Behind the Headlines Episode 27

Ask the Expert

Small Molecules, APIs, and Excipients—Trends, Challenges, and Opportunities

Drug Digest September 2025

Artificial intelligence, machine learning, and novel instruments are helping drug developers.

Enhancing Bioanalysis and Drug Development with Advanced Tools and Technologies

J.P. Morgan Report Lists Biologics, Obesity, China

Top Trends Reshaping Pharma R&D

Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

INTERPHEX Interview with Joe Bobacher

Companies want to prevent spills in their manufacturing facilities to avoid losing product, but they would also ideally like to avoid spilling product that is corrosive to the environment. Those were among the key points made by Joe Bobacher, regional sales manager for OPW Engineered Systems in Hamilton, Ohio, in a video interview with Pharmaceutical Technology® Group at the INTERPHEX 2025 conference in New York City.

Bobacher was asked where the greatest demand currently is in the hazardous chemicals industry and what areas those in the field are most seeking improvements.

“When you walk into, whether it's a pharmaceutical plant or a high-end chemical processing plant, the first thing you'll notice is the smell, and companies are moving away from the smell that you find creating those closed loop systems, whether that be a fluid product, whether that be vapor emissions,” Bobacher says in the interview. “So, our products help solve those problems, whether it's an emission situation with regard to vapors that protects the environment [and] the people in the community around that area, those are the products that we sell. And those companies are making their best efforts to come up with those closed loop solutions at their facilities, and we help aid that and support those efforts.”

The 2025 edition of INTERPHEX took place from April 1–3, 2025 in New York City.

Click the video above to watch the full interview.

Joe Bobacher, Regional Sales Manager, OPW Engineered Systems

Joe Bobacher is the Northeast Sales Representative for OPW Engineered Systems, headquartered in Hamilton, Ohio. Joe has been serving the industrial fluid transfer market for 20 years. OPW Engineered Systems designs, engineers, and manufactures loading arms, swivel joints, quick and dry disconnects, and other related fluid-transfer equipment. For more information on OPW Engineered Systems, please visit 

Videos

Joe Bobacher of OPW Engineered Systems spoke with Pharmaceutical Technology® Group at INTERPHEX 2025 about fluid transfer in controlled environments and the importance of guarding against product loss.

INTERPHEX 2025: Preventing Spills in the Manufacturing Process

INTERPHEX Interview with Todd Andrews

When single-use technologies began to be adopted, the attitude in the bio/pharmaceutical industry was a “wild wild West,” says Todd Andrews, global director of Applications and Business Development for CPC’s Biopharma business. Andrews spoke exclusively with 

® Group at INTERPHEX 2025 in New York City.

Andrews is also secretary of the executive board of directors of the Bio-Process Systems Alliance, and in that capacity, he said one current priority is keeping abreast of new and changing regulations regarding single-use technologies, which are evolving in a similar fashion to those concerning per- and polyfluoroalkyl substances, or PFAS.

Being able to customize services and offerings for individual customers is another important touchstone, according to Andrews.

“What we're seeing now is a lot of forward-thinking end users trying to break up—we call it ‘break up the octopus’,” Andrews says in the interview. “Instead of this giant tubing assembly, how do you break it up into the common subassemblies? And you almost can treat it like a Lego, where you may have a ‘T’ or a cross and you can basically customize at the point of use, instead of customizing with the OEM [original equipment manufacturer]. And if you're an OEM supplying this, this adds a lot more efficiency, because now, instead of making lower volumes of multiple part numbers, you can make higher volumes of lower part numbers.”

Todd Andrews, Global Director, Applications and Business Development, CPC

Todd Andrews is global director—Applications and Business Development for CPC's Biopharma business. For more than 20 years, he has focused on single-use connection technology development and integration into the bioprocessing industry, in addition to the emerging cell and gene therapy markets. With a Bachelor of Science degree in plastics engineering and a Master of Business Administration, Andrews has held roles in design engineering, product management, business development, and sales. Andrews also currently serves as secretary on the Bio-Process Systems Alliance (BPSA) executive board of directors.

As single use becomes more prevalent, end users are looking for more customization, and regulators are refining their rules, says Todd Andrews of CPC in an interview with Pharmaceutical Technology® Group.

INTERPHEX 2025: ‘Breaking Up the Octopus’ of Single-Use Systems

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

Nano particle molecule. Nano medicine and nanotechnology biotechnology concept. Organic or inorganic polymeric sphere, capsule, quantum. | Image Credit: ©Irina - stock.adobe.com

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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 5 (276) 116706. DOI: 10.1016/j.ejmech.2024.116706

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, 

Tenchov, R.; Bird, R.; Curtze, A.E.; and Ahou, Q. 

 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. 

Articles

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

Enhancing Solubility and Bioavailability with Nanotechnology

Dean Bornilla, Pace® Life Sciences, highlights his organization's future role in supporting biopharmaceutical development and manufacturing coast-to-coast.

Major Growth & Investment at Pace® Life Sciences

Pace® Life Sciences, a CRDMO, has experienced significant growth through recent acquisitions of analytical labs, substantially increasing their testing capacity and scientific expertise. Looking ahead to 2025, Pace® is undertaking key expansions at their Salem, NH, site to include sterile fill-finish capabilities for clinical trial manufacturing and at their Oakdale, MN, facility to double their biopharmaceutical analytical services. With a growing network of locations across major US pharmaceutical hubs, Pace® aims to enhance customer experience through consistent quality and timely delivery. The company anticipates continued growth through both organic initiatives and further acquisitions, supported by private equity investment.

Sterile fill-finish capacity coming during Q3 of 2025.

A headquarters expansion slated for 2025 for biopharmaceutical analytical services.

Major Growth & Investment at Pace® Life Sciences  

 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.

Electronic three dimensional plastic printer during work | Image Credit: © andrew_shots - stock.adobe.com

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).

 Schematic overview of 3D printing of personalized medications as part of a distributed manufacturing (DM) model. Upon consultation at the point of care (PoC), patient prescriptions would be anonymized and digitally transferred to a licensed DM site for production of the prescribed drugs. Process data (i.e., surrogate quality data) as well as drug product quality data would be transferred between DM and pharmaceutical quality system (PQS) sites. Data transfer may happen in real time, and the PQS site would be responsible for certifying the medicine quality would be appropriate for dispensing. If appropriate, drugs may be released from the DM site to the patient, potentially through the PoC. A single PQS site may oversee multiple DM sites. Figure courtesy of the authors; created with BioRender.com.

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. 

®
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. 

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

 is product manager, analytical services at Stevanato Group.

 is scientific director at Nelson Labs Europe.

Macro view on vials | Image Credit: © yuriygolub - stock.adobe.com

Dujuan Lu, PhD, manager and global lead of the extractables and leachables (E&L) team at SGS Health Science, spoke with 

 that expanded upon her talk at the conference, “Regulatory Expectations in Extractables and Leachables Testing of Combination Products.” One of the topics covered in those interviews was the common ground in analytical testing under both 

) and International Organization for Standardization (ISO) standards, despite different extractables that may be tested.

 How has the need for testing in single-use products evolved in recent years? Can you explain how the problem differs in single-use versus reusable products?


 The single-use product typically has a lower risk in terms of E&L, compared to reusable products, as the patients are exposed to the single-use packaging or devices for a limited time. The toxicological risk could be considered lower based on the duration and frequency of the treatment.


 What are the differences with combination products versus single/simplified drug products? How are regulations adapting to this?


 Per the definition from FDA, a combination product is a product composed of any combination of a drug and a device, a biological product and a device, or a drug and a biological product, or a combination of a drug, device, and a biological product (1). All aspects of the regulations will be considered when evaluating the regulation submission of the combination products. The product’s primary mode of action (PMOA) will be crucial and could lead to a suitable regulatory submission pathway. If the PMOA of a drug-device combination product is ‘drug,’ most of the pharmaceutical regulatory testing will apply. When a PMOA of a drug-device combination product is ‘device,’ the combination product will be considered as a medical device. There are different E&L regulatory guidances in pharmaceutical testing versus medical device testing. The extractables and leachables study designs of pharmaceutical and biological drug products associated with pharmaceutical packaging/delivery systems typically follow 

 <1664> for leachable testing (2,3). The Product Quality Research Institute (PQRI) guidance also provides good recommendations to design extractables and leachables studies for parenteral and ophthalmic drug products (PODP) and orally inhaled and nasal drug products (OINDP) (4). As for testing of extractables and leachables of devices, it is usually considered as a chemical characterization of medical device materials per ISO 10993-18 (5).


 What do testing teams miss most often in their attempts to detect and quantify extractables and leachables, or, what are their biggest challenges?


 There are a lot of analytical challenges regarding extractable and leachable testing. The major challenges are associated with analytical evaluation threshold (AET), confident identification, and semi-quantitation. They are outlined in one of our [SGS’] recent review articles (6).


 Financially, what is the state of the E&L testing market early in 2025, and how is the market positioned to grow through the second half of the 2020s? What factors are driving growth, and what could hold that growth back?


 The current E&L testing market is still growing, given more stringent regulatory requirements. There have been numerous E&L industry guidances published in recent years or expected in upcoming years, including 

<665>/<1665> for pharmaceutical/biopharmaceutical manufacturing materials, ISO 10993-18:2020, FDA guidance on chemical testing of medical devices, and the upcoming ICH (International Council for Harmonisation) Q3E. Most of the testings are carried out at third-party contract research organizations, as they have dedicated instrumentation and technical expertise built on many years in the industry. Some big pharmaceutical and medical device companies are also performing E&L testing in-house, due to confidentiality of the products in development or other historical reasons.


 Are there any emerging pharmaceutical areas where E&L testing is currently being emphasized?


 There are several emerging areas with more E&L focus these days. One of the areas is related to pharmaceutical/biopharmaceutical manufacturing materials. During the manufacturing process of the pharmaceuticals or biologics, more and more plastic single-use systems have been utilized these days, instead of the traditional stainless-steel materials in the old days. However, those plastic additives can easily leach out into the drug substance and drug product during the manufacturing process. With the new 

 <665> scheduled to become official in 2026, all drug/biological manufacturers will need to perform risk assessment and testing based on the risk level.

 <1663>, Extractables Associated with Pharmaceutical Packaging Systems, 

 Supplement No. 1, 7166 (Rockville, MD, 2015).
3. USP, 

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

 Supplement No. 1, 7166 (Rockville, MD, 2015).
4. Paskiet, D.; Jenke, D.; Ball, D.; et al. The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group Initiatives for Parenteral and Ophthalmic Drug Product (PODP). 

, 67 (5) 430–447. DOI: 10.5731/pdajpst.2013.00936
5. ISO, ISO 10993-18:2020, 

Biological Evaluation of Medical Devices—Part 18: Chemical Characterization of Medical Device Materials Within a Risk Management Process

, 2nd edition (2020).
6. Singh, G.; Lu, D.; Liu, C.; Hower, D. Analytical Challenges and Recent Advances in the Identification and Quantitation of Extractables and Leachables in Pharmaceutical and Medical Products. 

, 141, 116286. DOI: 10.1016/j.trac.2021.116286

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. 

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

Feliza Mirasol is the science editor for 

Discussion about advancements in flow sensor technologies with PSG Biotech's Michael Franco.

INTERPHEX 2025: Advanced Flow Sensor Technologies Enable More Accurate Measurement

At INTERPHEX 2025, Michael Franco, global sales director at PSG Biotech, spoke with the PharmTech Group about how recent advancements in pharmaceutical flow sensor technology focus on improving measurement accuracy as drug production becomes more expensive and precise. A key development, he notes, is the enhancement of Coriolis single-use flow meters, which now feature a higher turndown ratio. This enhanced feature allows a single sensor to accurately measure both high and low flow rates. With this innovation, inventory needs can be reduced, and sensor usability across various process conditions is extended, which improves sustainability.

“When we talk about high turndown ratio, it's very good for the industry, because with one sensor, you can measure more than just low flows or high flows. So, in terms of sustainability, there's less need for inventory, and the sensor can be used for longer, because it can be operated in different process conditions. [In] terms of the future, we're adding more digital communication platforms so customers can communicate to the sensors in different ways, making sure that the sensors talk to pumps, and to get a really good performance between the two. [Those] are the things that probably are going to be asked more and more from customers,” Franco says.

Looking forward, this integration of digital communication platforms to enhance sensor interoperability is expected to enable better coordination with pumps and optimize system performance. These advancements are increasingly demanded by customers for improved bioprocessing applications, including tangential flow filtration (TFF) and chromatography skids. The ongoing adoption of these technologies as observed at INTERPHEX, notes Franco, highlights their growing importance in pharmaceutical manufacturing.

INTERPHEX 2025 occurred in New York City on April 1–3.

Michael Franco, Global Sales Director, PSG Biotech

Michael Franco leads the PSG Biotech global sales team, focused on strategic business growth, with a strong focus on adding value to PSG Biotech customers, and building meaningful and in-depth partnerships. Mike’s abilities to connect with customers and understand business strategy stem from a rich educational and career experience in key roles in multiple industries:

Prior to Biopharma, Mike worked in several sectors including Aerospace, Industrial, Renewable Energy and Power. He progressed from positions such as Researcher, Applications Engineer, Commercial Engineer, Segment Leader and Regional Sales Manager where he excelled and elevated to his current position as Director of Global Biopharma Sales. Companies that have been graced with Michael’s employed expertise include Syntest Corporation, Panametrics, GE Power Systems, GE Oil and Gas, GE Industrial, GE Energy Services, and AMETEK.

Michael’s education achievements include a Bachelor of Applied Science in Electrical Engineering from Boston University, a Master of Science in Information Technology at Worcester Polytechnic Institute, and a Master of Business Administration with a concentration in Business Administration and Management at the Isenberg School of Management at UMass Amherst.

Michael Franco, global sales director at PSG Biotech, spoke with the PharmTech Group at INTERPHEX 2025 about recent advancements in pharmaceutical flow sensor technology.

Designing a Strategic Roadmap for Seamless Product Development

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

Magnifying glass and check mark icon. Business concept,idea,right choice, quality control, approval and contract assignment | Image Credit: ©olyphotostories - stock.adobe.com

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

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.

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