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

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Accurate and timely analytics are essential to successful development and manufacturing of biopharmaceutical products, whether they are small-molecule drugs, recombinant proteins or antibodies, or novel modalities such as cell and gene therapies. The correct choice of analytical technologies for process monitoring and optimization during process development can reduce timelines and risk while increasing the ability to develop robust, readily scalable processes. Outsourcing of analytics to contract research organizations (CROs) with state-of-the-art capabilities, meanwhile, can help drug developers realize these goals in a cost-effective manner.

Business and technical drivers for analytical outsourcing

Outsourcing of analytics and testing often occurs for a combination of business and biological reasons, according to Alex Sargent, director of process development for cell and gene therapy at Charles River Laboratories, particularly in the case of complex, novel modalities. “For instance, it may be more cost-effective and efficient to outsource routine testing rather than investing in the space, equipment, and personnel needed to run a limited number of assays, making it more practical to rely on external providers,” he explains.

In addition to providing more cost-efficient and scalable solutions, CROs can also offer faster turnaround times to adapt to the needs of client projects as they advance from early development to commercialization, notes Jincui Huang, senior vice-president and head of the analytical sciences and clinical quality control department at WuXi Biologics.

Outsourcing analytics to CROs is also driven by the need for specialized expertise and advanced capabilities, Huang observes. “Many biotech companies recognize that developing and maintaining in-house systems for comprehensive analytics for process monitoring and optimization can be resource-intensive. By partnering with CROs, biotech and biopharma gain access to advanced technologies and methodologies that may not be available internally,” she says.

As an example, Sargent highlights bioinformatics and DNA/RNA sequencing for cell and gene therapies as technologies often accessed by developers through strategic partnerships with CROs.

The increase in outsourcing of biologics production for both drug substances and drug products to contract development and manufacturing organizations (CDMOs) is also leading to more analytics outsourcing, according to Elliott Franco, vice-president of lab operations at Alcami. “Many CDMOs have become true experts in process development and gain deep understanding of each process they work on through establishment of comprehensive analytical capabilities. That expertise allows for easy correlation of data trends to process parameters and thus efficient optimization of processes to maximize reliability and robustness,” he comments.

Increasing automation with room for improvement

Driven by the demand for greater efficiency and robustness in biologics development, automation in analytics is becoming increasingly prevalent among leading CROs. Areas of application can include, according to Huang, sampling, real-time monitoring, and data analysis.

Integrated automated sampling systems, Huang says, allow for collection of samples from both continuous and traditional fed-batch processes in real time without interrupting the processes. Inline process analytical technology (PAT) tools such as Raman spectroscopy and bio-capacitance measurement, meanwhile, when applied in upstream processes, offer real-time, high-frequency, and non-invasive analysis of the cell-culture process through corresponding chemometric algorithms, she observes. In downstream processing, online liquid chromatography with robotic systems offers high-throughput and near-real-time analysis for monitoring of product quality attributes during purification steps, according to Huang.

The ability to follow process milestones (protein concentration, cell densities, critical impurities, etc.) with online sampling/testing capabilities provides the type of data needed to truly understand critical process parameters, Franco agrees.

Advanced digital tools, meanwhile, are transforming the way analytical data are analyzed and used. “Digitalized auto-integration/analysis and predictive modeling help us develop methods in a more efficient way and identify potential risks earlier while continuously improving assay accuracy by analyzing historical and real-time data,” Huang explains.

Additional improvements in automated testing are still needed, however, particularly with respect to process development and optimization for newer modalities such as cell and gene therapies, Sargent contends. “The state of automation in analytics within the cell and gene therapy sector has room to grow, especially when compared to manufacturing,” she states.

In the past few years, there has been a surge of new technologies and platforms for the automated manufacturing of cell and gene therapies that have the potential to streamline operations, expand access, and significantly reduce costs, particularly for autologous therapies, Sargent notes. He believes, however, that, although equally important, automating analytics for process monitoring and testing during development and commercial production has been more challenging. “When talking about autologous cell therapies, for instance, there are thousands of independent batches generated every year, all of which require analytics for quality control and release. To effectively reduce the costs of these life-saving therapies, prioritizing the automation of testing will be critical,” he asserts.

Many benefits of automating outsourced analytics

There are, in fact, many ways in which automation of analytics at outsourcing partners can benefit biologic drug developers. “Automated analytics capabilities provide customers with several significant advantages, particularly when offered by service providers with robust experience in PAT and other automatic analytics technologies,” Huang says.

Specific benefits highlighted by Sargent include faster, more cost-efficient, and more accurate analytics compared to manual techniques. “Removing human error and bias can improve robustness and reproducibility, and outsourcing testing to a partner with automated capabilities can really help someone scale up or scale out their clinical or commercial program,” he remarks.

“In addition to allowing drug developers to avoid the need to make significant capital investments in expensive and complex technologies, automated solutions at CROs often speed up process development and scale-up while also enhancing the robustness of large-scale production by leveraging the CRO’s technical expertise and comprehensive data analytics capabilities,” Huang agrees. This support helps clients make informed decisions, optimize their processes, and ultimately achieve higher yields and better product quality.

“Overall,” concludes Franco, “use of automated analytics typically ensures that processes are well characterized and less likely to encounter failures to meet specifications with access to better and more comprehensive process data.”

There are some challenges to establishing comprehensive automated analytics capabilities, even for CROs serving large numbers of clients. “In general,” summarizes Franco, “establishing automation is costly and requires significant expertise at the interface of manufacturing, process development, and analytical development.”

Cost is often the first challenge when implementing automation for process monitoring and optimization, as the upfront investment to implement new analytical technologies in a process workflow can be significant, Sargent observes. “When transitioning from manual methods to automated systems, it is essential to demonstrate that the new method delivers equivalent readouts and results. For therapeutics developers, particularly those in advanced clinical or regulatory phases, implementing such changes may be impractical or even infeasible, despite potential improvements in throughput or robustness. It thus falls on the CRO to identify clients well-suited to automation and new technologies, particularly early-stage developers or those looking to transition to new platforms,” he comments.

Another issue highlighted by Huang that CROs must be able to overcome is the need to integrate new automation technologies with client-specific practices, as many clients use specific and diverse systems that require harmonization with automated platforms. Use of many different platforms, meanwhile, creates a need to consolidate data from multiple sources into a cohesive format for analysis, which can be complex, she notes. It is also essential to ensure automated systems meet stringent compliance standards, which requires robust validation. In addition, training staff and adapting workflows to incorporate automation can take time.

One strategy for overcoming these challenges, according to Huang, is through investment in advanced infrastructure, development of proprietary integration frameworks, and having a commitment to operational excellence.

Several exciting advances in automation and analytical technologies are increasing CRO capabilities in the field. First, Huang points to high-throughput automated platforms leveraging robotic systems capable of executing multiple assays simultaneously, which are improving productivity and reducing turnaround times.Many of these systems are designed to be end-to-end platforms, she adds. “The use [of] multiple robotic arms or automated guided vehicles to connect different modules can provide seamless end-to-end automation, from sample management, to analysis and reporting,” she explains. Bioreactors with embedded sensors and integrated advanced analytical systems, meanwhile, enable continuous monitoring of critical process parameters. “These innovations are critical for improving efficiency, scalability, and precision in biologics development,” Huang states.

In cell and gene therapy, the rapid advance of next-generation sequencing technologies and bioinformatics is, according to Sargent, having a transformative impact. Rather than years, hundreds of genomes can be sequenced in a week. Similar advances in transcriptomics, proteomics, and other comprehensive assays are equally important, he observes.

Across all biologics, Sargent believes that the implementation of machine learning and artificial intelligence (AI) in process monitoring and analytics systems is tremendously important. “We are only at the beginning of what AI can do in analytics and process monitoring, and the potential for how it may transform this space cannot be ignored,” Sargent remarks.

While automation in analytics is providing many benefits, limitations remain for CROs looking to maximize the opportunities that can be realized for their customers. Lack of standardization between different vendor systems remains a major issue in this regard, says Huang. “Industry efforts are required to establish open-source standards from software to hardware perspectives,” she notes. That should include development of next-generation technologies for effectively managing and interpreting the overwhelming amount of data generated by automated systems.

Huang would also like to see the development of modular automation solutions, which she believes could help smaller CROs overcome the challenge of high upfront expenditures currently associated with existing automated analytics systems.

Sargent emphasizes the need for more end-to-end analytics solutions for process monitoring. As an example, he points to flow cytometry, which is an essential tool in the cell and gene therapy space. “New advances in cytometers have improved throughput, removed human subjectivity, and automated crucial analysis workflows, but sample prep and staining remain laborious, manual tasks. Having an end-to-end automated solution for sample collection, storage, preparation, testing, and analysis will be key for future development, both for CROs and their customers,” Sargent says.

Automation of potency assays, including testing and analysis, is also needed. “These assays can be a major challenge using existing technologies. Automation and innovative methods/techniques will therefore likely prove critical to enabling a deeper understanding of biology and cellular responses, which will benefit everyone in the field, from academic researchers to drug developers and their outsourcing partners,” he concludes.

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

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Vol. 49, No. 1
January/February 2025
Pages: 26–28

When referring to this article, please cite it as Challener, C.A. Outsourcing Analytics for Process Monitoring and Optimization. 

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Outsourcing Analytics for Process Monitoring and Optimization

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The development and production of biologics can be a complex process. And the manufacture of biopharmaceuticals requires that processes be developed and validated so that product specifications can be met to create a safe and effective biologic drug. Steps can be taken at each stage of the development and manufacturing of biologics to ensure processes are optimized for the best results.

Sponsor companies often look to contract development and manufacturing organizations (CDMOs) to help with process development of these products. The following article provides advice and insight from experts and bio/pharma CDMOs on how process development can be optimized.

A scalable production system is necessary when considering how to optimize upstream processes, according to Daniel Giroux, vice-president of Biologics Development at Abzena. Typical large-scale systems range from using 500- to 2000-L bioreactors, and the scale can prevent experiments. “If you have a single, 2000-L reactor, you can’t run multiple experiments for optimization,” says Giroux. A small-scale system will be needed in which growth and production parameters of the larger-scale system can be reproduced.

After the small-scale model is created, a design-of-experiment (DoE) approach can be used to identify parameters that may impact the titer or the product quality. “You create a statistical experiment where you’re varying those parameters in combination and singly. And then you execute that experiment in parallel bioreactor systems, so a small-scale reactor where you have many of them,” Giroux explains. Statistical tools can then be used to pull data from DoEs and models to optimize input parameters to achieve maximal titers.

Process intensification is another approach Giroux points to, where higher cell densities are used at inoculation to increase the area under the cell density versus culture time curve. “You want your cell density to be high for a longer period of time,” Giroux says. “And by starting at a higher cell density, it lets you do that, and you basically get 50 to 100% more titer in an intensified fed batch process. That means, though, that you have to develop a perfusion process for your penultimate reactor, your last seed reactor, so that you can actually have enough cells to inoculate your production systems at these higher densities.”

According to Paul Mugford, director, Biologics Process Development at BIOVECTRA, media optimization is an important part of upstream processing, especially in microbial fermentation. Media should be formulated to support optimal growth and productivity of the microorganism, says Mugford, which includes optimizing carbon and nitrogen sources, trace metals, vitamins, and other supplements. “All media components, of course, have to be animal free,” says Mugford. “And we also choose to start our process development with representative materials that will be used at large scale. These are raw materials that meet all the required GMP [good manufacturing practice] requirements, so there’s no issues transferring from small to large scale with respect to materials.”

Other areas that can be optimized are process parameters such as temperature(s), pH, dissolved oxygen, and feed rates. These can be optimized using DoE, Mugford points out. Early screening of equipment is used for initial optimization with shake flasks or higher throughput microtiter plate format.

“Once the initial screening is done, we would then move into our smallest fermenters, which are the Amber250 parallel reactor system, or our Dagsip system, where each one of those systems can run eight fermentations in parallel for further optimization of media and feeding,” explains Mugford. “And our goal here is to maximize the growth and also the productivity, so we monitor the process extensively for the carbon source (glucose or glycerol), acetate, ammonia, CO

, and use [these] data for further optimization. After that, we’d move into our larger fermenters, such as the 10-L and 50-L fermentor before scale up.”

When looking at viral-vector-based gene therapy products, larger and better-quality virus yields can be the result of optimizing upstream processes. “In cell therapy, the key is to scale up to gain higher cell yields while still maintaining the cell morphology and the genetic stability of the cells, so that it’s the same at small scale and large scale,” says Bob Schrock, PhD, senior director, Global Head of Process Development, at Lonza Group AG.

“And [for] viral vectors, keeping [the cells] happy and in culture[s] at bigger scales, larger scales, maintaining that all important yield of the number of virus per cell, [and] making sure that that stays similar the bigger, the larger and larger vessels you go up to, [is important],” Schrock explains. Multiplicity of infection (MOI), plasmid ratios, transduction amounts, and when to harvest after transduction are other parameters that need to be taken into consideration for viral vectors, says Schrock.

Passage number studies are also important. “Cells can change after multiple passages, and that can introduce variability into your process,” stresses Schrock. “So, you want to make sure that the conclusions you reached within a cell passage of 50 are the same as it is at a cell passage of 100 or whatever constraints you put in there for your minimum and maximum cell passage numbers. So, you don’t want to forget to do that as well to make sure that your process can handle cells at a variety of different passage numbers.”

Optimization of process development for cell culture is dependent on the type of product being produced, according to Schrock. Scale and purity are two important factors to consider as well if the product is cell based or single cell.

To optimize a cell culture process, the parameters that need to be optimized must be defined, says Giroux, either titer, product quality, or both. In addition, assays should be in place to identify target product quality parameters. “Typically, for product quality, we’re looking at glycosylation patterns on proteins to make sure that they are correct, or in the case of a biosimilar, that they match the originator,” Giroux says. One must then vary input parameters, both individually and in combination, and then measure their effect on productivity and product quality.

When it comes to performing process studies for cell culture, Giroux says parameters that vary in DoE studies include choice of basal medium and concentrated feeds. For fed-batch processes, parameters include choice of additives and trace elements, cush as minerals, trace metals, vitamins, anti-foam and anti-clumping agents, and surfactants.

“We then also vary or look at temperature, especially shifting the temperature. So, we typically start our productions at 37 degrees, or 36 and a half. But sometimes you get better productivity in a longer culture duration if you reduce the temperature part-way into the run to perhaps 32 degrees or 34 degrees,” explains Giroux. “But we could study that the effect of pH on productivity is assessed as well [as] agitation, and then again, [at the start] cell density can have an impact, and that’s whether it be an intensified process or not. Sometimes there’s an optimal cell density even at non frame, non-intensified process.”

“So, those are the types of parameters that we’re studying, but we generally [are] studying them in these design of experiments approaches where we can vary them in combinatorial fashion and understand the effects of the parameters individually, but also in combination with the other parameters,” Giroux continues. “So, for example, if a parameter affects your cell density, you may need higher feeds. So, a parameter that you know can’t be optimized by itself [has] to be optimized as a family.”

Schrock says it’s important to close open manual process steps to reduce contamination risks and the cost of production by reducing the required grade of the GMP production clean room (i.e., grade C cleanrooms are cheaper to maintain than grade B). Process automation for equipment and perfusion is also important, says Schrock.

“One really great example of this is the Lonza Cocoon Instrument. This is both a functionally closed system as well as automated system for manufacture of autologous cell therapies. This is a really good example of doing both automation as well as closing the process. Once you have a closed process, you move to optimizing parameters … things like pH, dissolved oxygen, agitation, speeds, gasses, and even temperatures, sometimes in certain viral vector types,” Schrock concludes.

Quality considerations, such as regulatory guideline requirements and critical quality attributes, play a role in the design and optimization of fermentation processes, according to Mugford. First, one should decide on which microbial strain to use, depending on what type of product is being produced, because each biologic has unique strain requirements. According to Mugford, engineered Escherichia coli (E. Coli) strains provide optimal performance for recombinant proteins or plasmid DNA.

“Considerations in strain selection include the protein solubility, whether or not you get correct folding, the expression location, [and] if the target protein is in the cytoplasm or the periplasm,” says Mugford. “And there’s also modified strains that allow to correct for any codon bias or disulfide bond formation. So, selecting the appropriate strain is important up front.”

The design of the plasmid is also important for protein production, says Mugford, specifically selection of the promoter to tightly control expression of genes that encode proteins. Productivity can also be improved by codon optimization of the gene of interest and removing non-essential plasmid elements, according to Mugford. “And also, you may want tunable expression in cases where inclusion bodies are formed for the protein. [Y]ou may want to express the protein slower to minimize inclusion body formation.”

Plasmid DNA products have other challenges that require attention paid to strain selection, and plasmid design, according to Mugford. Plasmid stability can be enhanced, and endonuclease activity can be reduced due to the mutations E. coli strains designed for plasmids production. A high copy number plasmid is therefore used to maximize productivity. Mugford recommends the use of a fragment analyzer to assess clones in order to select the most appropriate to produce high-quality plasmid DNA.

“One of the challenges we’ve seen in the plasmid DNA area is when you have repetitive elements in the plasmid,” says Mugford. “Long poly(A) tails are quite common in plasmids destined for in-vitro transcription to make mRNA [messenger RNA]-based therapeutics like the COVID vaccines. Long poly(A) tails are prone to recombination events, and this can give some plasmid instability and shorten the length of the poly(A) tail leading to different length products. That affects the integrity of the plasmid. An efficient clone selection process for plasmid DNA can identify clones with a single, correct length polyA tail. Another important quality parameter in plasmid DNA is the super cooling, which is an indication of how much damage has been done to the plasmid.”

The next step in optimization of microbial fermentation is setting the fermentation parameters, such as media optimization, feed rates, and other setting to ensure scalability, says Mugford. Small-scale production needs to be able to transfer to large-scale parameters.

“[A]t the early development scale, our smallest fermentors are the 250-mL Amber fermentors for condition screening. These increase to fermentors in the 10 to 50-L range in process development, and [then up to] 200-L scale at the pilot stage. At the manufacturing scale, we can scale up to our 100-L and 1000-L single-use fermentors, or our 3000-L and two, 17,000 -L stainless-steel fermentors for microbial fermentation. To go from the smallest scale to the largest scale, one of the most important parameters is the oxygen transfer coefficient (kLa). Our chemical engineers have developed models to scale up and down while reproducing the same growth rates, and providing consistent results across scales.”

Mugford recommends single-use fermenters for their ability to quickly transition between products and reducing cleaning and testing. He also points to heat transfer as an important parameter for scale up, specifically during aggressive microbial growth. “With rapid growth in E. coli, there’s a lot of heat produced. [U]nderstanding the oxygen transfer rate for the fermenters and the cooling capacities is important when moving from small to large scale,” Mugford says. “[T]here are a lot of scale-independent parameters that can also be evaluated directly using DoE at the process development [stage].”

One way to harvest cells in a bioreactor, according to Giroux, is to use depth filtration, which involves a multi-stage depth filter followed by membrane filters that remove the cells. Large surface areas are required; therefore, producing a lot of waste. “Especially at the large scale, they’re troublesome to install and remove and so on. So, the setup time is difficult to remove,” Giroux warns. He points to continuous centrifugation as a better approach, which often uses a single-use disk stack centrifuge to extract the cells and dense components from the media.

“[We] don’t lose very much of the liquid itself [with continuous centrifugation]. So, you get a pretty thick slurry of cells that comes out. It might be 80% cell mass and about 20% media,” says Giroux. “For example, if you had 8% packed cell volume in your reactor, you could basically remove only 2%; you’d remove your 8% cells and then 2% of the media. So, your yield would actually be very high. You generally follow that with a very small area depth filter, sometimes even a specialized depth filter that’s designed to remove any additional cells. These filters can be slightly charged, and they help to remove debris as well.”

Choosing the correct scale-down equipment is important at process scale so that representative material is generated for filtration, inclusion body refolding, and downstream processing steps, says Mugford. For harvesting recombinant protein in E. coli, disc stack centrifuges are often used. A key parameter used in centrifuge scaling and performance evaluation is the Q/Sigma factor, which represents the flowrate (Q) and the sigma factor (Σ), according to Mugford. “This represents the relationship between the flow rate Q to the sigma factor, which is the equivalent settling area for a given centrifuge,” he says. “It’s a fixed number for each type of centrifuge, from small to large scale, and we find this is the most reliable parameter for scaling the centrifuge harvest.”

“To optimize this step, you would typically look at the percent solids in the input, the flow rate and discharge interval, and the bowl safety factor,” Mugford explains. “Those are important parameters and measurements. And you would monitor the turbidity of the centrate as a key metric of how well the clarification is going. The percent solids is a key metric if they will be carried forward, as in cases where the product is located within the cells.”

Because plasmid DNA is sensitive to shear, it requires a different approach for harvesting. During the discharges of the centrifuge, some damage can occur to the plasmid DNA, resulting in a reduced percentage supercoiling, stresses Mugford. He points to tangential flow filtration (TFF) as a better approach for plasmid DNA harvesting. Mugford says that optimizing the TFF requires selecting the appropriate cassette type (the micron/molecular weight size of the cassette).

“Typically, you would use an open channel cassette. You need to determine the loading, so liters per meter squared for the cassette and the flux rate,” says Mugford. “So, an advantage of the TFF harvest is that the cells can be washed during filtration, so this removes any spent media and some other impurities, which gives you a cleaner product into downstream processing. After this, you would typically go into clarification with a series of depth filters followed by cell lysis. For the lysis of cells containing proteins, you would typically use a high-pressure homogenization. Because plasmid DNA is shear sensitive, we developed a different method [in collaboration with Sartorius], using a chemical lysis in a continuous flow reactor to give a mild lysis and preserve quality through the midstream steps, allowing us to extract the plasmid DNA without doing any damage to it.”

The complex nature of biologics development and product offers a variety of ways in which companies can maximize their efforts and produce safe and effective medications. CDMOs and other contract organizations can provide sponsor companies with the expertise and infrastructure to streamline these complex processes. Planning ahead and using the correct parameters and approaches can ensure a cost-effective process.

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Vol. 49, No. 1
January/February 2025
Pages: 31–33

When referring to this article, please cite it as Haigney, S. Steps to Process Development Optimization. 

The optimization of processes for the development and manufacture of biopharmaceuticals is pivotal for producing quality products. 

Steps to Process Development Optimization

Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

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Saying the combined issues of drugs—namely fentanyl—and illegal immigration constituted an “extraordinary threat” and national emergency in the United States, the Trump Administration announced on Feb. 1, 2025 an implementation of 25% additional tariffs on imports from Canada and Mexico, and a 10% additional tariff on imports from China (1).

But some of those enactments were delayed after President Donald Trump, on February 3, agreed to a 30-day pause with respect to Canada and Mexico when both countries said they would negotiate with the United States about how best to combat the problems Trump is prioritizing, according to the 

also reported that China’s response was not as conciliatory, with that country announcing retaliatory tariffs against the US as well as an antitrust investigation into Google (3).

Whatever the eventual outcome, the administration’s fact sheet on the proposed tariffs listed the overcrowding of hospitals as a residual effect of illegal immigration, and holds both Mexico and Canada responsible for funneling international narcotics distribution through the US (1). Those justifications, however, have not kept the pharmaceutical industry from speculating on the possible consequences of the penalties.

The Brookings Institution, a Washington, D.C.-based nonprofit research firm, predicts that if the 25% tariffs on Canada and Mexico wind up being imposed by the US, pharmaceutical exports from Mexico could fall by 61% (4). Should Canada and Mexico enact retaliatory tariffs, as China has done, Brookings estimates the dropoff to climb to 72%. And the Council on Foreign Relations calculated that US exports of vaccines, blood antisera, toxins, and cultures could collectively be one of the top five export categories most affected by the tariff “war,” to the tune of $5 billion in exports to China, $2 billion to Canada, $994 million to Mexico, and $41 billion to the rest of the world (5).

“We are concerned about the unintended, adverse consequences [the tariffs] may have on the cost of medicines in the US,” Susan A. Cantrell, CEO of the Academy of Managed Care Pharmacy, said on February 3 (6). “Many critical medications and raw materials are sourced internationally, and imposing tariffs risks driving up prices, creating supply disruptions, and impeding patient access to essential treatments.”

John Murphy III, president and CEO of the Association for Accessible Medicines, said drug shortages are already problematic, and that that challenge could continue to grow (7).

“Generic[-drug] manufacturers simply can’t absorb new costs. Our manufacturers sell at an extremely low price, sometimes at a loss, and are increasingly forced to exit markets where they are underwater,” Murphy said. “The overall value of all generic sales in the US has gone down by $6.4 billion in five years despite growth in volume and new generic launches. Tariffs would make this much worse.”

“We respectfully urge caution on instituting tariffs on sectors that will impact medical products,” the Healthcare Distribution Alliance said in a statement (8). “Accordingly, we ask the administration to consider establishing exemptions for pharmaceutical products and long implementation timelines.”

Meanwhile, the 13 Democratic members of the US Senate Finance Committee sent a letter on Jan. 30, 2025 to Department of Health and Human Services Secretary nominee Robert F. Kennedy Jr., asking him not to pause Medicare drug price negotiations, as leading pharmaceutical CEOs have requested (9).

“Medicare drug price negotiation is a powerful tool available right now to President Trump to make good on his long-standing promise to stand up to Big Pharma,” the senators wrote. “On behalf of the tens of millions of Americans who count on Medicare, Democrats on the Senate Finance Committee want to know whether the Trump Administration will follow through.”

1. The White House. Fact Sheet: President Donald J. Trump Imposes Tariffs on Imports from Canada, Mexico and China. 

, Feb. 1, 2025 (accessed Feb. 4, 2025).
2. Boak, J.; Sánchez, F.; and Gillies, R. Trump Agrees to Pause Tariffs on Canada and Mexico After They Pledge to Boost Border Enforcement. 

, Feb. 3, 2025 (accessed Feb. 4, 2025).
3. Moritsugu, K. and Wu, H. China Counters with Tariffs on US Products. It Will Also Investigate Google. 

, Feb. 4, 2025.
4. Meltzer, J. P. Trump’s 25% Tariffs on Canada and Mexico Will Be a Blow to All Three Economies. 

, Feb. 3, 2025 (accessed Feb. 4, 2025).
5. O’Neil, S. K. and Huesa, J. What Trump’s Trade War Would Mean, in Nine Charts. 

, Feb. 1, 2025 (accessed Feb. 4, 2025).
6. Academy of Managed Care Pharmacy. Statement from AMCP CEO Susan A. Cantrell on President Trump’s New Tariffs. Press Release. Feb. 3, 2025.
7. Association for Accessible Medicines. Association for Accessible Medicines Comments on New Tariffs. Press Release. Feb. 2, 2025.
8. Healthcare Distribution Alliance. HDA Statement on Proposed Tariffs of Pharmaceutical Products. Press Release. Feb. 2, 2025.
9. United States Senate Committee on Finance. Wyden, Finance Democrats Press RFK Jr. to Reject Big Pharma Pause on Medicare Negotiation. Press Release. Jan. 30, 2025.

The tariffs President Trump wants to levy against Canada and Mexico are on hold, for now, but China has already announced it intends to proceed with retaliatory tariffs against the US.

Pharmaceutical Industry Responds to Proposed Trump Administration Tariffs

Feliza Mirasol is the science editor for 

3d rendering of Antibody drug conjugates (ADCs) are targeted medicines that deliver chemotherapy agents to cancer cells | Image Credit: © Love Employee - stock.adobe.com

*Editor's note: article updated on March 3, 2025 to fix typographical errors.

Following a long road to success with antibody-drug conjugates (ADCs), developers today are seeing regulatory approvals for ADCs as a more common occurrence. Better success in the current environment is largely due to technology improvements that have helped minimize risk and enhance therapeutic efficacy for these complicated drugs. However, the manufacturing of ADCs remains a complex process, involving requirements for both the large-molecule and small-molecule components. The linker technology joining the two pieces also has its own requirements. Because of their manufacturing complexity, ADC development and production increasingly requires outsourcing services.

Three major challenges for drug developers trying to bring ADCs to market include lack of capacity, lack of expertise in scaling up, and the complexity of the supply chain, notes Christian Morello, vice-president and head of the Bioconjugates Business Unit at Lonza.

In looking at the overall dynamic of innovation in the ADC space, the majority of innovation is coming from small biotech companies, and those companies are not necessarily well equipped with the internal capacity to produce the product, Morello points out. “There is also a lack of knowledge about the industrialization and the scale up of ADCs,” he says. “And [there is also] the complexity of the supply chain; Indeed [we] within the bioconjugate field, we are bringing different pieces, like a puzzle, to produce the drug substance. It implies [much] complexity [and requires] management of different sourcing in order to make it happen.”

These challenges are what ADC developers have to face and overcome to produce clinical supply or commercial supply, Morello emphasizes. “This is where CDMOs [contract development and manufacturing organizations] bring a lot of benefit, because we have [experience with] different modalities. [Especially at Lonza,] we’re totally integrated, so we offer fully integrated services to make it happen and to accelerate [the developer’s] path to commercialization,” Morello says.

ADCs have unique manufacturing requirements, which is part of their complexity. “With ADC specificity, we are merging two worlds,” explains Morello. “We are merging the water and the solvent, the biologic and the chemistry. So, with this integration of two worlds, it requires specific skills.” Morello also cautions carefulness when dealing with the risks associated with the chemistry involved in ADC manufacture. “You need to take care about potential explosion or flammable risk associated [with] the chemistry, but you also need to take care about the potential contamination due to microbes if you’re not working with adequate procedure for clean environment. So, the operating model is very specific.”

The science of ADCs has evolved significantly over the past 20 years, Morello also points out. Many improvements can be seen in the carrier component (protein or peptide), the linker component, and the payload, all of which makes the conjugation technology more complex.

“There have been a lot of new developments in terms of conjugation and linker technologies,” agrees Nicolas Camper, senior director, Bioconjugation, at Abzena. “There is a definitive move towards site-specific conjugation technologies and away from stochastic conjugation approaches that allows [us] to prepare better-defined antibody-[drug] conjugates,” he says.

Camper also points out another new development that he’s observed over the past few years, which is that linker technology is becoming more sophisticated. “Quite often, when you conjugate cytotoxic drugs, they are quite hydrophobic, and that can impact the performance of your ADC. So, there has been a lot of effort put into developing more hydrophilic linkers,” he explains.

Another noticeable advancement has been in the development of branch linkers. These branch linkers give some options for preparing the ADC and modulating the drug loading. “[T]hat is something relatively new and should have an impact on the performance of ADCs and ultimately result in better ADCs and more programs,” he says.

Technological gaps are one area of unmet need in the ADC space. In Lonza’s case, the CDMO realized it needed a certain technology that would be valuable to its customers, which prompted it to acquire the Netherlands-based Synaffix in 2023 (1). Morello explains that the technology Synaffix brings offers a new way to do the conjugation “where we are connecting the linker at the glycan location on the mAb.”

“That is something that no one else has,” Morello emphasizes. This technology specifically addresses the challenge of how to manage the number of linkers and payload that can be connected to the carrier, the mAb. “So, it brings some solution to address the needs the customer has,” he says.

Morello also notes that Lonza is following the evolution of conjugation technology day-to-day to be able to capture new technologies and bring the best solutions to customers. “We have also created a toolbox [where we] identify very innovative companies/technology outside, bring them into the [Lonza] network, and identify where the customer may require this type of support, and then facilitating, connecting this technology at an early stage,” Morello states.

“When it is confirmed that [a] molecule is really interesting … then [we use] our ability to … master this very breakthrough technology [and bring it] into an industrial and GMP [good manufacturing practice] environment and to scale up this technology to support Phase I, Phase II, or Phase III [development], and then, later on, [scale up to] the commercialization of the drug,” Morello says.

ADC development has a robust future with much potential. Camper points out an important aspect currently driving ADC development: diversification. “I think that we’ve seen a lot of diversification. That’s a key word. The increased diversity can be noticed in the targeting moiety. Smaller targeting fragments, which allow for better penetration into the tumors, are being developed as targeting moieties; that can be nanobodies or fat fragments,” he explains.

“There is also diversity which is encompassed in the use of bispecific antibodies. They allow for targeting more selectively cancer cells,” Camper says. Camper also notes that there is a lot of diversity today in the payloads. “Traditionally, they were cytotoxic payloads, but, now, people are revisiting all potent small molecules, such as potent kinase inhibitors or payloads that have radically different mechanisms of action, such as molecular glues or PROTACs [proteolysis-targeting chimeras].”

Camper additionally observes how, in the past few years, there has been development of bioconjugates outside the area of oncology. “There are lots of antibody-drug conjugates being developed for the treatment of inflammation, for instance, or—something which is extremely hot at the moment—the development of antibody oligonucleotide conjugates for the treatment of genetic disorders,” he states. “Having access to more complex and linked payloads and conjugation technologies—more advanced conjugation technologies—that definitely results in better therapeutic profiles for antibody-drug conjugates, and we’ll see more and more of those in the future.”

“The technology is now at the level of maturity that enable a lot of different things,” adds Morello. For instance, going back to Lonza’s Synaffix acquisition, Synaffix presents another type of linker technology in which the developer can define how many payloads it wants to have per mAb. “That is another possibility that will enable [the developer] to fine tune the benefits/risk ratio for the patient,” Morello states. “We can see [that] today for some cytotoxic compounds for oncology, for sure, but we also have radiolabeled compounds to facilitate diagnosis. [This is] also oncology treatment, but with a different approach.”

“We have nucleotide and mRNA [messenger RNA] that are more and more used for some applications. We have polysaccharides that are also used as a vaccine. So, the applications associated with bioconjugation is much broader than it was in the past,” Morello says.

In addition, Morello points out, when looking at the overall portfolio of clinical trials that are ongoing in the bioconjugates field, half of them is associated with oncology applications and the other half is associated with non-oncology products. The ability to tackle different type of disease is one clear direction where ADC development is heading. Another area is having the ability to improve the benefits/risk ratio to decrease side effects, particularly in oncology, while increasing efficiency. Being able to target a specific ratio of linker to payload to mAb is also an interesting area, he adds. 

“Last but not least is the ability to simplify the process, again, through more integration,” Morello states. “We will need to accelerate the time to market and will accelerate, as well, the time to commercialization.”

1. Lonza. Lonza to Acquire Synaffix and Strengthen Antibody-Drug Conjugates Offering. Press Release. June 1, 2023.

®
Vol. 49, No. 1
January/February 2025
Pages: 29–30

When referring to this article, please cite it as Mirasol, F. Advancing ADCs to the Next Level. 

CDMOs who have integrated technologies can help further the advancement of ADC development.

Advancing ADCs to the Next Level

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Facility Monitoring Systems (FMS), a contamination control solutions provider based in Malvern, United Kingdom, announced on Feb. 3, 2025 that it has joined the calibration services company Trescal. In a company press release, the transaction is referred to as a “strategic acquisition” by Trescal of FMS (1).

“Becoming part of the Trescal family is a transformative opportunity for FMS,” Deborah Haisman, FMS commercial director, said in the press release (1). “We are proud of our strong reputation and the trust our customers place in us. Working with Trescal’s experts and calibration solutions will allow us to enhance our services, expand our reach, and deliver even greater value to our customers in all contamination control sectors in the UK and Ireland.”

Among the benefits FMS said the new partnership would provide to customers in the UK and Ireland are expanded resources and service capabilities, cutting-edge cleanroom contamination control solutions, and a stronger commitment to customer support (1). While FMS has specialized in the design, installation, and maintenance of environmental monitoring systems, Trescal’s focus has been on calibration and metrology services.

“By bringing FMS into the Trescal family, we are boosting our capabilities and strengthening our commitment to serving highly regulated industries,” Karolina Lachi-Kolarova, managing director of Trescal in the UK, Ireland, and Norway, said in the release. “The complementary skills and experience of the two companies is a powerful asset to our global business.”

Astech Ltd is the strategic partner to FMS in Ireland and will continue to be a direct interface for customers in the Irish market, according to the release (1). TSI Inc., of Shoreview, Minn., in the United States, has endorsed the transaction; TSI is a longtime principal to FMS, the Gold Channel Partner for TSI’s contamination products in the UK and Ireland.

“We are confident that its integration with Trescal will unlock new opportunities for innovation and growth,” Simon Tebb, Europe, Middle East and Africa sales manager for Controlled Environments at TSI, said in the release. “TSI looks forward to continuing our collaboration with FMS as part of Trescal to advance contamination control technologies in the UK and Ireland.”

This transaction is just one of several mergers and acquisitions that have been announced so far in 2025. On January 7, Molex, the parent company of Phillips Medisize, said it had 

completed an acquisition of Vectura Group

Telix Pharmaceuticals entered into an asset purchase agreement

 with ImaginAb for a pipeline of next-generation therapeutic candidates, a proprietary and novel biologics technology platform, and a protein engineering and discovery research facility (3). And on January 28, 

 it was acquiring the clinical stage radiopharmaceutical contract development and manufacturing organization Evergreen Theragnostics (4).

1. Facility Monitoring Systems. FMS Acquired by Trescal, Driving Growth and Innovation in the Contamination Control Industry. Press Release. Feb. 3, 2025.
2. Phillips Medisize. Phillips Medisize Expands Its Inhalation Drug Delivery Capabilities. Press Release. Jan. 7, 2025.
3. Telix Pharmaceuticals. Telix to Acquire Next-Generation Therapeutic Assets and Innovative Biologics Technology Platform. Press Release. Jan. 13, 2025.
4. Lantheus. Lantheus to Acquire Evergreen Theragnostics for Upfront Payment of $250 Million to Drive Strategic Evolution into Fully Integrated Radiopharmaceutical Leader. Press Release. Jan. 28, 2025.

While FMS has specialized in the design, installation, and maintenance of environmental monitoring systems, Trescal’s focus has been on calibration and metrology services.

Trescal Acquires Facility Monitoring Systems to Bolster UK Contamination Control Services Market

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Alvogen announced on Jan. 31, 2025 that it is voluntarily recalling one lot of Fentanyl Transdermal System 25 mcg/h transdermal patches because of the potential of multi-stacked patches. It is possible the patches, which were manufactured by Kindeva Drug Delivery, are adhered one on top of the other in a single product pouch. The recalled lot, Lot 108319, 25 mcg/h, has an expiration date of 04/2027 and was distributed nationwide (1).

Fentanyl Transdermal System 25 mcg/h transdermal patches are used to manage severe and persistent pain in opioid-tolerant patients for an extended treatment period with a daily opioid analgesic, and for patients who don’t respond well enough to alternative treatment options. According to Alvogen, application of multi-stacked patches could cause serious or fatal respiratory depression, especially in first-time recipients, children, and the elderly.

While the company has not received any reports of adverse events related to the recalled product, as of the date of the press release, adverse events can be reported to FDA via its 

MedWatch Adverse Event Reporting program.

Final inspection of a product is essential in reducing recalls and ensuring the safety of drug products. In an episode of 

 series, Dirk Margosch, vice president Visual Inspection, Assembly & Secondary Packaging at Vetter Pharma-Fertigung GmbH & Co KG, 

 to mitigate risk in future batches of vials during secondary packaging after defective units have been found during an inspection (2). A thorough investigation should be performed to discover the root cause of the defects to prevent future occurrences.

“This [investigation] should involve reviewing all processes related to production. That means aseptic filling, visual inspection, assembly and secondary packaging, of course, always including the relevant packaging components. And then second, define the right preventive action, if the investigation comes, for example, to the conclusion that the defective vials were already present after the filling,” says Margosch.

Recalls are a factor in drug shortages, which can lead to patients not getting the medicines they need. Both FDA and the European Medicines Agency (EMA) have initiatives to monitor drug shortages that require manufacturers to provide information to regulators about things like product recalls and quality problems that might impact the availability of a drug. In January 2025, EMA announced the European Shortages Monitoring Platform is fully functional. This tool was created for marketing authorization holders and national competent authorities to directly report information about the supply, demand, and availability of authorized medicines to EMA during crises situations (3).

FDA. Alvogen Issues Voluntary Nationwide Recall for One Lot of Fentanyl Transdermal System 25 mcg/h Due to a Defective Delivery System. Press Release. Jan. 31, 2024.

Haigney, S. and Thomas, F. Ask the Expert: Product Inspection, Part One; Risk Mitigation in Secondary Packaging. 

https://www.pharmtech.com/view/ask-the-expert-product-inspection-part-one-risk-mitigation-in-secondary-packaging

EMA. European Shortages Monitoring Platform Fully Operational for Monitoring of Shortages in the EU. Press Release. Jan. 29, 2025.

The company is recalling one lot of Fentanyl Transdermal System 25 mcg/h transdermal patches because of possible multi-stacking of patches.

Alvogen Recalls Fentanyl Transdermal System

Cheryl Barton is director of PharmaVision, 

On 1 Jan. 2025, the European Medicines Agency (EMA) introduced a new legal framework, fees, and charges for its regulatory activities and services to medicine developers (1). The New Fee Regulation (NFR) is governed by Regulation (EU) 2024/568 which amended Regulations (EU) 2017/745 and (EU) 2022/123 of the European Parliament and the Council (EPC) and repealed Regulation (EU) No 658/2014 and Regulation (EC) No 297/95 (2–5).

Since the EMA became operational in 1995, it has depended on “fees payable” to offset the cost incurred for providing a range of activities and services listed in the Council Regulation (EC) No 297/95. EMA and the National Competent Authorities (NCA) need to receive efficient funding to carry on their activities and “ensure an efficient, responsive, and innovative regulatory system in Europe for human and veterinary medicines,” according to Jean-Michel Mastio, head of the Finance Department at EMA (6). The EMA budget is currently around €0.5 billion, and a large part of this budget is used to support the NCAs; more than 95% of the budget is generated from fees, and the remainder is contributed by the European Union (EU).

The fees were introduced in 1995 and recognize 23 different basic procedural fees including those associated with applications for certificates, marketing authorization applications (MAA), scientific advice (SA), inspections, as well as supplemental authorization of additional strengths and pharmaceutical forms (7). Other fee-related regulations include Regulation (EU) No 658/2014 regarding pharmacovigilance inspection activities, and Regulation (EC) No 2049/2005 for reduced fees associated with non-orphan medicinal products submitted by small and medium-sized businesses (SMEs), medicinal products with orphan designation (OD) or paediatric use, advanced therapy medicinal products (ATMPs), and medicinal products for preparedness against biological agents (8–11).

Since 2015, the European Commission (EC) has been working on reviewing the EMA fee system. The EMA’s user fee system was evaluated in 2019 to assess if the fees were in alignment with the underlying activity cost of the EMA and NCAs, to identify areas for improvement, and to reduce the complexity of the fee system (12). EMA previously amended fees in 1999 and 2005 to ensure there was adequate provision for the services it provides. Fees increase on an annual basis to adjust for inflation, with the last adjustment having been published in April 2022, which resulted in an increase in the fee level by 0.3% for 2020 and 5.3% for 2021 (13).

In December 2022, the EC published a proposal for the revised EMA Fee Regulation, and the EPC agreed on the revised EMA Fee Regulation in September 2023. It was adopted and formally published on 7 Feb. 2024 (6). In 2024, EMA published a working arrangements document that clarified the requirements and terminology of the new regulation, established fee reductions for certain types of services, and provided further details on payment modalities; the working arrangements were adopted by EMA’s Management Board in June 2024 (11). The key principles and objectives for the NFR are: harmonization, flexibility, alignment, and sustainability. The new fees are “proportionate” instead of the previous “standard” or flat-rate fees.

The provisions outlined in Regulation (EU) 2024/568 will apply to all requests validated and starting in January 2025 and will impact human and veterinary medicines. A few examples of the new fees compared with previous fees (2024) are summarized in 

 (14). Applications with OD or drugs for use in paediatrics will be exempt from fees; however, there are some special circumstances where administrative fees will be applicable. Namely, if an applicant submits the application and withdraws it after 24 hours or EMA rejects the application during the validation phase (15). If an applicant applies for certificates, parallel distribution, or SA, EMA will issue an invoice, and once the payment is received it will deliver the service. The application will be cancelled if EMA does not receive payment within 30 days (15).

A few examples of fees payable under New Fee Regulation (NFR) versus previous regulation. MAA is marketing authorization applications.

For veterinary medicine, EMA has adopted a single framework to deliver a streamlined fee system, and the fees payable to EMA will be proportionate to the work carried out based on the complex evaluation, workload, and actual costs for the services delivered by EMA and NCA (6). The key changes to the fee regulations for veterinary medicines are summarized in 

. EMA will charge a fee for certificates, SA, and MAAs, and the amount payable will be dependent on the type of active substance (i.e., new active substance or known active substance). The fee will be calculated after the submission of the application in conjunction with the related fee reductions. For more details, see Annex I, Section 2, or Annex II, Section 1, of the Fee Regulation and Chapter 1.1 of the Fee Regulation Working Arrangements (11,16,17).

High-level changes to fees based on new fee regulation from 1 Jan. 2025.

Overhauling of the EMA fees legislation is long overdue and should provide EMA and NCAs with sufficient funds to ensure they can continue to deliver high-quality services and adapt to future market demands. The simplified proportionate fee structure should be easier to navigate but may lead to significant increases in the fees payable for medicine developers particularly when obtaining or maintaining MAAs from January 2025 onwards (14).

1. EMA. Fees Payable to the European Medicines Agency. 

. 1 Jan. 2025.
2. EMA. Regulation (EU) 2024/568. 

. 4 Feb. 2024.
3. EMA. Regulations (EU) 2017/745. 

. 5 April 2017.
4. EMA. Regulation (EU) 2022/123. 

. 25 Jan. 2022.
5. EMA. Regulation (EU) No 658/2014. 

. 15 May 2014.
6. EMA. New Fee Regulation. Webinar. 20 June 2024.
7. EMA. Council Regulation (EC) No 297/95. 

. 10 Feb 1995.
8. EMA. Regulation (EU) No 658/2014. 

. 15 May 2014.
9. EMA. Regulation (EC) No 2049/2005. 

. 15 Dec. 2005.
10. EMA. Regulation (EC) No 141/2000. 

. 22 Jan. 2000.
11. EMA. Fee Regulation working arrangement. 

. 13 June 2024.
12. EC. Evaluation of the European Medicine Agency’s Fee System. 18 Sep. 2019.
13. AgencyIQ. What You Need to Know about the Status of the Proposed EMA Fees Regulation. 

. 3 Nov. 2023.
14. DLCR. EMA Updated Fees: What Does This Mean for My Applications? 9 Aug. 2024.
15. Vignol, C. EMA – New Fee Regulation (NFR). RPN Group.com. 9 Aug. 2024.
16. EMA. Annex I to Regulation (EU) 2024/568; Q&As. 

. 14 Nov. 2024.
17. EMA. Annex II to Regulation (EU) 2024/568; Q&As. 

Cheryl Barton is director of Pharmavision, info@pharmavision.co.uk.


Vol. 37, No. 1
January/February 2025
Pages: 6–7

When referring to this article, please cite it as Barton, C. Introducing a New Legal Framework, Fees, and Charges. 

EMA introduced its New Fee Regulation in January 2025, but what impact will the new fees and charges have on medicine developers? 

Introducing a New Legal Framework, Fees, and Charges

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

Bio/pharma companies have a lot to consider when tackling social media communications, especially within Europe.

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