Aligning mRNA Progress with Regulatory Streamlining

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Dosage Forms: Roundtable on Oral Solid Dosage Trends

Drug Solutions Podcast: 

Pharmaceutical packaging must advance to adapt to new, complex modalities

Out-of-the-Box Packaging Advancements

From Theory to Reality: Automating Process Development

Drug Digest: 

The Importance of Appropriate Supplier Oversight

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Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

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FDA’s Center for Drug Evaluation and Research (CDER) Division of Drug Information said on March 10, 2025 that FDA has approved the first generics of rivaroxaban, in tablet form, to reduce risk of major cardiovascular events in adult patients with coronary artery disease, as well as major thrombotic vascular events in adults with peripheral artery disease (PAD), including those who recently underwent a lower extremity revascularization procedure due to symptomatic PAD (1).

Rivaroxaban is more commonly known by its brand name, Xarelto, manufactured by Johnson & Johnson Innovative Medicine, formerly Janssen Pharmaceuticals. It is an anticoagulant, the likes of which are among the most commonly prescribed medications in the United States, according to CDER (1).

 aims to address, among other objectives, both the challenges of developing generics and promoting more generic competition (1). The agency further said that first generics are a public health priority, and that it prioritizes reviews of applications for such products. In rivaroxaban’s case, CDER said the risk of major cardiovascular events—such as heart attack or stroke related to blood clots forming in the body, and traveling to the brain—is a serious concern, and that approval of the first generics for the drug will provide more treatment options to Americans reliant on anticoagulants.

Rivaroxaban has long been an option on the market to reduce risk of cardiovascular events such as stroke and blood clots. 

 Janssen recalled 13,500 bottles of Xarelto following a customer complaint of a microbial contaminant in a sales sample (2). The affected lots were traced to a facility in Gurabo, Puerto Rico, according to FDA at the time.

A generic form of rivaroxaban, Rivaroxaban Accord, was 

 by the European Medicines Agency (EMA) in September 2020, for treatment and prevention of venous thromboembolism, pulmonary embolism, and the prevention of atherothrombotic events (3).

In August 2023, the drug as manufactured by Janssen was 

 announced by the Centers for Medicare & Medicaid Services (CMS) whose prices would be directly negotiated with drug companies at the end of that month (4). Negotiations were to have occurred through the end of 2024, with negotiated prices coming effective at the beginning of 2026, according to CMS at the time. The other drugs listed were Eliquis (apixaban), Jardiance (empagliflozin), Januvia (sitagliptin), Farxiga (dapagliflozin), Entresto (sacubitril/valsartan), Enbrel (etanercept), Imbruvica (ibrutinib), Stelara (ustekinumab), and Fiasp and Novolog (insulin aspart) as well as various derivatives.

A Medication Guide will be dispensed along with generic rivaroxaban, according to CDER, which will list instructions on use and safety information (1). The drug already includes a boxed warning to healthcare providers about increased risk of thrombotic events. Additionally, CDER said, epidural or spinal hematomas may occur in those patients treated with rivaroxaban who are also receiving neuraxial anesthesia or undergoing a spinal puncture. In these cases, the agency said, the hematomas could result in long-term or permanent paralysis.

1. CDER Division of Drug Information. FDA Approves First Generics of Xarelto (rivaroxaban). Press Release. March 10, 2025.
2. Hernandez, R. 

Janssen Pulls 13,500 Bottles of Xarelto, Cites Contamination.

, Oct. 24, 2014.
3. EMA. Meeting Highlights from the Committee for Medicinal Products for Human Use (CHMP) 14–17 September 2020. Press Release. Sept. 18, 2020.
4. Playter, G. 

White House Sets Medicare Price Negotiation Targets.

Articles

Rivaroxaban, long known under the brand name Xarelto, is an anticoagulant, a classification that is among the most-prescribed medications in the United States.

FDA Approves First Generics of Rivaroxaban Tablets

Felicity Thomas is the former Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

In an interview with Pharmaceutical Technology®, Miguel Forte from ISCT and Kiji Therapeutics talks about the potential impact of a changing European political landscape. 

Industry Outlook 2025: Fostering the Development of Biotech in Europe

During 2024, many European countries held political elections, resulting in shifts in leadership. “First of all, the commission, the member states, and some of the programs have highlighted the commitment to biotechnology,” says Miguel Forte, president of International Society for Cell & Gene Therapy (ISCT), board member of Alliance for Regenerative Medicine, and CEO of Kiji Therapeutics when commenting on how the political shifts may impact the bio/pharma industry. “Obviously, the evolving political landscape gets people worried about it, focused on that, and potentially leading to less attention to other aspects.”

Another potential outcome of a change in leadership for a member state may be their approach to deploying funding and support. “If we look at some more conservative approaches, they may be conducive to certain business perspectives but may be less conducive to certain other practices that would be important in terms of fostering the development of biotech in general, and cell and gene therapy in particular,” Forte explains.

Europe needs to be more competitive on the global platform within the field of biotech, Forte specifies, which has been recognized by relevant authorities across the region. “Take, for instance, [Europe’s stance] on cell and gene therapy, making it less of an exception and more of the mainstream, which I think is a recognition that [these therapies should be] part of our day to day,” he says.

However, it takes time for such changes to be fully realized and implemented, as various checks and balances need to be considered, Forte continues. “The key elements that to be to be considered [are] an investment in biotech and a recognition that we all need to work together to improve the competitiveness of Europe for the sake of the overall business, for the sake of the overall patient, and clearly, for the sake of us in Europe,” he summarizes.

Miguel Forte, president of International Society for Cell & Gene Therapy, board member of Alliance for Regenerative Medicine, and CEO of Kiji Therapeutics

Miguel Forte is president of International Society for Cell & Gene Therapy, board member of Alliance for Regenerative Medicine, and CEO of Kiji Therapeutics—a company developing engineered cell therapies for inflammatory diseases. Miguel holds an MD and a Specialist in Infectious Diseases from the Faculty of Medicine, University of Lisbon, a PhD in Immunology from the University of Birmingham, and a certificate on Health Technology Economics from the Stockholm School of Economics. Additionally, he is Fellow of the Faculty of Pharmaceutical Medicine of the RCP in the UK.

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Almac Pharma Services, a part of Almac Group, officially opened a new, state-of-the-art, £65 million (US$84.2 million) commercial manufacturing facility in Craigavon, United Kingdom, on March 11, 2025 (1). The Northern Ireland site is also home to Almac’s global headquarters.

Construction of the facility was completed in late 2024, and, according to Almac, manufacture of good manufacturing practice batches will commence by March 18, 2025 pending successful completion of validation activities at the regulatory approved Center of Excellence (1).

Measuring 100,000 square feet, the facility enhances current capabilities, the company reported, in commercial oral dose treatment manufacturing in a variety of therapeutic areas, with high-specification production suites, an extension to current production scales of potent and highly potent drug products, and opportunities for partner companies to install custom technology or that which is dedicated to be tailored to those companies’ needs (1)

"We are thrilled to officially open our new commercial manufacturing facility at our global headquarters site," John McQuaid, president and managing director of Almac Pharma Services, said in a company press release (1). "This investment underscores our commitment to supporting our clients' growing needs with the highest level of service and expertise ... The new facility not only expands our range of capabilities but also reinforces our position as an industry leader in pharmaceutical development and commercial manufacturing with an ability to tailor our services to suit individual products. It also demonstrates our commitment to working in true partnership with our clients as we support them in bringing important new therapies to the patients we serve."

 about the challenges in providing services that face contract development and manufacturing organizations amid a growing pharmaceutical industry, higher demand for analytical services, and trends for future investment (2).

According to McQuaid, at that time, Almac’s plans for expansion were well on their way to taking shape.

“We're investing in cold chain capabilities, both for the clinical phases and the commercial phases, and then we have peptide synthesis coming online early next year [in 2025] at our API plant in Craigavon, with small molecule expansion kicking in later next year, and then further program for larger-scale API manufacturing,” he said in the CPHI Milan interview (2).

In January 2025, Almac announced a £500,000 (US$611,500 approximate) investment in state-of-the-art instrumentation for its spectroscopy laboratories at the Craigavon headquarters, namely a quadrupole-time-of-flight mass spectrometer (6545XT AdvanceBio Q-TOF, Agilent) and a diffractometer (Empyrean X-Ray Powder Diffractometer, Malvern Panalytical) (3).

That instrumentation investment came in addition to a previously announced £11 million (US$14.7 million) spend, made public in October 2024, intended to expand the company’s global analytical services capabilities and create 100 jobs, all of which followed an initial £250 million (US$324 million) commitment in capital investment, along with an intended workforce growth of 1800, made in 2022; that investment, according to Almac, has since increased to more than £400 million (US$518.5 million) (1,4).

View John McQuaid’s full interview with 

1. Almac Group. Almac Pharma Services Opens Doors on £65m New Commercial Manufacturing Facility. Press Release. March 11, 2025.
2. Thomas, F. CPHI Milan 2024: 

, Oct. 11, 2024.
3. Almac Sciences. Almac Invests £500,000 in State-of-the-Art Instrumentation Within Spectroscopy Laboratories. Press Release. Jan. 16, 2025.
4. Almac Group. Almac Group Announces £11m Investment to Expand Global Analytical Services. Press Release. Oct. 1, 2024.

The company’s 100,000-sq.-ft. space is expected to enhance its capabilities for commercial oral dose treatment manufacturing in a variety of therapeutic areas.

New Almac Pharma Services Commercial Manufacturing Facility Opens in Northern Ireland

Stäubli Robotics, a division of the global manufacturer Stäubli, is announcing one piece of its exhibit for INTERPHEX 2025, which will be held at the Javits Center in New York City from April 1–3, 2025. Sterimove, which the company describes as the first mobile robot designed for cleanrooms in the world, is scheduled to make its North American debut at the annual event (1).

According to Stäubli, whose North American headquarters are in Duncan, SC, Sterimove is engineered for Grade A/B/C/D cleanroom environments and meets highest industry standards for minimal contamination risk (1). The company said the robot offers numerous other advantages that improve compliance and ensure the safety of product and worker alike, including safety features such as sensors, collision avoidance systems, emergency stop buttons, and an LED status communication strip—plus easy access to wheels and resistance to vaporized hydrogen peroxide decontamination, to facilitate cleaning.

The robot, according to Stäubli, has a modular design, small footprint, and maneuverability in narrow spaces. It has an encapsulated design that is free of retention areas, which, according to the company, means that all sensors and other critical components are housed within the body of the robot; this prevents the ingress of contaminants and allows for resistance to rigorous cleaning and chemical disinfection (1). Taken together, the design features are intended to bring efficiency and productivity gains other sectors have experienced with mobile robotics into the pharmaceutical industry and enable manufacturers to optimize material flows.

“Sterimove exemplifies our commitment to innovation and excellence in automation technology for the pharmaceutical industry,” Rudolf M. Weiss, global head of Life Sciences & Food at Stäubli Robotics, said in the press release (1). “We are excited to showcase this groundbreaking technology at INTERPHEX 2025.”

®, Irina Rau, regional sales manager for Stäubli Robotics, explained that one driver for new technologies in robotics development is better compliance with European Union Good Manufacturing Practice Annex 1 (Manufacture of Sterile Medicinal Products) (2). This aligns with Stäubli’s disclosure that the Sterimove robot was designed following European Hygienic Engineering & Design Group guidelines as well as FDA compliance in mind, with the help of a Stäubli customer and “major player in the pharmaceutical industry,” according to the company (1).

Regarding specific technical elements, Rau also said new technologies also, among other advantages, can allow an operator outside an isolator to use a robotic arm to perform interventions inside the isolator without breaking the barrier. These technologies can provide an opportunity to avoid opening the isolator, thereby losing a batch of product (2). An inherent challenge is to design a robot’s movements to ensure ease of use for all operators—while keeping in mind flexibility, sensitivity, and safety of the process for both operators and the equipment itself.

In addition to its South Carolina headquarters, Stäubli North America has facilities in Novi, Michigan; Queretaro, Mexico; and sales personnel located on both the east and west coasts of the United States, serving the US (including Puerto Rico) and Canada (1).

Stäubli Robotics exhibited at INTERPHEX 2024 and will be at the event again in 2025, at Booth 3443 (1). You can find more of 

1. Stäubli. Stäubli Robotics to Unveil the World’s First Mobile Pharma Robot at INTERPHEX 2025. Press Release. Feb. 21, 2025.
2. Markarian, J. 

Sterimove will make its North American debut at the April 1–3, 2025 event.

Stäubli Robotics Previews World’s First Cleanroom Mobile Robot for INTERPHEX Display

Miguel Forte from ISCT and Kiji Therapeutics provides his insights into the changing political landscape in the US as well as legislative and regulatory adjustments, in an interview with Pharmaceutical Technology®.

Industry Outlook 2025: US Political Motivations and Legislative Discussions

According to Miguel Forte, president of International Society for Cell & Gene Therapy (ISCT), board member of Alliance for Regenerative Medicine, and CEO of Kiji Therapeutics, there are two aspects to consider when assessing the potential impact on industry of the new administration in the United States. “One is a conservative attitude to business, which I think might have some potential positive impact. That's good [because it] will support the economy and give a certain confidence to investment,” he says.

Additionally, Forte specifies that the leadership must impact business positively while also managing to make careful decisions around technological aspects of the industry, allowing organizations, such as FDA, the ability to perform their jobs. “I would also want to see that public health and product considerations are done the right way,” he adds.

A legislative change in the US that will more than likely have an impact on the bio/pharma industry is the introduction of the BIOSECURE Act, which was passed in September 2024. “I can understand some political motivations on how to manage the flow of the data [in relation to the BIOSECURE Act],” Forte says. “Some companies may get impacted, not only the ones that are directly targeted by the BIOSECURE Act, but also the ones that had deals and partnerships and collaborations with those companies, they will have to readjust their businesses again.”

Looking at industry regulations in more detail, Forte specifies that FDA has been keen on engaging in discussions about cell and gene therapy and becoming more comfortable with these novel modalities. “I believe that regulators [are] in a much better position today to make the right decisions and support the field in terms of the development [of cell and gene therapies], and that will translate in legislation, for sure, as well,” he adds. “I think, from a new technology point of view, we saw some good decisions in terms of reimbursement into the US recently, which I think is a good signal to the field.”

The Noramco Group, a Wilmington, Del.-based provider of products and services to the API and drug product supply chains, has announced a $25 million investment in the Whippany, NJ, facility of one of its subsidiaries, Halo Pharma (1). The purpose of the investment, The Noramco Group announced on March 10, 2025, is to establish sterile injectable manufacturing capabilities—namely ready-to-use syringe, cartridge, and vial filling—to address capacity shortages in the injectable supply chain in the United States that the company said are “critical.”

“This investment is a significant step in our commitment to build on our position as one of the only fully integrated domestic supply options for our customers,” said Lee Karras, CEO of The Noramco Group, in the company’s press release (1). “We recognize the challenges facing the industry and are dedicated to providing solutions that address both immediate and long-term supply chain needs. We anticipate the new line to be qualified and operational within the next 12 months, ensuring we can support customers with the high-quality capacity they require. While this investment enhances our capabilities with contemporary technologies, with the addition of sterile manufacturing we remain committed to our already established and proven focus on manufacturing APIs, oral solid dose, and liquid dosage forms, which continue to be essential in meeting our customers’ needs.”

Halo Pharma, a contract development and manufacturing organization, has focused on oral solid dose, semi-solid, and liquid formulation manufacturing for the past 20 years, but the Whippany facility will now undergo “significant renovations,” The Noramco Group said in the release, to maintain those primary production capabilities while adding a new sterile filling line (1). That installation will be done over the balance of 2025, upgrading the facility to meet European Union Annex 1 compliance for European market access, as well as maintaining US quality standards.

 examined the state of supply chains across the bio/pharmaceutical industry and how contract manufacturers are responding, 

 in the same vein as The Noramco Group’s March 10 release (2).

The announcement of the $25 million investment was made just days prior to the one-year anniversary of the launch of The Noramco Group, 

which Noramco announced on March 14, 2024

 as the umbrella term for its namesake API manufacturing business plus fellow subsidiaries Purisys, located in Athens, Ga., and Halo Pharma, which has operations not only in New Jersey but also Montreal (3). At that time, Noramco had only recently (in November 2023) acquired Halo Pharmaceuticals, which was actually the former name of Cambrex Drug Product Business Unit as of when the transaction was made (4).

The March 2025 news also comes one week before the start of the 2025 Drug, Chemical & Associated Technologies Association (DCAT) Week, to be held from March 17–20 in New York City (5). The Noramco Group said its executives will be on site to provide more information about the new sterile injectable manufacturing capabilities at the Halo Pharma site, and DCAT Member Companies are invited to interface with them during the event at the Intercontinental New York Barclay Hotel, suites 1007, 1141, and 1223.

 will be covering DCAT Week 2025 in depth, prior to, during, and after the event, and the landing page for all relevant content can be accessed 

1. The Noramco Group. The Noramco Group Invests $25 Million in Halo Pharma’s Whippany Facility to Offer Sterile Injectable Manufacturing. Press Release. March 10, 2025.
2. Lavery, P. 

Adopting Flexible Strategies to Combat Capacity Shortages.

, 49 (2).
2. Noramco. Noramco Announces Strategic Alignment with Purisys and Halo Pharma, Launching the Noramco Group as an Integrated North American-Based API and Drug Product Supply Chain Services Provider. Press Release. March 14, 2024.
3. Noramco. Noramco Announces the Acquisition of the Cambrex Drug Product Business Unit. Press Release. Nov. 2, 2023.
4. The Noramco Group. Noramco Group Announces $25 Million Sterile Injectable Manufacturing Investment at DCAT Week 2025. 

The investment is intended for the Halo Pharma facility in Whippany, NJ, and aims to help relieve capacity shortages in the injectable supply chain in the United States.

Noramco Group Establishes Sterile Injectable Manufacturing Capabilities with $25 Million Investment

Pramote Cholayudth previously was the managing director of the Professional Conference Center, Ltd. He currently is a validation consultant to Biolab Co., Ltd., in Thailand. He is the founder and manager of PM consult, cpramote2000@yahoo.com.

research, doctor, microscope, experiment, dx, digital transformation, data, analysis, science, researcher, graph, chart, pharmaceutical, pharmacy, medicine, information, development, research institute | Image Credit: ©metamorworks - stock.adobe.com

The requirements for uniformity of dosage units using large sample size data collected and analyzed from process analytical technology (PAT) processes can be met by applying either 

) <1099> Limit on Number of Large Deviations When Assessing Content Uniformity in Large Samples or 

.) 2.9.47 Uniformity of Dosage Units Using Large Sample Sizes. However, both methods are designed to detect the number of dosage units falling outside the specification range of 75–125% of the label claim (% LC) to determine whether these numbers do not exceed the predetermined values based on the sample size.The ‘full tolerance coverage method’ is introduced as a coverage estimation approach for assessing the uniformity of dosage units from large sample sizes, ensuring that no dosage unit exceeds the specification range.

) <905> Uniformity of Dosage Units (UDU; using small sample sizes) (1), the acceptance value (AV) limits are statistically adjusted (95% coverage) (2) and reintroduced in (3; Figure 1). However, a key weakness is that the AV result does not adequately describe the specific characteristics of UDU. To address this limitation, the application and use of tolerance intervals are extensively discussed in the article,“Using Tolerance Intervals to Assess Conformance to Requirements” (4).

To address the small gaps between the calculated tolerance intervals and specification ranges, the upper and lower tolerance limits (UTL and LTL) are set at 115% and 85% label claim (LC), respectively. The tolerance coverages above and below the mean are estimated and summed to obtain what is called “full tolerance coverage” (FTC), yielding a value close to 100%. Because the sample mean is directly used, larger sample sizes provide a more accurate batch mean estimate. Therefore, the FTC method is more practical and suitable for assessing UDU data in production batches, particularly those monitored through process analytical technology (PAT) instrumentation.

Pramote Cholayudth, cpramote2000@yahoo.com, is the founder and manager of PM Consult. He is an industrial pharmacist with more than 40 years of experience. He is a guest speaker on process validation to industrial pharmaceutical scientists organized by Thailand’s FDA.

®
Vol. 49, No. 2
March 2025
Pages: 18-23

When referring to this article, please cite it as Cholayudth, P. Full Tolerance Coverage Method for Assessing Uniformity of Dosage Units with Large Sample Sizes. 

The ‘full tolerance coverage method’ is introduced as a coverage estimation approach for assessing the uniformity of dosage units from large sample sizes, ensuring that no dosage unit exceeds the specification range.

Full Tolerance Coverage Method for Assessing Uniformity of Dosage Units with Large Sample Sizes

Pharmaceutical Technology® chats with Miguel Forte from ISCT and Kiji Therapeutics about expectations for 2025 and the future technology agenda for industry.

Industry Outlook 2025: Setting the Tone for Industry

One thing that Miguel Forte, president of International Society for Cell & Gene Therapy (ISCT), board member of Alliance for Regenerative Medicine, and CEO of Kiji Therapeutics, wants to see discussed in 2025 is the overall value proposition of drug products to patients. Companies should have a clear focus on manufacturing and optimization of technology to improve cost efficiency and improve access to patients, he asserts.

Looking at the potential technology agenda for industry in 2025, Forte remarks that the use of novel technologies is a key pressure point that will set the tone for industry as we move forward. “There's probably two elements,” he says. “One is the technical element itself: How do we manage and control and flow of information of those technical elements? And that's where we're going to see more closed systems, more automated systems, and more devices that can do things on their own. But then we need to control that in terms of information. That's where AI [artificial intelligence] will be particularly relevant.”

Additionally, from a technology agenda perspective, decentralized manufacturing will be important for industry in the future, Forte adds. “For the decentralization of the manufacturing, we need two things,” he continues. “We need devices that are able to be deployed closer to the patients, and information technology that is able to control those multiple devices. Because if you do decentralized manufacturing, you continue to have a single product that needs to be consistently released and have consistently the same characteristics across those multiple devices, and that requires flow of analytical data, flow of control in process, control data, and fine tuning that will require significant IT and adaptive IT, which is where AI comes in.”

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Big expectations for nanoscale organic delivery technologies

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

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

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

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

®
Vol. 49, No 2
March 2025
Pages: 14–17

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

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

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

Women's Day poster with woman silhouette and fists inside in paper cut and copy space, 3D illustration. Girl face poster for feminism, independence, freedom, empowerment, activism for women rights | Image Credit: © AdriaVidal – stock.adobe.com

The world is celebrating International Women’s Day on March 8, reviewing the current state of gender equality in workplaces and seeking out opportunities to reduce potential disparities. For the bio/pharma industry, promoting science, technology, engineering, and mathematics (STEM) subjects and careers and increasing support for women within the industry to progress further in their career paths are ways that gender equality can be improved, particularly at more senior corporate levels.

Below is a selection of recent coverage from 

In this video interview, Agnes Cwienczek, director of Product Management at ArisGlobal, chats about how women can be supported in the pharmaceutical industry and other STEM fields. “While more and more pharma companies have established dedicated STEM programs and are fostering related career paths, men continue to outnumber women in this field across the globe, particularly at the higher levels,” she says.

https://www.pharmtech.com/view/international-day-of-women-and-girls-in-science-fostering-stem-careers-for-women

This article explores why investing in STEM programs for girls in an education setting and then supporting women as they excel in their professional careers is key to ensuring that vital highly skilled personnel are not left behind.

https://www.pharmtech.com/view/leaving-stem-skills-on-the-table

 sat down with Sabine Gölden, eLearning & Training Lead at MAIN5, a European consulting firm, about her experience working in the pharmaceutical industry and her perspective on gender equality in STEM fields. “Gender should never be the basis for deciding which field of study is right for you, regardless of any evolutionary advantages or disadvantages. Ultimately, someone’s path should be determined by their unique talents, passion, dedication, and interests—not by their gender,” she notes.

https://www.pharmtech.com/view/international-day-of-women-and-girls-in-science-2025-inspiring-and-supporting-women-in-stem

Women bring a unique perspective to the use of artificial intelligence (AI) in the pharmaceutical industry. In this article, the various benefits and opportunities that can be gained from women being involved at all levels of development and use of technological advances are detailed.

https://www.pharmtech.com/view/women-stem-and-ai-in-pharma

Jean Redmond, chief operating officer at Biologit, discusses the importance of diversity in research, the unique role women play in the field of AI, and what can be done to enrich programs to encourage girls to pursue jobs in STEM, in this video interview. “Women in STEM need to be intimately involved in the development and deployment of AI to ensure it is built ethically and representatively and in a fit-for-purpose way for problems that affect women,” she remarks.

https://www.pharmtech.com/view/international-day-of-women-and-girls-in-science-research-diversity-and-ai

In this video interview, Michelle Bridenbaker, COO of Unbiased Science, provides her perspective on how women can be empowered to excel in these crucial roles, as women provide unique and important perspectives. “The pharma industry should absolutely be investing in and promoting STEM career paths for girls. It’s incumbent on them to do so. It’s about investing in a sustainable talent base, and about doing the right thing by half of the population,” she asserts.

https://www.pharmtech.com/view/international-day-of-women-and-girls-in-science-support-and-empowerment

Supporting the prosperity of women in science fields benefits the bio/pharmaceutical industry.

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