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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Leveraging AI and predictive modeling tools

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

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

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

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

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

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

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

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

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

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

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

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

Articles

Cover Story

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


Navigating the Complexities of Emerging Therapy Development

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

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

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

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

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

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

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

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

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

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

Nanoscale delivery optimal for the most challenging APIs

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

https://doi.org/10.3390/molecules29204854

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Li, M.; Azad, M.; Davé, R.; and Bilgili, E. 

8 (2) 17. DOI: 10.3390/pharmaceutics8020017

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Vega-Vasquez, P.; Mosier, N.S.; and Irudayaraj, 

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 16 (1) 28. DOI: 10.3390/pharmaceutics16010028

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

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

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

Development

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

Enhancing Solubility and Bioavailability with Nanotechnology

By definition, three-dimensional (3D) printing is an advanced additive manufacturing technology where a computer-designed 3D object is created by consecutive layer depositions. While 3D printing of medications has seen one commercialized mass-manufactured product, the real opportunity for the technology lies in its ability to manufacture drug products at small scales (1). Positive clinical outcomes of treating patients with 3D-printed medicines have already been demonstrated in children affected by rare disorders (2,3). The technology has now been implemented into point-of-care facilities as well as major pharmaceutical company laboratories, and even NASA aims to tackle future medical therapy in outer space through 3D printing (4). Research has also shown how pharmaceutical 3D printers can be adapted as platforms for automation of medicine compounding to reduce production time and enhance product quality, and implications for early-stage development and first-in human studies are actively being explored by the pharmaceutical industry (5).

Several 3D printing technologies exist, with ones that are currently more clinically applicable including semi-solid extrusion (SSE), fused deposition modeling (also known as fused filament fabrication), and direct powder extrusion, due to their use of FDA-approved, generally recognized as safe excipients. These are already available in good manufacturing practice (GMP) grades and, with the continuous advancements in design, functionalities, and software of pharmaceutical 3D printers, they enable partially automated manufacturing processes. The flexible nature of 3D printing allows for a variety of implementation strategies, where certain scenarios are already realistically attained under current and emerging drug manufacturing paradigms.

Automated compounding strategy in pharmacies

Pharmaceutical compounding constitutes a small proportion of all administered solid dosage drugs and, in some countries, may be considered a technique of former times. Being a highly manual process, conventional compounding is prone to human errors leading to either over- or underdosing of drugs, while being less efficient than mass manufacture processes (6). Nonetheless, there is still clinical demand by many patients and patient groups (i.e., children) for medications not available off-the-shelf, such as differentiated doses and allergen avoidances (7). Although compounded medicines generally do not have to undergo FDA approval and be manufactured under GMP conditions, processes with tighter product and process controls are desired to yield better and safer clinical outcomes. Therefore, adopting novel technologies providing tighter and/or automated process and product controls could reinforce pharmaceutical compounding for better therapy and potentially increase its extent. A study of hospital pharmacy professionals has previously highlighted their positive views on implementing SSE 3D printing for compounding of medicines not commercially available (8). Although pharmaceutical 3D printing is considered an advanced manufacturing technology, the use of 3D printers to automate compounding workflows would already be possible in many countries under their existing guidelines.

Early in 2025, the world’s first study implementing a pharmaceutical 3D printer for compounding and dispensing minoxidil medications directly in a retail pharmacy was published (9). Minoxidil is used to treat different types of hair loss and is most commonly available in topical formulations; however, prescription and compounding of low-dose oral solid minoxidil medicines is common. Working under applicable compounding guidelines, capsules were automatically filled in two dose strengths using the SSE 3D printing technology available in the M3DIMAKER 1 3D printer in the community pharmacy in Madrid. In parallel, a traditional compounding procedure was used to prepare the same strengths of minoxidil capsules; the two methods were compared in uniformity of batches and resource requirements (i.e., labor and production time).

Using both in-house, prepared pharma-ink (drug-loaded formulations for 3D printing) compositions and commercially available, premade ones, it was shown how a pharmacist’s working time could be reduced at lower cost. Consistent flow of pharma-ink through the nozzle and mass uniformity assessment for each of the capsules was completed automatically and in real time through the integrated analytical balance and pressure sensor and healthcare software, enabling process monitoring and exact identification of out-of-specifications dosage units according to applicable limits. While both conventional and 3D printer-compounded capsules fell within the applicable mass uniformity specifications, the partially automated process using the 3D printer reduced the overall time requirements for manufacturing. A significant 55% reduction in time required for pharmacist involvement was observed, leaving much less margin for human-induced errors while liberating valuable pharmacist time. In connection with the in-line, automated mass uniformity assurance, this may be a real game changer for compounding of medications in pharmacies.

Rapid manufacturing process on-site enabling clinical trials in hospitals

The capsule filling approach by SSE attachment in pharmaceutical 3D printer M3DIMAKER 2 has also been implemented in the hospital pharmacy of Europe’s leading cancer research hospital, Institut Gustave Roussy, located in Paris (10). Here, the aim was to develop a process for manufacturing a large number of targeted pharmaceutical interventions in a suitable timeframe for a clinical trial in 200 cancer patients. The team of pharmacists demonstrated a process capable of manufacturing 200 multi-drug capsules in 45 minutes via the semi-automated compounding platform, which included time for pharma-ink manufacture and offline quality control. The manufacturing time may be significantly reduced in the future if pharma-inks could be supplied directly to the hospital pharmacy from a licensed manufacturer and through the integration of in-line quality control systems. The pharmaceutical 3D printers are also now used routinely to produce ‘traditional,’ layer-by-layer 3D-printed medicines in the hospital pharmacy under existing compounding regulations, to treat cancer patients through more tailored medications (11).

3D printing of medications may fall under a distributed manufacturing scheme. Distributed manufacturing is often referred to as decentralized manufacturing outside the United States. Despite the difference in utilized terms, the two designations are paradigmatic and denote the same type of framework. In a distributed manufacturing strategy, one or more distributed 3D printing manufacturing sites (i.e., small manufacturing facilities) would be enabled by centralized pharmaceutical quality system (PQS) sites, similar to multiple spokes connected to a centralized hub in hub-and-spoke models (12) (

). Data transfer in real time between distributed manufacturing sites and PQS sites would enable close monitoring of data pertaining to drug product quality and the manufacturing process for dispensing of appropriate personalized medicines to patients. In a distributed manufacturing framework, pharma-inks may be externally produced with appropriate quality control measures at licensed manufacturing sites, akin to conventional pharmaceutical manufacture (13).

New legislation coming into effect in the summer of 2025 in the United Kingdom recognizes distributed manufacturing of medications through 3D printing. In the UK, the Medicines and Healthcare products Regulatory Agency has termed the process ‘modular manufacture’ with oversight of production activities at the self-contained modular manufacturing units by a centralized control site, similar to the previously described PQS site (14). Distributed manufacturing frameworks are still under development by FDA and the European Medicines Agency, but are expected to follow in the near future (15,16). Once finalized, these frameworks will officially mark the beginning of a new dimension for pharmaceutical manufacturing and personalized medications within their respective regulatory realms.

3D printing of drug products was once only seen as an alternative manufacturing technology for conventional large-scale manufacture. However, persistent efforts have more recently proven its applicability in producing small batches of tailored medicines. Clinicians and pharmacists alike have implemented 3D printing of personalized drug products under existing compounding regulations in both hospital and retail pharmacies, proving the approach’s benefits in terms of dosing accuracy and reduced manual labor. A new regulation coming into effect in summer 2025 in the UK will see 3D printing of drug products possible under a distributed manufacturing paradigm, and discussions for implementing similar frameworks in other independent legislative areas in other parts of the world are currently ongoing.

1. Seoane-Viaño, I.; Trenfield, S. J.; Basit, A. W.; and Goyanes, A. Translating 3D Printed Pharmaceuticals: From Hype to Real-World Clinical Applications. 

, 174, 553–575. DOI: 10.1016/j.addr.2021.05.003
2. Goyanes, A.; Madla, C. M.; Umerji, A.; et al. Automated Therapy Preparation of Isoleucine Formulations Using 3D Printing for the Treatment of MSUD: First Single-Centre, Prospective, Crossover Study in Patients. 

, 567, 118497. DOI: 10.1016/j.ijpharm.2019.118497
3. Rodríguez-Pombo, L.; de Castro-López, M. J.; Sánchez-Pintos, P.; et al. Paediatric Clinical Study of 3D Printed Personalised Medicines for Rare Metabolic Disorders. 

, 657, 124140. DOI: 10.1016/j.ijpharm.2024.124140
4. National Aeronautics and Space Administration. 3D Printing at University College of London (UCL) School of Pharmacy. 

 (accessed March 10, 2025).
5. Tracy, T.; Wu, L.; Liu, X.; et al. 3D Printing: Innovative Solutions for Patients and Pharmaceutical Industry. 

, 631, 122480. DOI: 10.1016/j.ijpharm.2022.122480
6. Gudeman, J.; Jozwiakowski, M.; Chollet, J.; and Randell, M. Potential Risks of Pharmacy Compounding. 

, 13, 1–8. DOI: 10.1007/s40268-0130005-9
7. Carvalho, M. and Almeida, I. F. The Role of Pharmaceutical Compounding in Promoting Medication Adherence. 

, 15 (9) 1091. DOI: 10.3390/ph15091091
8. Levine, V. R.; Paulsson, M.; Strømme, M.; et al. Off-the-Shelf Medication Transformed: Custom-Dosed Metoprolol Tartrate Tablets via Semisolid Extrusion Additive Manufacturing and the Perception of This Technique in a Hospital Context. 

, 8, 100277. DOI: 10.1016/j.ijpx.2024.100277
9. Rodríguez-Maciñeiras, X.; Bendicho-Lavilla, C.; Rial, C.; et al. Advancing Medication Compounding: Use of a Pharmaceutical 3D Printer to Auto-Fill Minoxidil Capsules for Dispensing to Patients in a Community Pharmacy. 

, 671, 125251. DOI: 10.1016/j.ijpharm.2025.125251
10. Denis, L.; Jørgensen, A. K.; Do, B.; et al. Developing an Innovative 3D Printing Platform for Production of Personalised Medicines in a Hospital for the OPERA Clinical Trial. 

, 661, 124306. DOI: 10.1016/j.ijpharm.2024.124306
11. Gustave Roussy. Améliorer les Traitements Pédiatriques Grâce à l’impression 3D. Press Release. Feb. 11, 2025.
12. CDER. 

Distributed Manufacturing of Drugs: Stakeholder Feedback and Action Plan

; FDA, November 2023.
13. Seoane-Viaño, I.; Xu, X.; Ong, J. J.; et al. A Case Study on Decentralized Manufacturing of 3D Printed Medicines. 

, 5, 100184. DOI: 10.1016/j.ijpx.2023.100184
14. UK Statutory Instruments (UKSI). 

The Human Medicines (Amendment) (Modular Manufacture and Point of Care) Regulations 2025

; 2025 No. 87; UKSI; January 2025.
15. FDA, 

Draft Guidance for Industry, Considerations for Complying with 21 CFR 211.110

 (CDER/CBER/CVM, January 2025).
16. EMA. Fourth Listen-and-Learn Focus Group Meeting of the Quality Innovation Group. Online presentation from EMA, Amsterdam, The Netherlands, Nov. 19–20, 2024.

 is a PhD student in the Department of Pharmaceutics, UCL School of Pharmacy, University College London. 

 is a professor in the Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, honorary lecturer in the Department of Pharmaceutics, UCL School of Pharmacy, University College London, and co-founder of FABRX Ltd and FABRX Artificial Intelligence. 

 is a professor in the Department of Pharmaceutics, UCL School of Pharmacy, University College London and co-founder of FABRX Ltd.

®
Vol. 49, No. 3
April 2025
Pages: 24–27

When referring to this article, please cite it as Jørgensen, A. K.; Goyanes, A.; and Basit, A. W. Entering New Domains for 3D Printing of Drug Products. 

Manufacturing

3D printing of personalized medications is currently possible under existing compounding regulations, offering enhanced process control through automation. But new legislation coming in 2025 will allow 3D printing as part of a distributed manufacturing framework.

Entering New Domains for 3D Printing of Drug Products

Lyophilization is a sophisticated preservation technique designed to stabilize sensitive pharmaceutical compounds by removing water through a meticulously controlled process of freezing and sublimation under vacuum conditions. This method is indispensable for the stability and long-term efficacy of medications that otherwise would have excessively stringent requirements for temperature and humidity control. Despite its advantages, the lyophilization process introduces a complex interplay between the drug product and its packaging materials. Exploring the challenges inherent in testing and mitigating extractables and leachables (E&L) risks require innovative solutions grounded in regulatory guidance as well as advancements in analytical methods, primary packaging, and systemic collaborations.

Key benefits and associated challenges of lyophilization

Lyophilization involves transforming liquid formulations into stable, lightweight, and portable solid forms known as lyo cakes. The process consists of three primary stages: freezing, primary drying (sublimation), and secondary drying (desorption). This transformative process not only ensures the preservation of the drug’s chemical and physical integrity but also allows simpler storage and transportation such at room temperature. However, the absence of water and the unique characteristics of the resulting solid-state product amplify certain E&L contamination risks due to interaction with packaging materials.

Primary packaging materials, including glass vials and rubber stoppers, are integral to maintaining the stability of lyophilized drug products. However, these materials can release volatile and semi-volatile compounds through mechanisms such as outgassing, which accumulate on the highly absorbent surfaces of the lyo cake. Secondary packaging systems, such as multilayer films and aluminum pouches, though designed to shield against external contaminants, may also contribute to E&L risks under varying environmental conditions such as temperature and humidity fluctuations. These interactions necessitate rigorous testing and validation protocols to mitigate potential contamination and ensure the drug product’s long-term stability.

Extractables are chemical entities that can be released from packaging materials under controlled but often extreme conditions, such as exposure to solvents, elevated temperatures, or pressure. Leachables are substances that migrate into the drug product under standard storage or usage conditions, potentially compromising its safety, efficacy, and stability.

In lyophilized drug products, E&L interactions predominantly occur through outgassing, where volatile and semi-volatile organic compounds from packaging materials, particularly rubber stoppers, migrate into the vial’s headspace and adsorb onto the dry lyo cake. The high surface area and extreme dryness of the lyo cake exacerbate this absorption. Additionally, reactive leachables may interact with APIs or excipients, creating byproducts that can compromise drug quality and pose safety risks to patients.

) <1664> categorize product interaction risk (1) or specifically leachables risk (2) based on the dosage form and administration route. For lyophilized drugs (powders for injection/reconstitution), while the leachables risk of direct interaction during solid-state storage is considered low, the reconstitution phase significantly elevates these risks. Furthermore, worst-case scenario testing can be utilized to ensure leachables remain within acceptable safety limits under real-world conditions.

The European Medicines Agency (EMA)’s guidelines includes a decision-tree approach for assessing packaging interactions (3). For drugs intended for parenteral administration, the International Council for Harmonisation (ICH) also recommends long-term stability studies and accelerated testing to identify cumulative leachables over the product’s lifecycle (4). Real-world simulations, including variations in temperature and humidity, are emphasized to ensure comprehensive compliance.

Challenges in E&L testing for lyophilized products

The following are some challenges in E&L testing for lyophilized products.

 Rubber stoppers release volatile and semi-volatile organic compounds, which continuously accumulate on the lyo cake during storage. This progressive outgassing, coupled with the lack of equilibrium in the vial’s headspace, leads to increasing contamination levels over time.

 Reconstitution introduces additional complexities as volatile and semi-volatile compounds solubilize in the diluent. This step also allows short-term interactions between the liquid drug product and the primary packaging, potentially introducing new contaminants, including metals and ions. Such multifaceted interactions demand extensive testing to ensure product safety.

Analytical complexities and the absence of true blank solutions.

 A major limitation in E&L testing for lyophilized products is the challenge of establishing a true blank solution. Because the lyophilization process inherently involves packaging contact, alternative approaches, such as time-point zero baselines, must be employed. However, these methods are imperfect and introduce uncertainties in distinguishing between inherent impurities and leachables. Advanced analytical techniques, including high-sensitivity liquid chromatography–mass spectrometry (LC–MS) and gas chromatography–MS (GC–MS), are indispensable but require significant expertise and resources to implement effectively.

The choice of packaging materials plays a pivotal role in minimizing E&L risks. Utilizing low-alkali glass and high-quality, low-residual rubber stoppers can significantly reduce contamination. Proactive collaboration with suppliers during material selection and validation helps demonstrate compatibility with the lyophilized drug product.

E&L studies must encompass both extractables and leachables testing under simulated real-world and worst-case scenarios. This includes rigorous assessments during storage, reconstitution, and administration. Predictive modeling tools and accelerated testing techniques can enhance study efficiency and provide robust data.

Innovative packaging designs, such as non-contact systems and reduced headspace configurations, minimize the accumulation of leachables. Coated or laminated materials further reduce the migration of harmful compounds, ensuring better product safety.

Developing standardized methodologies across the pharmaceutical industry ensures consistency, improves compliance, and facilitates data sharing. Such protocols should address the entire lifecycle of lyophilized products, from manufacturing to patient administration.

Post-market surveillance programs and ongoing reviews of packaging materials and processes are essential for adapting to emerging risks and regulatory changes. Pharmaceutical companies can leverage feedback from real-world usage to help collaborate with container manufacturers and analytical laboratories to identify and address vulnerabilities proactively.

The unique characteristics of lyophilized drug products amplify the unique E&L risks associated with them. These various challenges arise from complex interactions between the drug product and its packaging during storage, reconstitution, and administration. Addressing these risks requires a multidisciplinary approach that involves, among other factors, advanced material science, rigorous testing methodologies, and compliance with global regulatory standards. By adopting innovative packaging technologies, implementing comprehensive E&L studies, and fostering continuous improvement, the pharmaceutical industry will be able to ensure the safety, efficacy, and quality of lyophilized medications. As advancements in both the areas of analytical tools and packaging materials continue to be made, continuous investment in E&L practices will further enhance the reliability of life-saving therapeutics, safeguard patient health and maintain global trust in pharmaceutical innovations.

Guidance for Industry, Container Closure Systems for Packaging Human Drugs and Biologics

 General Chapter <1664>, Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems, 

, 1850 (Rockville, MD, 2016).
3. EMA. CPMP/QWP/4359/03, 

Plastic Primary Packaging Materials—Scientific Guideline

Pharmaceutical Development—Scientific Guideline

 is product manager, analytical services at Stevanato Group, and 

 is scientific director at Nelson Labs Europe.

®
Vol. 49, No. 3
April 2025
Pages: 28–30

When referring to this article, please cite it as Xu, A. and Christiaens, P. Extractable and Leachable Challenges in Lyophilized Drug Products. 

Analytics

The authors examine the risks of extractables and leachables, and present solutions that emphasize the importance of a strategic, multi-prong approach.

Extractable and Leachable Challenges in Lyophilized Drug Products

The bio/pharmaceutical industry is, understandably, strictly regulated and, as such, companies seeking commercialization of a therapeutic product must ensure they meet the relevant requirements at all stages of development through to dossier submission and beyond. Unfortunately, the breadth of knowledge and level of expertise required to ensure full regulatory compliance, the requirements for which can differ depending upon geographic location, is not always found within a company’s internal team.

However, when seeking out support for quality-related matters and regulatory affairs, sponsor companies need to understand how to qualify external employees or consultants correctly to avoid potential pitfalls and issues with the regulatory authorities later down the line.

Applying modern technologies in development

Artificial intelligence (AI) is being increasingly used across many aspects of everyday life. Within the bio/pharmaceutical industry, AI is also being employed for various tasks, including formulation of novel drug products. However, with novel technologies comes uncertainty and usually a lack of expertise.

“Of course, using modern methodologies, technologies, is not only making sense from a commercial perspective, but the regulators are also really encouraging [their use],” remarked Siegfried Schmitt, vice president, Technical at Parexel, during episode two of Pharmaceutical Technology®’s Ask the Expert video series (1). “Now, when you apply something that new, then it’s very likely that you may need external support by experts, external experts, and when you use a third party to help you, especially with GMP [good manufacturing practice], GxP [good practice]-related activities like development, then you need to apply some vendor assessment process.”

Yet, with such a new technology, Susan J. Schniepp, distinguished fellow and quality assurance expert at Regulatory Compliance Associates, a Nelson Labs company, questioned how it is even possible to qualify the external experts that will be required. “I think, when putting in an AI system or looking at it, the one thing I would highly recommend companies do is quality management risk assessment,” she noted. “[Companies] cannot put in a system without doing that very comprehensive risk assessment.”

Requirements for submitting regulatory applications

When specifically looking at the requirements for a new drug (NDA) or biologics license applications (BLA), Schniepp explained, during episode three of the Ask the Expert video series (2), there is basic information that is required, which can be easily researched on FDA’s website.

FDA provides guidance on the information that they require to ensure successful submission of an NDA (3) or BLA (4), including notes on critical information that, if it isn’t included, will mean rejection of the application as an incomplete file, Schniepp added. “But the best way to make sure that you’re giving [FDA] what they need is to really talk with them,” she said.

Communication with the agency is particularly imperative when dealing with novel biologic therapeutics, Schniepp advised. “When we talk about ATMPs [advanced therapeutic medicinal products] that are probably going to go in a BLA, [there will be] a lot of complications, and [companies] need to be working with the agency up front to make sure [they] are handling those filing issues,” she noted.

“It’s not just with FDA,” continued Schmitt in the same Ask the Expert video series episode (2). “All the agencies I know of have provided the opportunity to applicants for pre-approval meetings, pre-submission meetings, and you should take note of this and make good use of it.”

Within the biologics space too, Schmitt explained that many companies are smaller in size. “Of course, these [companies] are the ones who need the most support, and when you look at the agencies, they have special support programs for such companies,” he said. “Now, of course, [the company] can ask the agency [and they] hopefully have some in-house expertise, but again, it is sensible to understand, where are the gaps? Where would [the company] perhaps need external support?”

Understanding the need for the right people

For smaller companies, the expertise is not always available in-house, leading to some companies outsourcing quality functions, Schniepp specified. “But the relationship of how [a company] qualifies contract employees or consultants is very critical,” she asserted.

As quality consultants themselves, Schniepp and Schmitt emphasized that they need their clients, the sponsor company seeking expert assistance, to understand all the relevant background information and not simply choose a quality consultant based solely on the cheapest price option. “[Companies] need to look into the consulting firms they’re going to use and make sure they have the right expertise to support the [regulatory] filing,” Schniepp explained.

“[Companies] have to understand when outsourcing critical functions that [it is imperative] to have the right people,” Schniepp continued. Ultimately, when the filing has been completed, the consultant’s work is done and they are no longer needed, which means the sponsor company must understand the work that has been done to complete the filing as they are then responsible in the eyes of the regulator, she stressed.

If a company hires a quality consultant who doesn’t have the expertise needed for the task, but they were the cheapest for example, then there will more than likely be regulatory problems later down the road, Schniepp warned.

“[Companies] need to have a quality system that makes sure that whatever external support [they’re] calling for [they] select those who are most suitable for [their] needs and can provide quality expertise,” confirmed Schmitt.

Thomas, F.; Haigney, S. Quality Considerations for Using AI in Bio/Pharma. 

Thomas, F.; Haigney, S. Submitting Regulatory Applications Connects to Quality. 

www.fda.gov/drugs/types-applications/new-drug-application-nda

FDA. Biologics License Applications (BLA) Process (CBER). 

www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/biologics-license-applications-bla-process-cber

Felicity Thomas is former associate editorial director of 

Bringing in external expertise may be necessary when internal knowledge is lacking, but it is critical that any contract employee or consultant is comprehensively assessed to ensure the right person is employed.

Pharmaceutical Technology April 2025

Navigating the Complexities of Emerging Therapy Development

Enhancing Solubility and Bioavailability with Nanotechnology

Entering New Domains for 3D Printing of Drug Products

Extractable and Leachable Challenges in Lyophilized Drug Products

Qualifying Expertise for Quality Support

Engineered T Cell Receptor-T Cell Therapies

Drug Shortages and Complying with FDA’s 21 CFR 211.110 Guidance

Critical Medicines Act Plans to Improve Supply Chain

Facing the Latest Patent Cliff