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

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. 

Articles

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

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

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.”

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.

Videos

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.

International Women’s Day 2025: Celebrating Women in Science

Woman face silhouette in profile with group of multicultural and multiethnic women faces inside.Concept of racial equality anti-racism and a woman who gives voice to other women. Allyship | Image Credit: © melita – stock.adobe.com

International Women’s Day is recognized annually on March 8, providing an opportunity for all to reflect on gender diversity and seek out ways to address disparity and inequalities. For the pharmaceutical industry, the gender gap has reduced over the years, with a healthier proportion of female representation in the workforce (1)—albeit in less senior positions than their male counterparts.

In fact, according to the Deloitte Global Boardroom Program’s 

Women in the Boardroom: A Global Perspective 

report, less than a quarter of board seats worldwide are held by women (2). Narrowing down to the pharma industry and the research has found that women hold approximately 29% of executive positions and are represented in approximately 28% of corporate boards, rising slowly and steadily over the past 10 years (3).

However, better diversity and gender equality in senior, leadership positions have been shown to improve profitability and return on equity for companies through greater innovation and more creative solutions being found for problems (4). To get some insights into the ways that women can help to improve innovation within the pharma industry, 

reached out to some of the women on our Editorial Advisory Boards.

Q. How can women help improve innovation within the pharma industry?

Evonne Brennan, Consultant at Evonne Brennan Consulting:

 Women continue to empower teams in driving innovation through their own belief and/or through the strength of support through their peers. Their combination of power in bringing teams together, logical reasoning, strong driving force, and recognition of diversity generates a solid advantage on the journey to success.

Emily Heffernan, US Director New Process Technology, Arcadis U.S., Inc.:

 Women are essential to innovation in the pharmaceutical industry, bringing unique and diverse perspectives that drive scientific breakthroughs. In recent years, female scientists have been recognized with Nobel Prizes for pioneering advancements, such as CRISPR [clustered regularly interspaced short palindromic repeats] gene-editing and mRNA [messenger RNA] vaccine technology. Looking to the future, women in leadership roles can both mentor and inspire the next generation of women innovators and entrepreneurs, fostering a continuous cycle of progress and discovery.

Christa Myers, Senior Fellow–Aseptic & Sterile Products, CRB:

 The great innovators in the industry have been devoted to excellence above all. It takes effort and intention to dig past what the everyday offers.That is where innovation lies.Innovation happens when you push a solution to consider new methods, new ideas, or reuse old ideas in a new way.Women and men have to dedicate their thoughts to look for better instead of status quo in everything we do.In the pharmaceutical market—it is still true that there is a C in CGMP [current good manufacturing practice] that requires us to be ever improving, ever thoughtful, and ever reaching for higher quality, safety, and value for the patient. Innovation does not happen without intention. It takes study, curiosity, research to fuel that intention. Be ever vigilant in your daily planning to set aside time to look through different types of technology offered in ‘other’ parts of the industry to see what crossover technologies may be useful to the solution you are working on.Attend technical conferences and ask questions of component and equipment manufacturers about where they are seeing new uses for their technologies.Write down the technology and spend time later comparing the approach to different parts of the industry to tickle out where ‘else’ this technology might fit in.Stay engaged.Join membership groups and communities of practice and other thought leading groups to stay abreast of changes.Keep growing, keep chasing innovation, and keep jumping out of the status quo—it is easy to be innovative once—it is more difficult to continue to drive to innovate again and again.

Sue Schniepp, Distinguished Fellow, Regulatory Compliance Associates: 

Women have great compassion and insight which helps them relate to the patient experience. By staying in tune with their feelings, they can continue to make sure the industry continues to produce safe and effective medicines for patients.

1. Sterrett, L. Can Women Break Glass Ceilings in Healthcare/Life Sciences? Health Forward Blog. Deloitte, April 6, 2023.
2. Deloitte. Women in the Boardroom, Eight Edition. 

, March 6, 2024.
3. East Street Pharmacy. The Growing Role of Women in Pharmaceutical Leadership. 

(accessed March 6, 2025).
4. One Nucleus. Women in Pharma—Are We There Yet? 

Gender diversity and equality in leadership positions have been shown to improve profitability and return on equity through greater innovation and more creative solutions. 

International Women’s Day 2025: Improving Innovation in Industry

Feliza Mirasol is the science editor for 

The forward movement of the bio/pharmaceutical industry is driven by fast-paced advancements in manufacturing technology innovations. As manufacturing technology advances, so does the shift to continuous manufacturing (CM), a process that enables real-time monitoring, improved scalability, and enhanced quality control. As the industry increasingly adopts CM, it is undergoing a transformative shift.

In the current environment, one of the most significant applications of CM is in the production of RNA-based therapeutics, including messenger RNA (mRNA), self-amplifying RNA (saRNA), and circular RNA. In an interview with Aaron Cowley, chief scientific officer at ReciBioPharm (1), Cowley noted how industry leaders have spearheaded the development of CM platforms for RNA manufacturing with funding from FDA. These CM platforms hold the promise of significantly increasing production efficiency while maintaining rigorous quality standards.

In particular, the COVID-19 pandemic sharply highlighted the necessity of having rapid and scalable RNA manufacturing to meet global vaccine demand at the time. Traditional batch manufacturing poses bottlenecks that hinder timely drug availability. In comparison, CM integrates all unit operations into a seamless and continuous process and allows for real-time release and significant reduction in production timelines (2).

One of the key advantages of CM in RNA therapeutics is its ability to maintain small-scale yet high-throughput production. And, unlike monoclonal antibodies or conventional biologics that require thousands of liters in bioreactors, RNA production runs at much smaller scales—typically a few hundred milliliters to several liters per batch (3). CM becomes an ideal approach to tackling production of RNA-based products because it facilitates rapid adaptation and scale-up while at the same time minimizing waste and inefficiencies.

A significant innovation in CM for RNA therapeutics is the integration of in-vitro transcription (IVT) into a continuous process. Traditionally, IVT reactions are performed in batch mode, in which RNA synthesis is followed by downstream purification and formulation. But the continuous integration of IVT with purification and fill/finish operations allows for real-time monitoring and control, which leads to enhanced product consistency and yield (4).

“Being able to have eyes on the process and the product as it goes along, the full train of manufacturing, and be able to release that real time—is the overall goal that we are after,” said Cowley in the interview (1), explaining that if another pandemic comes along there won’t be a bottleneck in manufacturing, and that an RNA-based vaccine, for example, will be available and the manufacturing process will still be able to produce extra material.

On the small-molecule side, there is a trend toward higher potency and smaller dosing of APIs as, for the past 20 years, development and innovation in the pharma industry have focused on patient safety, meaning product quality, while also addressing cost efficiency and promoting greater sustainability, says Guia Bertuzzi, product manager of processing equipment for oral solid dosage (OSD) at IMA Active, the specialized division of the Italian company IMA Group.

“Modernizing the pharmaceutical industry requires both a more robust drug formulation design and better control of the production process, ensuring the highest quality and availability of the drug throughout its entire life cycle,” Bertuzzi states, adding that, “This concept strongly aligns with the adoption of the quality-by-design (QbD) approach, which prioritizes quality in drug development, as recommended by regulatory authorities. Furthermore, it paves the way for CM and other emerging technologies.”

Bertuzzi points to how CM fully supports the growing trend toward low-dose OSD forms and the increasing need for process containment and accuracy in quality control. “By definition, CM systems are designed for high-containment processes: they are typically compact, closed systems with a smaller process surface compared to batch manufacturing systems of equivalent productivity,” she explains. “Additionally, CM enables the integration of different production technologies in series, allowing for an uninterrupted material flow, from raw materials to the final pharmaceutical form, within a closed system that eliminates the need for product transfers between equipment, thereby minimizing the risk of product leakage.”

Because the CM process is continuously monitored in real-time with advanced instrumentation and an advanced control philosophy (i.e., process analytical technology [PAT]), the critical quality attributes (CQAs) of the product is also instantly monitored, allowing for increased sampling frequency without requiring physical sample collection, Bertuzzi states.

Modular and flexible manufacturing systems

The flexibility of CM, meanwhile, allows for modular process design, which enables manufacturers to switch between different modalities without major overhaul of infrastructure. The ability to switch between modalities is particularly important in RNA manufacturing as RNA therapeutics expand beyond vaccines to include gene therapies, cancer immunotherapies, and rare disease treatments. Having the ability to modify purification steps—such as adjusting the number of chromatography columns (based on impurity profiles)—will ensure that different RNA therapeutics can be produced efficiently and on a single platform (5).

However, despite the advantages that CM has demonstrated so far, the transition from traditional manufacturing to fully CM processes will continue to present challenges. Small and medium-sized enterprises (SMEs) will particularly face obstacles, including high initial investment costs, integration complexities, and the need for specialized expertise—factors that remain barriers to widespread adoption.

“Adopting CM requires a significant initial effort, including cultural and organizational changes within most pharmaceutical companies,” Bertuzzi says. “A company looking to implement CM must adequately prepare and structure itself. Beyond simply acquiring and integrating machinery in series, production and quality must be designed with a QbD approach, incorporating a higher level of automation and ensuring seamless integration between various technologies. This necessitates a strong orientation toward digitalization.”

Continuous manufacturing has gained increasing recognition by regulatory agencies such as FDA and the International Council for Harmonisation (ICH), which acknowledge CM’s potential and have issued guidelines (e.g., ICH Q13) to facilitate implementation (6).

“The drive toward CM will undoubtedly intensify due to the recent publication of regulatory guidelines (ICH Q13, FDA Q13, etc.) by major global authorities. Additionally, ongoing global challenges—such as pandemics, wars, and raw material shortages—further highlight the need for more efficient and resilient manufacturing processes,” Bertuzzi emphasizes.

Overcoming the challenges to full CM adoption will require strategic collaborations between biopharmaceutical companies, contract manufacturing organizations/contract development and manufacturing organizations, and technology providers. These collaborations will be crucial moving forward. In addition, standardization of CM technology platforms, especially those that incorporate modular automation, AI-driven process control, and cloud-based data analytics, will further enable CM adoption (7).

“From an equipment vendor’s perspective, we are actively driving the transition toward CM, particularly for SMEs, by providing process engineering support to facilitate adoption and implementation,” adds Bertuzzi.

1. Spivey, C. Biopharma’s Progress with Continuous Manufacturing in mRNA (BIO 2024). 

, Sept. 27, 2024.
2. Plumb, K. Continuous Processing in the Pharmaceutical Industry. 

 (A6), 730–738.
3. Kempf, H.; et al. RNA Manufacturing and Process Development: Current Trends and Future Outlook. 

 (10), 1168–1180.
4. Karmakar, S.; et al. Continuous Manufacturing of RNA Therapeutics: Opportunities and Challenges. 

, 107840.
4. Uhl, P.; et al. Flexible Manufacturing Strategies for RNA-Based Therapeutics. 

Guidance for Industry, ICH Q13 Continuous Manufacturing of Drug Substances and Drug Products

 (CDER, March 2023).
6. Konakovsky, S.; et al. Smart Manufacturing Approaches for Continuous Biopharmaceutical Production. 

®
Vol. 49, No. 2
March 2025
Pages: 24–26

When referring to this article, please cite it as Mirasol, F. How Continuous Manufacturing is Advancing Bio/Pharma Production. 

Continuous manufacturing offers advantages in both biotherapeutic and API manufacturing but still poses challenges.

How Continuous Manufacturing is Advancing Bio/Pharma Production

In an interview with Pharmaceutical Technology®, Sheryl Johnson from Orbia Fluor & Energy Materials chats about gender diversity, how women are helping to advance innovation, sustainability challenges, and progress in the field of inhaled drugs.

International Women’s Day 2025: A Promising Future for Gender Diversity in Pharma

While the pharmaceutical industry has made strides towards diversity, equity, and inclusion, there is still room for improvement, asserts Sheryl Johnson, pharma application development manager at Orbia Fluor & Energy Materials. Many companies, such as Orbia, are taking proactive approaches to help improve gender diverse representations within their workforces. Ongoing commitment from all areas across the industry is required to achieve full diversity, she explains.

“Women in particular, can bring unique perspectives, talents, [and] approaches that can drive innovation, particularly in the pharma industry,” Johnson adds. “For instance, female leaders can often excel in collaborative and inclusive leadership styles, which I feel can help foster creativity and new ideas. I find women are very open to sharing of new ideas and provide supportive attitude to research management and development through considered and empathetic communication.”

Looking at sustainability challenges in particular and drawing on her experiences within the inhaled drug space, Johnson points to the groundbreaking research and leadership being performed by women helping to drive greater sustainable practices, “people like Sara Panigone from Chiesi, who's leading initiatives in developing carbon minimum inhalers and has been prominent voice in sustainability and in within the industry, and Maureen Hardwick from the International Pharmaceutical Aerosol Consortium, [who’s] been a key figure in advancing environmental policies and sustainable efforts,” she says.

“I think the future of gender diversity in the pharma industry looks promising with more women taking on leadership roles and contributing to decision making processes,” Johnson summarizes. “I think the shift will likely lead to a more inclusive, innovative approach to healthcare for inhalers and inhaled drugs, we can probably expect continued advancements in technology, in formulation and making treatments more effective, more environmentally friendly, and I think the industry is poised to make significant strides in both areas benefitting both patients and the world alike.”

Sheryl Johnson, Pharma Application Development Manager at Orbia Fluor & Energy Materials

Sheryl Johnson is Pharma Application Development Manager at Orbia Fluor & Energy Materials. Sheryl is a highly respected authority in the pharmaceutical aerosol industry with almost two decades' worth of experience in medical chemical development and research. She is on the board at the International Pharmaceutical Aerosol Consortium on Regulation & Science(IPAC RS), frequently contributed to the publishing of papers through working groups, and actively participates at industry organised conference events such as Respiratory Drug Delivery. After earning her Master's in Organic Chemistry from the University of Hull, she worked as a senior development chemist at Contract Chemicals, where she discovered her love for laboratory work. Her subsequent role at Orbia provided experience in process development, hazardous materials handling and formulation chemistry. Now, with over 13 years at Orbia Fluor & Energy Materials, she serves as Pharma Application Development Manager, overseeing the safe production and development of Zephex 152a MDIs.


Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

Text sign showing Industry News. Business photo text delivering news to the general public or a target public | Image Credit: © Artur - stock.adobe.com

The Munich-based contract development and manufacturing organization Adragos Pharma announced on March 6, 2025 that it has completed the installation of a new liquid filling line at a facility located in Leipzig. Germany, the site of the company’s headquarters (1).

The announcement represents the culmination of a €4 million (US$4.3 million) project intended to install and commission an advanced, current good manufacturing practice (CGMP)-compliant liquid filling line as well as an accompanying cartoning machine (1). Combined, Adragos Pharma said the new equipment would increase production capacity at the Leipzig site nearly tenfold in the face of rising demand—at a maximum of 13 million bottles per year, in various formats, to supply the pharmaceutical, cosmetic, and healthcare supplement product markets.

Two pre-existing, semi-solid commercial manufacturing lines at the 13,300-square-meter (143,160 sq. ft.) facility have been relocated to new production areas, which was the initial phase of the installation process, according to Adragos Pharma, and are now once again fully operational (1).

“This new flexible production line marks a key milestone in the development of our Leipzig site, expanding its capabilities and reinforcing our dedication to delivering state-of-the-art manufacturing solutions to our customers,” Florian Prell, site head of Adragos Leipzig, said in a company press release. “Adragos is committed to growing and investing in innovation, and we are looking forward to the opportunities and client partnerships that this project will create, as we continue to lead the industry in high-quality liquid dose form manufacturing.”

John McQuaid, president and managing director of Almac Pharma Services, summarized capacity concerns, including in fill/finish operations, 

“There's never been a larger number of molecules in clinical development, and we're certainly seeing that increasing demand,” McQuaid said in the interview (2). “We've got demand in areas such as [highly] potent [APIs], [and] age-appropriate formulations, such as pediatrics. We've got poorly soluble compounds, and the need for technologies to address that. And then we've got personalized medicines, such as, … cell and gene therapies, which drive particular needs in areas such as fill/finish and cold chain requirements.”

 its acquisition of the Swiss aseptic fill/finish manufacturing company Baccinex (3). Adragos Pharma said the transaction was made to enhance its sterile manufacturing capabilities and expand the company’s global network, leveraging Baccinex’s expertise in sterile liquids and lyophilization. Earlier that month, Adragos Pharma said it was launching a cutting-edge ampoule filling line at its Livron, France facility, enhancing its production capacity to over 160 million ampoules per year. And in April 2024, the company announced its intention to reinvest in the solid dosage market, through its plans to enhance manufacturing capacity at its plant in Kawagoe, Japan (4,5).

Meanwhile, liquid filling was one of the specializations noted by Piramal Pharma Solutions, a division of Mumbai-based Piramal Pharma Limited, 

 of a planned $80 million investment to expand a site in Lexington, Ky., for which a previous $25 million expansion had been announced in 2016 (6,7). At that facility, a new filling line, two commercial-sized lyophilizers, a capping machine, and an external vial washer are to be added by the first quarter of 2027.

1. Adragos Pharma. Adragos Pharma Completes the Installation of a New Liquid Filling Line in Leipzig, Germany. Press Release. March 6, 2025.
2. Thomas, F. 

CPHI Milan 2024: Pharma Industry Growth and Investment.

, Oct. 11, 2024.
3. Adragos Pharma. Adragos Pharma Acquires Baccinex—A Leading Swiss Sterile Fill-Finish Expert. Press Release. Nov. 25, 2024.
4. Adragos Pharma. Project Future: We Launched Our New Production Line in Our Livron Facility! Press Release, Nov. 7, 2024.
5. Adragos Pharma. Our Strategic Expansion in Japan: Reinforcing Production to 2 Billion Tablets and Aiming to be the “Most Trusted CDMO”. Press Release, April 8, 2024.
6. Piramal Pharma Solutions. Piramal Pharma Solutions Announces $80M Expansion Plan for Sterile Injectables Facility in Lexington, Kentucky. Press Release. Sept. 30, 2024.
7. Pharmaceutical Technology Editors. 

Piramal to Expand Sterile Manufacturing in Kentucky.

The €4 million (US$4.3 million) project is current good manufacturing practice compliant, and includes an accompanying cartoning machine.

Adragos Pharma Completes Liquid Filling Line Installation in Germany

On March 5, 2025, Emerson announced the release of its Rosemount 625IR Fixed Gas Detector, with the company citing a need for end users to be able to detect hydrocarbon gases quickly and reliably without false alarms (1). The detector is designed for all plant environments, utilizing advanced optical absorption detection technology.

The Rosemount 625IR model has specialized, solid-state dual infrared (IR) sources and dual IR receivers, the purpose of which are to provide continual cross-checking and make adjustments internally that hold the detector to its factory calibration (1). Emerson said advanced drift monitoring technology and health monitoring diagnostics allow the detector to be installed simply and maintain that factory standard for life—resulting in long-term reliability and minimal maintenance even in differing weather conditions and/or hazardous environments.

Accessories listed by Emerson in a press release include heaters on the optical surfaces of the detector and other protective measures that help to eliminate downtime, and mechanisms to perform function testing using either test gas or a gas-free test filter, plus ways to make the detector usable in extractive gas detection applications (1).

Emerson said duct-mounted versions are available in two lengths; these options allow for representative detection across ducts or voids that the company says is fast and accurate.

The Rosemount 625IR’s standard operating temperature range is -40 to +167 degrees Fahrenheit (-40 to +75 degrees Celsius), and it has been rated for hazardous areas throughout North America, South America, and Europe, according to Emerson (1). It has a five-year proof test interval, permitting end users to significantly reduce the frequency of scheduled maintenance visits.

Emerson, which is headquartered in St. Louis, Mo., 

 the opening of a 62,000-sq.-ft. gas analysis solutions facility in Cumbernauld, Scotland (2). The site was designed to help companies reduce their environmental impact by providing more than 10 different sensing technologies to measure more than 60 different gas components. It was also designated with the responsibility of engineering and manufacturing the Rosemount line of gas analyzers and chromatographers.

In August 2023, Emerson said it would be 

 to integrate that company’s Biostat STR Generation 3 family of bioreactors with Emerson’s DeltaV distributed control system (3). That partnership was forged with the aim of helping manufacturers build a connected plant not only through easily configurable and integrated equipment, but also increased access to advanced automation strategies and diagnostics.

® had the opportunity to sit down with Michalle Adkins, director of Life Sciences Consulting for Emerson, to discuss the structure of manufacturing organizations and how novel technologies may play a role in operations (4). The video of that interview can be accessed by clicking 

1. Emerson. Emerson’s New Fixed Point Gas Detector Provides Fast and Reliable Detection without False Alarms. Press Release. March 5, 2025.
2. Emerson. Emerson Opens Gas Analysis Solutions Center to Help Plants Meet Sustainability Goals. Press Release. Aug. 29, 2022.
3. Emerson. Sartorius Bioreactors Integrate Emerson Technology to Speed New Therapies to Market. Press Release. Aug. 3, 2023.
4. Playter, G. 

Discussing Manufacturing Operations with Michalle Adkins (Emerson Automation Exchange).

The detector features specialized, solid-state dual infrared (IR) sources and dual IR receivers which provide continual cross-checks and internal adjustments to adhere to factory calibration.

Emerson Releases Fixed Point Gas Detector Cutting Down on False Alarms

Aimee Penko is an engineering execution manager for Arcadis.

Isometric View of a Pharmaceutical Factory - Industrial Design for Prints, Cards, Posters, and Digital Graphics | Image Credit: © Anna– Stock.Adobe.com

The successful build or retrofit of a pharmaceutical facility or lab area depends on competent design deliverables. The design team is challenged with designing a facility that meets client business and regulatory requirements but also incorporates all applicable codes and standards while understanding and mitigating site constraints. Speed to market for a product is often a critical project charter that emphasizes design schedule compression, adding another challenge for the design team. All of these challenges can lead to poor quality of design deliverables if a robust quality plan is not in place.

As the industry faces increased scrutiny to bring drugs to market quicker, and at the same time reduce costs, understanding the nuances of design quality becomes paramount. This commentary is intended to be a primer for companies that are just setting off down their own design path or working with outside consultants to build or retrofit their pharmaceutical facility.

Regardless of one’s level of expertise, however, it pays to be more fully versed on the ins and outs of design quality, and the implications of paying insufficient attention to this aspect throughout the project design phase life cycle.

It’s important to understand the difference between design quality and manufacturing quality. When people in the industry hear the word “quality,” they typically think of “manufacturing quality”—the process of ensuring the product meets validated quality acceptance criteria and is thus safe to release to the public.

Design quality refers to the process of producing technically correct design deliverables that will be used to build or modify an existing pharmaceutical facility. Technical correctness is more than just individual disciplines working on their scope. Accuracy of deliverables takes into account that all scope is shown correctly, follows appropriate codes and standards, meets client requirements, and is coordinated with other disciplines to provide a design that can be constructed and validated.

Drawings should be coordinated with specifications so there is no conflict or ambiguity. Deliverables between disciplines should look uniform by following well-defined project standards. If an engineering or architectural drawing is 100% technically correct but contains multiple spelling and graphical errors, the customer (owner/client, permitting Authority Having Jurisdiction [AHJ], or constructor) may question the accuracy of the deliverable because spelling, format, title block, and revision information errors reflect poor attention to detail.

The backbone of effective design quality is a robust quality management system (QMS). A QMS provides the framework by establishing standardized processes and procedures that the design team will follow. It encompasses the procedures for the entire firm, covering all aspects of design delivery, down to seemingly mundane elements like how drawings are set up and numbered. Adherence to the QMS aligns the team on policies and procedures to streamline operations, but also enhance traceability and accountability.In addition, the QMS establishes a means for continuous improvement of deliverables and procedures through lessons learned feedback.

The QMS framework should be developed in compliance with ISO 9001, which defines the requirements for a quality management system (1). ISO 9001 is the most recognized QMS standard and the only standard within the ISO 9000 series that organizations can be certified to. The International Council for Harmonisation (ICH) Q9 Quality Risk Management guideline is another valuable reference (2). It provides guidance on managing quality risk by providing tools and principles for controlling and communicating the risk.

It’s crucial to understand that while the QMS provides a strong quality framework and documents the processes required for project review stage gates, it’s not enough. Checking a box on a checklist does not always ensure technical quality is achieved.

Technical quality is achieved by orchestrating many different types of design reviews, facilitated by experienced peers, before deliverables are issued on a project. A second set of qualified eyes helps to identify items that might have been missed by someone who has been looking at the same documents for months. This collaborative effort also fosters accountability for design outcomes, for an overall better result that directly addresses facility requirements.

Sustaining design quality throughout the project with a rigorous design review process is paramount. The reviews should happen at a frequency defined in the project execution plan, and certainly before deliverables are issued to the customer. There are multiple different types of design reviews that can be performed on a project.

 All deliverables should undergo an intra-discipline technical check.This check should be performed by a peer from that discipline that is technically competent to review the deliverables. The discipline check should involve reviewing both drawings and specifications for intra-discipline coordination between documents and technical correctness. The checker should also verify quality attributes like format, spelling, revision information, notes, etc. to ensure they are presentable to the customer.

 The squad check is an inter-disciplinary review by all disciplines on a project. It provides the opportunity to review other discipline’s deliverables to ensure scope is coordinated between the team.

For example, a mechanical engineer should review electrical drawings to ensure all mechanical equipment is powered as-specified and safely. A reflected ceiling plan (RCP) should be checked by multiple disciplines such as electrical, mechanical, fire protection, and architecture to ensure there are no clashes between lights, diffusers, sprinkler heads, and ceiling system. The squad check also provides another opportunity to ensure spelling, format, and revision information is correct on the documents. If desired, the squad check exercise participants may include external team members such as the client, construction manager, and/or sub-contractors

 Clash detection is similar in many ways to a squad check, but it’s conducted in the project three-dimensional (3D) model. Coordination software looks for clashes between (new and existing) design elements such as equipment, piping, duct, lighting, walls, and building columns just to name a few. Clashes are not always evident on two-dimensional (2D) drawings, so using 3D visualization makes them easier to identify. The clashes are published to the design team for resolution.

A Building Information Modeling (BIM) coordinator will facilitate this exercise by running the clash detection software, logging the occurrences, and expediting clash resolution between disciplines. Although no design will ever be 100% clash free, the majority of clashes should be resolved before issue, and those that aren’t reconciled shall be documented for the field team to review and mitigate before constructing in the field.

 It’s important to review and mitigate risk throughout the project. Risk assessments can take on many different forms. Initially, the project should be reviewed by leadership to make sure it’s set up for success. The review should focus on scope, project risk, budget, schedule, and execution strategy.

Design quality in pharmaceutical facilities is crucial for meeting business, regulatory, and safety requirements. It involves producing technically correct design deliverables that adhere to codes and standards, ensuring coordination across disciplines. A robust Quality Management System (QMS) is essential, providing a framework for standardized processes and continuous improvement. Design reviews, including discipline checks, squad checks, and clash detection, are vital for maintaining quality. Poor design quality can lead to safety risks, financial losses, and reputational damage. Prioritizing design quality mitigates risks and ensures successful project outcomes.

Being fully versed on the ins and outs of design quality can improve the project design phase life cycle.  

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