydrogel technology as offering a long-term option for delivering small molecules to the posterior segment. Hydrogels, he says, are well-suited to deliver extremely low solubility, lipophilic drugs because the release rate is being controlled by drug solubility. “Drug solubility in both the hydrogel matrix and in the vitreous humor fluid are important rate control factors. These factors may be combined to create a constant release rate in the eye,” he explains.

In addition, the bioresorbable hydrogel vehicle can be designed to break down into water soluble molecules that are neutral pH, non-reactive, and readily cleared from the eye, with timing of resorption tailored to synchronize with drug depletion, allowing repeat injections without crowding the vitreous with empty vehicles or “shells” from earlier injections.

Implants have, in fact, been developed for insertion into both the anterior and posterior segments of the eye. The devices are either implanted surgically or via injection (intracameral for anterior and intravitreal for posterior applications). Injected implants are typically smaller as they must be able to fit into a needle (7).

Two examples of FDA-approved intracameral implants are Durysta (Allergan) and iDoseTR (Glaukos), both of which provide sustained release of drugs (bimatoprost and travoprost, respectively) to treat intraocular pressure in open-angle glaucoma/ocular hypertension.

There are also several intravitreal implants approved by FDA, including Ozurdex (AbbVie) for macular edema and Dexycu (EyePoint Pharmaceuticals) for post-operative inflammation. Encelto (Neurotech Pharmaceuticals), which leverages an encapsulated cell therapy technology to continually deliver therapeutic doses of ciliary neurotrophic factor to the retina to treat macular telangiectasia type 2, received FDA approval in early 2025 (9).

FDA approval was also granted in early 2025 to Susvimo (Roche) for the treatment of DME, which continuously delivers ranibizumab via the Port Delivery Platform, a refillable (every six months) eye implant surgically inserted into the eye (10).

While there remain many challenges to effectively treating diseases of the eye, significant strides have been made with recent advances in technologies supporting sustained, targeted release of effective ocular therapies. With many additional, innovative solutions in preclinical through late clinical development, additional progress is expected.

Whalen, M.; et al. Seeing the Future: A Review of Ocular Therapy. 

Chandel, A. and Kandav, G. Insights into Ocular Therapeutics: A Comprehensive Review of Anatomy, Barriers, Diseases, and Nanoscale Formulations for Targeted Drug Delivery. 

https://doi.org/10.1016/j.jddst.2024.105785

Gautam, M.; et al. Intracameral Drug Delivery: A Review of Agents, Indications, and Outcomes.

 39 (2), 102-116. DOI:10.1089/jop.2022.0144

Natarajan, J.V.; et al. Sustained Release of an Anti-Glaucoma Drug: Demonstration of Efficacy of a Liposomal Formulation in the Rabbit Eye. 

Johnson & Johnson Vision. Johnson & Johnson Vision Care Receives FDA Approval for ACUVUE® Theravision™ with Ketotifen - World's First and Only Drug-Eluting Contact Lens. Press Release, March 2, 2022. 

https://www.prnewswire.com/news-releases/johnson--johnson-vision-care-receives-fda-approval-for-acuvue-theravision-with-ketotifen--worlds-first-and-only-drug-eluting-contact-lens-301493964.html

Cleveland Clinic. Punctal Plugs. ClevelandClinic.org (accessed June 20, 2025). 

https://my.clevelandclinic.org/health/treatments/25249-punctal-plugs

Charters, L. New Canalicular Gel Shows Promise for Dry Eye Treatment. 

https://www.ophthalmologytimes.com/view/new-canalicular-gel-shows-promise-for-dry-eye-treatment

Wykoff, C.C.; Kuppermann, B.D.; and Saïm, S. Extended Intraocular Drug-Delivery Platforms for the Treatment of Retinal and Choroidal Diseases. 

Neurotech Pharmaceuticals. Neurotech’s ENCELTOTM (revakinagene taroretcel-lwey) Approved by the FDA for the Treatment of Macular Telangiectasia Type 2 (MacTel). Press Release, March 6, 2025. 

https://www.neurotechpharmaceuticals.com/wp-content/uploads/Neurotech_Press-Release_BLA_Approval_FINAL.pdf

Roche. FDA Approves Roche’s Susvimo as the First and Only Continuous Delivery Treatment for the Leading Cause of Diabetes-related Blindness. Press Release, Feb. 3, 2025.

https://www.roche.com/media/releases/med-cor-2025-02-04#:~:text=Susvimo%C2%AE%20(previously%20called%20Port,edema%20(DME)%20that%20continuously%20delivers

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

®
Vol. 49, No. 6
July/August 2025
Pages: 12–15

When referring to this article, please cite it as Challener, C. Advanced Solutions for Sustained Delivery of Ocular Therapies. 

The aging global population and rise in chronic diseases like diabetes have led to increased eye diseases, prompting pharmaceutical companies to invest in novel ocular treatments and drug delivery systems. These include small-molecule drugs, cell and gene therapies, and nanoparticle delivery solutions. Sustained delivery systems are crucial for reducing dosing frequency and improving bioavailability, especially for posterior eye treatments. Innovations like drug-eluting contact lenses, canalicular plugs, and ocular implants are being developed to enhance treatment efficacy and patient compliance, with nanoscale drug-delivery systems showing promise for targeted, sustained delivery.

Hydrogels, drug-eluting contact lenses, and other implant technologies show real promise.

Advanced Solutions for Sustained Delivery of Ocular Therapies

Efficient and effective delivery of complex and challenging drug substances is an ongoing issue facing developers of modern medicines. Delivery systems must overcome poor solubility and bioavailability while achieving targeted delivery to achieve maximum efficacy with lower doses while also minimizing unwanted side effects. Nanoscale technology is proving to be an attractive solution on all accounts, particularly for realizing targeted delivery into specific types of cells and across biological barriers.

Many of the unique properties of nanoscale delivery systems can be attributed to their small size (< 100 nanometers). At this scale, the surface area/volume ratio is high, leading to unique physical, chemical, and biologic properties. The ability to tune the surface properties of nanomaterials through functionalization further increases their utility for drug delivery, particularly with respect to their targeting capabilities. Nanoscale delivery systems can not only increase the bioavailability of poorly water-soluble drugs; they can also protect sensitive APIs from degradation and, when appropriately designed, remain stable in the bloodstream, allowing long-term sustained release and more consistent pharmacokinetics (1). The greater cellular uptake of nanoscale delivery systems also contributes to improved efficacy and reduced side effects.

Another important advantage of nanoscale delivery systems is the ability to deliver two or more APIs simultane

Nanoscale co-delivery systemsoffer improved performance for combination therapies because they deliver the different drug substances in a homogeneous manner (2). Ideal nanoscale carriers are stable, small, but able to support sufficient drug loading of both hydrophobic and hydrophilic APIs; protect the loaded drug from degradation; are suitably functionalized to exhibit a high binding affinity to target cells/ tissues; and have good biocompatibility.

Many different types of nanoscale delivery systems (e.g., lipidic, polymeric, inorganic, biomimetic) provide opportunities for designing solutions with high specificity for the particular API, disease target, and route of administration. In fact, they support the loading of most types of drug substances, including small molecules, proteins, nucleic acids, and diagnostic agents (1). They can also be customized in support of personalized medicines, and some have been developed that are capable of exhibiting both therapeutic and diagnostic activities (theranostics).

As more information is gained about the benefits of nanoscale delivery systems, researchers are exploring the applicability of a growing variety of nanoscale materials for this purpose (1–3). Nanoparticles have attracted particular attention, including those based on lipids, polymers (natural and synthetic), lipid-polymer hybrids, dendrimers, inorganic materials (metals, magnetic compounds, carbon nanotubes, silica-based systems, etc.). Other nanocarriers include nanocrystals; DNA-based systems; extracellular vesicles such as exosomes, microvesicles, apoptotic bodies, and phagosomes; nanoemulsions; and micelles.

Like any drug delivery technology, nanoscale systems are not perfect solutions and, depending on the particular nanotechnology, have different sets of limitations (1). Some of the nanomaterials used for drug delivery can, if the systems are not designed appropriately, pose toxicity and biocompatibility issues. One example is metallic nanoparticles if they accumulate in the body.

Similarly, while some nanoscale delivery systems can exhibit prolonged lifetimes in the bloodstream, others have short circulation times or can be viewed as foreign materials by the immune system and rapidly cleared. Some nanomaterials may also exhibit unexpected/unpredictable interactions with biological systems that lead to detrimental effects. These uncertainties and complexity of nanoscale drug delivery systems often lead to regulatory challenges.

The development of robust, predictable large-scale manufacturing processes can be a significant hurdle for some nanomaterials/nanoscale delivery systems. In addition, stability during storage can be an issue for some nanoscale systems, requiring careful formulation development. All these challenges tend to lead to high costs for therapeutics and vaccines leveraging nanoscale drug delivery systems.

Highly targeted delivery with nanoscale systems can be achieved using passive or active mechanisms. Passive delivery involves accumulation of the nanoscale system in the targeted cell/ tissue through enhanced permeability and retention (EPR), which is dictated by the shape, size, charge, and other surface properties of the unfunctionalized nanomaterial (4). This approach does not, however, completely reduce delivery to healthy cells, which can result in off-target effects.

Active targeting, meanwhile, is realized through functionalization of the surface of the nanocarrier system to both increase cellular uptake and ensure delivery to specific cells/tissues (4). Ligands are attached to the surfaces of the nanocarriers that have high binding affinity to receptors specific to the target cells. These ligands can include a range of compounds, including antibodies, aptamers, peptides, small molecules, and biomimetic materials such as cell membranes, among others. As an example, nanoscale delivery systems can be functionalized with PD-L1 monoclonal antibodies in anticancer therapies.

The targeting ability of nanoscale systems can benefit treatments for all disease classes, but this capability is of even greater importance in certain applications. Targeting of cancer cells is a major goal in oncology, as traditional systemic treatment result in severe side effects. The ability of nanocarriers to selectively attack targeted tumor cells allows for delivery of higher doses to improve efficacy while reducing cytotoxicity (1).

Therapeutic hyperthermia is a unique treatment made possible by use of nanoparticle delivery systems (1). Once the nanoparticles are localized in the tumor, they are exposed to laser radiation or an applied magnetic field, leading to an increase in temperature sufficient to kill the cancer cells. The improved targeting capability of nanoscale delivery systems also leads to improved activation of immune cells in cancer vaccines.

Nanoscale delivery systems are improving treatments for infectious diseases including human immunodeficiency virus (HIV) due to their targeting ability. Patient adherence with traditional medications is often low due to the high incidence of side effects. The high on-target bioavailability of nanoscale drugs thus has a measurable, positive impact.

Finally, nanoscale delivery systems are also improving the effectiveness of treatments for autoimmune diseases due to their improved targeting capability (1). Nanoparticles have been shown to deliver antigens and immunomodulators to antigen-presenting cells and lymphocytes with high specificity, and thus more efficiency, inducing antigen-specific tolerance 

Lipid nanoparticles (LNPs) have received significant attention in recent years as attractive systems for the delivery of nucleic acids for vaccine applications. Their success was clearly demonstrated with the approval of the two messenger RNA vaccines against COVID-19, according to McDavid Stilwell, CFO with CPTx. He notes, however, that some of the properties that make LNPs useful for vaccine applications (inflammatory behavior) also present substantial hurdles for systemic therapeutic delivery applications that require higher doses and for which adverse inflammation is undesirable.

There are also issues with targeting LNPs away from the liver, Stilwell observes. The field is working hard to overcome cell targeting challenges, but solutions are not expected soon. Stilwell notes that LNPs have now been successfully engineered to target immune cells, and CPTx is using this approach to deliver single-stranded DNA for its in vivo chimeric antigen receptor (CAR)-T development program.

In addition to ensuring targeted specificity and minimal off-target effects, key challenges with LNPs— and nanoscale delivery systems in general—include achieving consistent manufacturing scalability, controlling batch-to-batch variability, overcoming biological barriers (immune recognition, clearance, endosomal escape), and demonstrating robust safety profiles, adds CPTx’s CEO Hendrik Dietz. “Achieving reliable, reproducible, and cost-effective large-scale production remains critical, especially for transitioning from preclinical validation to clinical and commercial stages,” he says.

CPTx believes that DNA nanostructures presenting an immune-silent vector are a better alternative to currently available gene delivery technologies. “These nanocarriers are optimal for precision targeting, programmable drug release, and transient genetic expression, making them valuable for controlled gene editing and transient immunotherapies,” Stilwell contends. The goal, he adds, is to present a delivery solution that is not only technically superior, but that can also be manufactured in a cost-effective fashion.

The single-stranded DNA nanocarriers CPTx is developing are intended to enable direct, targeted in-vivo gene delivery. Scalable, high-purity DNA single- strand synthesis platforms, both for the gene encoding components of the nanoparticles and the helper material needed to build the nanocarriers, have been an important initial focus to ensure manufacturing challenges are not an issue, according to Dietz.

These new DNA nanostructures are precision engineered from therapeutic immune-silent DNA single-strands using a technique known as programmable DNA nanofabrication, uniquely combining precise control over composition and 3D shape, as well as delivery functionality. “The result is precise cell targeting without external carriers, bypassing issues associated with existing delivery technologies such as viral vectors and lipid nanoparticles, including manufacturing hurdles, immunogenicity (in the case of viral vectors), and targeting challenges,” Dietz states.

The DNA nanocarriers “integrate therapeutic payloads and delivery functionality into rationally engineered particles designed to realize episomal, non-integrated gene expression in target cells or tissues with minimal side effects,” Dietz explains. Functionalization in a site-specific fashion with molecular targeting motifs promotes highly selective binding to specific cells or tissues and efficient cellular uptake, he says.

The modular approach also allows for simultaneous delivery of multiple therapeutic gene payloads and/or simultaneous targeting of multiple tissues or cell types, enhancing effectiveness, safety, and control compared to traditional approaches, according to Dietz.

CPTx is currently working to improve the delivery efficiency in various prototypes while also validating safety and efficacy in animal models with the goal of licensing this DNA nanocarrier delivery solution to drug developers with established payload genes and target tissues.

1. Tenchov, R. et al. Transforming Medicine: Cutting-Edge Applications of Nanoscale Materials in Drug Delivery. 

. 2025 19 (4). https://pubs.acs.org/ doi/10.1021/acsnano.4c09566

2. Sun, L. et al. Better Together: Nanoscale Co-Delivery Systems of Therapeutic Agents for High-Performance Cancer Therapy. F

ront. Pharmacol., Sec. Pharmacol. Anti-Cancer Drugs

. 2024 Vol. 15. DOI: 10.3389/fphar.2024.1389922.

3. Li, Y.; et al. A Nanoscale Natural Drug Delivery System For Targeted Drug Delivery Against Ovarian Cancer: Action Mechanism, Application Enlightenment And Future Potential. 

Front. Immunol., Sec. Canc. Immun. & Immunother.

, 2024 Vol. 15. https://doi.org/10.3389/\ fimmu.2024.1427573

4. Fan, L.; Wang, A.; and Shi, D. Targeted Nanoscale Drug Delivery Systems For Melanoma Therapy. 

. 2023 Vol. 86, 104724. https://doi. org/10.1016/j.jddst.2023.104724

Unique surface properties and ligand functionalization provide real advantages.

Achieving Targeted Delivery with Nanoscale Systems

While many parenteral products can be stored and shipped in the liquid state at room temperature, some, including most based on biologic drug substances, must be maintained at low temperatures. When refrigeration is not sufficient, two options remain: keeping the products in a frozen state or freeze-drying (lyophilizing) them into a powdered form. There are advantages and disadvantages to both, with many factors to consider when choosing between the two solutions.

The biggest driver for freezing or freeze-drying parenteral products is instability of the drug substance when in solution. This issue does not often arise for small-molecule APIs, but is common for recombinant proteins and antibody-based molecules. “Developing freeze-dried or frozen parenteral formulations is primarily driven by the inherent instability of biological molecules in solution at or below room temperature, limited shelf life in liquid form, high sensitivity to temperature fluctuations and air-liquid interfaces, and excipient-related limitations,” says Maria Fernanda Zuluaga Estrada, principal scientist and formulation development group leader at Lonza.

Protein molecules, explains Jeremy Guo, senior vice president and head of drug-product development and clinical drug-product manufacturing at WuXi Biologics, are physically and/or chemically unstable during long-term storage, suffering from aggregation and visible particle formation, deamidation, oxidation, and other degradation pathways, even in optimized aqueous formulations after formulation screening.

“Freezing or lyophilizing these formulations is the optimal choice, because physical and/or chemical reactions will be inhibited in the frozen glassy state or freeze-dried state with minimal water content,” Guo says. At Lonza, advanced analytical tools are used for diagnosing vulnerabilities potentially leading to instabilities, including mass spectrometry to detect and foresee post-translational modifications, holistic (i.e., stability-indicating) surfactant analytics, subvisible particle characterization to differentiate potential protein-versus-surfactant instability, in-depth root cause analysis in case of surfactant degradation, in-depth host-cell protein, especially lipase, characterization and quantification, and container-closure integrity testing and qualification.

Beyond instability, time can also be a driver for choosing to freeze or lyophilize a drug candidate. “When the development timeline is very limited for early filing of an investigation new drug (IND) application, the final formulation needs to be locked down without completion of comprehensive formulation screening or generation of sufficient stability data. Freezing or freeze-drying can help ensure long-term stability while still meeting these shorter timelines. Comprehensive screening can then be performed during late-stage development to determine the final, commercial formulation,” Guo observes.

There is one other significant reason for moving forward frozen or freeze-dried formulations during the development of biologics, according to Zuluaga Estrada. Many liquid biologic formulations have limited expected shelf-lives when stored at or below room temperature due to surfactant degradation, which is why Lonza conducts so many surfactant-related analyses. “For cases where extensive lipolytic activity is demonstrated, Lonza’s proprietary lipase assay can support the removal of lipolytic activity during downstream processing,” she notes. The company also has a proprietary approach to lipase inhibition that involves addition of low concentrations of citrate to mitigate surfactant degradation, which can potentially prevent the need for frozen or lyophilized storage, Zuluaga Estrada adds.

Advantages and disadvantages of frozen formulations

The primary advantage of frozen formulations is their ability to preserve unstable formulations due to the immobilization of molecular components, thereby extending the shelf life, observes Zuluaga Estrada. Development of frozen formulations also generally takes less time and is less expensive than the development of lyophilized products, according to Guo. The lack of the need for a reconstitution step, which is required for freeze-dried formulations, is another benefit noted by Guo.

There are several disadvantages to frozen formulations, however. “The complexity of developing frozen formulations is often not considered in full, and the related challenges present a substantial risk in the development of biologics,” Zuluaga Estrada contends. She highlights lack of molecule or excipient stability in certain frozen formulations (e.g., cold denaturation and aggregation of proteins, crystallization of excipients, phase separation) and compromised integrity of the container-closure system at ultralow temperatures as two examples.

Beyond stability issues, the key challenge with frozen products is the need for extensive infrastructure and shipping capabilities to support the cold chain, says Zuluaga Estrada. “Robust freezing parameters, appropriate storage conditions, and adequate supply chain management need to be considered,” she notes.

Temperature excursions during storage and shipment of frozen products, adds Guo, can lead to ice crystal formation, protein denaturation, and a potential decrease in drug efficacy. In addition, the need for temperature control during storage and shipment at manufacturing sites, depots, and clinical centers adds significant cost and inconvenience, he comments.

Other concerns pointed out by Guo include the higher risk of vial breakage and the need for lower filling volumes compared to liquid drug products in the same container to reduce this risk.

To avoid these issues, often redevelopment to a liquid or lyophilized formulation is pursued once a candidate reaches later development stages and looks to be commercialized. However, switching to a liquid or freeze-dried product during late-phase development requires significant additional effort and adds cost and time for programs, according to Zuluaga Estrada.

Lyophilized formulations present opportunities and challenges

Freeze drying also has both positive and negative attributes. In addition to overcoming formulation instability issues, one of the biggest benefits is the ability to store and ship products at refrigerated (2–8 °C) or even room temperatures, Guo says.

Appropriate storage of lyophilized cakes within these temperature conditions (i.e., below their glass-transition temperatures), significantly reduces the logistical and storage constraints compared to frozen products, agrees Zuluaga Estrada. “That translates to greater storage and transport efficiency, particularly for global products and patient-centric delivery,” Guo concludes.

Scientific, economic, and practical factors should be considered when choosing between the frozen state and lyophilization.