The multi-product facility, which doubles Rentschler Biopharma’s global cGMP capacity, is focusing mainly on commercial production of highly complex molecules. The original Milford site went from a single-product commercial facility to producing multiple products in an up to 500L bioreactor setup.

The new production line has added 22,000 square feet of manufacturing cleanroom space and houses four new 2,000L single-use bioreactors, bringing the total of production lines at the site up to three.

“The completion of our new production line is an important milestone for our company and emphasizes Rentschler Biopharma’s strong capabilities in the U.S.,” said Benedikt von Braunmühl, CEO of Rentschler Biopharma. “Indeed, in 2023, Rentschler Biopharma was proud to contribute to nearly 25% of the biopharmaceuticals approved by the FDA.”

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The existing analytical workflow for biomanufacturing is full of blind spots and bottlenecks that contribute to increased time to market and manufacturing costs for critical drugs, according to a number of experts. Therapeutic development is an iterative and complicated process requiring analysis at each step of the process and suffers from either no data or slow data collection. If samples are taken, they are typically sent to a core analytical lab for HPLC analysis, and drug development timelines are often delayed for 4–6 weeks waiting on its retrospective data.

Atlas, powered by tunable laser spectroscopy (HPTLS) technology, reportedly enables simultaneous analysis of buffer excipients, such as surfactants and amino acids, and high concentration proteins, such as monoclonal antibodies, peptides, and vaccines in one minute throughout the bioprocess.

Critical data

“This simple to use system delivers critical data with the accuracy and sensitivity of HPLC, bringing the power of the core lab right to the point of sampling,” said Greg Crescenzi, CEO of Nirrin. “Atlas quickly reveals blind spots and overlooked issues that can become bigger problems throughout the bioprocess, giving scientists more predictive and proactive control over their process like never before. Armed with the needed insights to make confident decisions in-hand, they can eliminate unnecessary wait time and be more selective on which samples are sent to the core lab for further analysis.”

Early adopter studies conducted by ten top global pharmaceutical companies demonstrated the potential of Atlas’ HPTLS as a reliable method that overcomes the limitations of traditional analysis techniques and opens new possibilities for studying and optimizing protein formulations, continued Crescenzi.

Nirrin’s HPTLS technology unlocks the power of near-infrared (NIR) spectroscopy with a tunable laser source to provide unique, quantitative signatures for excipients, proteins, surfactants and more, noted. Bryan Hassell, PhD, Nirrin founder and CTO.

“Bioprocess groups shouldn’t have to wait for retrospective data from the core lab, they need data they can trust, now,” said Hassell. “Atlas debottlenecks current analytical workflows with a system anyone can use and get accurate, reliable data in a minute or less. There are no other at-line technologies that can provide the data-driven insights biopharma needs to react quickly and effectively.”

“With Atlas, bioprocess groups now have a single tool that can be used to benchmark their unique processes in both development and manufacturing, and deliver cost-effective, actionable answers on-demand,” added Crescenzi. “Atlas is Nirrin’s first step towards what the biopharmaceutical industry has been waiting on for a long time—real-time monitoring and integrated control of their bioprocess. Our current development focus is on continuous manufacturing, and early collaborators are already having great success with Atlas for analysis of their critical process parameters.”

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“With biosimilars, it’s cost that drives the market. Process optimization gives the best possible yield while having a minimal effect on potency and safety,” says Hausfeld who will be discussing how to fund biosimilar development at the Bioprocessing Summit in Boston next month.

As part of his talk, he will detail the optimization techniques that BioFactura has adopted to cut costs as, for example, intensified perfusion which, according to Hausfeld, uses more expensive culture media, but also produces higher yields.

The company has also adopted CO₂ stripping to maintain the pH of the bioreactor without adding bio-carbonates that can affect the health of the cells. “From what we can tell, the CO₂ doesn’t have any negative effects on the critical quality attributes of our product,” he says.

Role for metabolomics

Finally, they’ve analyzed cell lines with metabolomics to see how their productivity varies over time and, we’ve identified three supplements to improve productivity,” he says, adding that process optimization is best done after Phase I.

“Until Phase I, you tend to have a locked process,” Hausfeld explains. “Afterwards, you might realize how you can tweak without a major change that would raise the eyebrows of a regulator.”

Regulators look to make sure that a biosimilar product resembles the original drug. Too many variations, and they will expect costly clinical trials. Hausfeld also recommends that biosimilar manufacturers carefully record the steps they take to optimize processes during development. This, he says, can help companies more easily transfer their technology to a contract manufacturer for commercial-scale production.

“The complexity of tech transfer can be [a] major issue that people don’t always think about when developing drugs,” he says.

“There are nuances that occur during every bioreactor run, and the tech transfer process can take a long time and go astray if you don’t document what you do in a stringent manner,” he continues while also recommending that instructions sent to contract manufacturers be readable, understandable, and actionable, keeping in mind that there are lots of opportunities to ask questions and exchange information before beginning a manufacturing process.

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As a tool developer, “our mission is to make analytical tools easily accessible so the bioprocess scientists developing processes can perform key analysis themselves,” rather than having to hand off analyses to other labs, Graziella Piras, a senior director at 908 Devices, tells GEN.

The benefits for biomanufacturers accrue in the form of accelerated processes, lower analytical costs, and process intensification, culminating in reduced time to market.

For example, 908 Devices’ Rebel at-line cell culture media analysis device claims to reduce analytical process time from the conventional three to six weeks to 12 minutes. In the biopharma industry, such time savings add up to major money savings.

“One month of process development costs approximately $1 million,” Piras said, citing a 2020 study by University College London and AstraZeneca.

That study showed that to achieve an overall 12% approval rate for Phase I drugs, for material preparation alone, a biopharma company should expect to spend about $60 million from preclinical to Phase II and about $70 million for Phase III to regulatory review. For a 4 percent success rate—like that of drugs targeting Alzheimer’s disease—the costs increase 2.5-fold.

Therefore, she said, “If you can save a couple of weeks’ time, it matters.”

Real-time analysis matters

On the biomanufacturing side, the focus is on maintaining drug quality and efficacy. “We’re talking about living cells,” she stresses. Anything less than optimal conditions can reduce the quantity of drug produced. Even a small reduction can have “a huge effect on the cost of goods.”

To manage that, Piras advises real-time monitoring and analysis to pinpoint where and when optimal parameters vary, and to enable near-real-time responses. When Terumo Blood and Cell Technologies (a client of 908 Devices) implemented real-time monitoring to control glucose and lactate concentrations in cell cultures, sampling data points increased from one or two per day to as many as 720 per day, thereby providing deeper insights into the process. The risk of contamination also was reduced by eliminating the need for manual sampling.

It’s important for process specialists to not only have the data in real-time, but also to have the interpretation of that data immediately, she points out.

The challenge, Piras says, is that, “the industry is slow to adopt innovative solutions. In that regard, biopharma companies have a fear of being first. They are risk averse.”

That’s natural in highly regulated industries, but regulators, she points out—including the FDA—are eager to work with companies. The FDA wants to help developers adopt platforms that enhance development and manufacturing efficiency and improve drug safety and efficacy.

To reduce the risks, Piras advocates becoming involved in consortia, like NIIMBL, that bring together industry, academia, and innovative tool developers. By collaborating early on, they can advance biomanufacturing innovation.

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Today most purification methods are based on separating biopharmaceuticals from cellular debris, reagents, and nutrients present in the process stream. The aim is to pass large volumes of liquids through filtration systems as efficiently as possible.

However, for personalized medicines produced in smaller quantities the challenges are different, according to Dong-Pyo Kim, PhD, director of the Center for Intelligent Microprocess of Pharmaceutical Synthesis at Pohang University in South Korea.

“The personalized medicines industry needs new, super-efficient purification technologies because it handles complex biological molecules like nucleic acids, proteins, and cells that must be extremely pure for safety and effectiveness. A small impurity can result in significant immunological side effects.”

And there are other motivations for the development of more efficient downstream technologies, with cost reduction being the obvious example.

Kim tells GEN: “The purification process represents approximately 60–90% of the total cost involved in producing biotherapeutics. New approaches must be focused on boosting purity, cost reduction, flexibility in production scale, and fit smoothly with other manufacturing steps.

“Current technologies just aren’t flexible or precise enough for small, individualized batches, making it tough to keep consistent quality and meet regulations, which also pushes up production costs,” he says.

Microfluidics

Instead of using current tech—Kim and colleagues argue in a new study—personalized medicine developers should use systems designed to process smaller volumes—so called “microfluidics”—for downstream processing.

“Microfluidic technologies are a game-changer for purifying personalized medicines, specifically for those small population patients suffering from genetic and rare disorders because they offer high precision and scalability. They can handle small, customized batches efficiently, which is perfect for personalized treatments.

“These systems cut costs by using smaller quantities of reagents and minimizing waste. Plus, they provide high-resolution separation to distinguish closely related biomolecules and achieve great recovery rates, making the most of valuable therapeutic agents,” Kim says.

He also advocates combining microfluidics with automated artificial intelligence (AI) based monitoring, analytics, and modeling technologies.

“Combining microfluidic technologies with AI and automation systems brings a lot to the table, specifically for producing biotherapeutics and personalized medicines. AI can analyze real-time data from microfluidic processes to fine-tune things like flow rates and reaction conditions, making everything run smoother and more efficiently. It also uses past data to predict outcomes, helping us make better decisions, and keeping experiments on track.

“With automation in the mix, tasks like preparing samples and purifying substances become super precise and repeatable. This setup speeds up the whole development process by cutting down on manual work and analyzing data faster. It also keeps a close eye on quality, ensuring each batch meets high standards while managing costs better by optimizing how we use resources.”

Kim adds, “Overall, it’s a powerhouse combo that’s pushing the boundaries of biopharmaceutical processing.”

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In the introduction to Recent Advances in Bioprocess Engineering and Bioreactor Design, published earlier this year, Archana Vimal, PhD, assistant professor of bioengineering at Integral University in Lucknow, India, and her colleagues wrote: “Besides umpteen useful traits, bioprocess technology still needs to overcome a large number of hurdles and possess an advantage over other competing methods such as chemical engineering to be viable in any specific industrial context.”

To Vimal and her colleagues, a key bioprocessing hurdle is “developing the enabling technologies for industry to fully utilize the potential of contemporary biology and chemistry through synthesis and innovation.” As if that’s not enough, these authors want tomorrow’s solutions to also be sustainable and more.

As they noted, the bioprocessing industry should incorporate “manufacturing processes into environmentally acceptable and financially viable process concepts, rapid purification and monitoring of purification processes to produce products of high-quality, high-purity, and consistent output are some of the challenges that bioprocess technology must overcome.”

Techno-economic analysis

For one aspect of economic sustainability in bioprocessing, Satya Eswari Jujjavarapu, PhD, an assistant professor in biotechnology at the National Institute of Technology (NIT) Raipur in India, and Swasti Dhagat, PhD, a research scientist at SRISTI (Society for Research and Initiatives for Sustainable Technologies and Institutions), explored the economics of fermentation, including techno-economic analysis (TEA). As they pointed out, “many online tools are available that help in evaluating the feasibility of a production process.”

To provide an example, these authors noted that Michael Lynch, MD, PhD, the W. H. Gardner, Jr. Associate Professor of Biomedical Engineering at Duke University, developed a bioprocess TEA calculator.

“Techno-economic analysis connects R&D, engineering, and business,” Lynch explained in an article about his bioprocess TEA calculator. “By linking process parameters to financial metrics, it allows researchers to understand the factors controlling the potential success of their technologies.”

Perhaps the biggest challenge in bioprocessing is inherent in the name. It is a process. As shown here, many steps in bioprocessing need improvements, and tools exist to take on some of those challenges. Really, though, as bioprocessing jumps one hurdle, more will appear, often because of improvements in technology or evolving societal needs. It’s just the nature of the industry.

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This expanded partnership solidifies Just – Evotec’s commitment to providing long-term commercial supply of biosimilars to Sandoz from its newly built J.POD^® biologics manufacturing facility at Evotec’s Campus Curie in Toulouse, France, according to Matthias Evers, PhD, CBO of Evotec.

Just – Evotec and Sandoz have been engaged in a multi-year technology partnership aimed at the rapid development and manufacturing of biosimilars.

“We are thrilled to expand our partnership with Sandoz, building on the successes we’ve achieved since the initial launch,” says Evers. “Introducing additional molecules has the potential to enhance access for millions of patients, while commercial manufacturing from Toulouse will ensure the long-term supply of Sandoz’ biosimilar portfolio. This commercial supply aspect also validates our strategy to establish our second J.POD in Toulouse.”

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Their approach involves mixing bacteria with food and drug additives from a list of compounds that the FDA classifies as “generally regarded as safe.” The researchers identified formulations that help to stabilize several different types of microbes, including yeast, gram-negative and gram-positive bacteria, and they showed that these formulations could withstand high temperatures, radiation, and industrial processing that can damage unprotected microbes.

In an even more extreme test, some of the microbes recently returned from a trip to the International Space Station, coordinated by Space Center Houston Manager of Science and Research Phyllis Friello, and the researchers are now analyzing how well the microbes were able to withstand those conditions.

“What this project was about is stabilizing organisms for extreme conditions,” said Giovanni Traverso, PhD, an associate professor of mechanical engineering at MIT, and a gastroenterologist at theBrigham and Women’s Hospital. We’re really thinking about a broad set of applications, whether it’s missions to space, human applications, or agricultural uses.”

Senior author Traverso, together with lead author Miguel Jimenez, PhD, a former MIT research scientist and now an assistant professor of biomedical engineering at Boston University, and colleagues reported on their results in Nature Materials, in a paper titled “Synthetic extremophiles via species-specific formulations improve microbial therapeutics.” In their report the team concluded, “… these synthetic extremophiles stand to transform our capacity to disseminate bioactive organisms across human applications, from shelves across the globe to fields for agricultural practices to shuttles for space exploration.”

Microorganisms typically used to produce food and pharmaceuticals are now being explored as medicines and agricultural supplements, the authors wrote. “Microorganisms have been central to human technological progress and continue to be key in wide-ranging fields from food production (for example, baked goods) to biologics manufacturing (for example, synthetic insulin.” And for these types of application “… the microbial cells are kept alive only during the manufacturing process and are destroyed, deactivated or removed from the final product.”  In contrast, the team continued, “… the pharmaceutical, agricultural and space health fields have now turned to developing live microorganisms as the final product to cure disease, to enhance crop production and for on-demand bioproduction…Critical to these new microbial technologies is the maintenance of high cell viability throughout the entire life cycle of the product.” An ideal solution, they suggested, would be dry, microbial formulations that are easy to package, ship and use.

About six years ago, with funding from NASA’s Translational Research Institute for Space Health (TRISH), Traverso’s lab began working on new approaches to make helpful bacteria such as probiotics and microbial therapeutics more resilient. As a starting point, the researchers analyzed 13 commercially available probiotics and found that six of these products did not contain as many live bacteria as the label indicated. “… when we surveyed the viable cell counts (colony-forming units, CFUs) across a range of probiotics … we found only 7 in 13 products contained viable cell counts at or higher than the promised amount on the label … with a mean (geometric) viability of ~21% of that promised,” they wrote.

“What we found was that, perhaps not surprisingly, there is a difference, and it can be significant,” Traverso explained. “So then the next question was, given this, what can we do to help the situation?” For their reported experiments, the researchers focused on three bacteria and one yeast. The bacterium Escherichia coli Nissle 1917 is a probiotic. Ensifer meliloti, is a bacterium that can fix nitrogen in soil to support plant growth. The bacterium Lactobacillus plantarum is used to ferment food products. The yeast Saccharomyces boulardii is also used as a probiotic.

For medical or agricultural applications microbes are usually dried into a powder through a process called lyophilization However, they cannot normally be made into forms such as a tablet or pill because this process requires exposure to an organic solvent, which can be toxic to the bacteria. The MIT team set out to find additives that could improve the microbes’ ability to survive this kind of processing. “In designing our approach, our overarching requirement was regulatory and industrial translatability,” they explained. Their strategy was to apply material stabilizers rather than apply genetic changes that would ‘add regulatory burden.’” Similarly, they pointed out, rather than develop new synthetic materials, we designed what they described as a material library composed primarily of materials generally recognized as safe by FDA.

“We developed a workflow where we can take materials from the ‘generally regarded as safe’ materials list from the FDA, and mix and match those with bacteria and ask, are there ingredients that enhance the stability of the bacteria during the lyophilization process?” Traverso noted.

The approach allows them to mix microbes with one of about 100 different ingredients and then grow them to see which survive the best when stored at room temperature for 30 days. These experiments revealed different ingredients, mostly sugars and peptides, that worked best for each species of microbe.

The researchers then picked one of the microbes, E. coli Nissle 1917, for further optimization. This probiotic has been used to treat “traveller’s diarrhea,” a condition caused by drinking water contaminated with harmful bacteria. The researchers found that if they combined caffeine or yeast extract with a sugar called melibiose, they could create a very stable formulation of E. coli Nissle 1917. This mixture, which the researchers called formulation D, allowed survival rates greater than 10 percent after the microbes were stored for six months at 37° Celsius=. In contrast, a commercially available formulation of E. coli Nissle 1917 lost all viability after only 11 days under those conditions. “Both melibiose and formulation D outperformed the commercial product Mutaflor (E. coli Nissle 1917) by over 3.5 orders of magnitude when stored at room temperature for one month,” the investigators noted.

Formulation D was also able to withstand much higher levels of ionizing radiation, up to 1,000 grays. “At this radiation level a liquid suspension of the same bacteria lost all measurable viability,” the scientists wrote. The typical radiation dose on Earth is about 15 micrograys per day, and in space, it’s about 200 micrograys per day.

Their formulation was in addition compatible with pharmaceutical processing and tableting. “We also showed that these synthetic extremophiles withstand pharmaceutical manufacturing workflows enabling the production of controlled release microbial dosage forms,” they stated. The researchers don’t know exactly how their formulations protect bacteria, but they hypothesize that the additives may help to stabilize the bacterial cell membranes during rehydration.

The investigators in addition showed that these microbes can not only survive harsh conditions, they also maintain their function following such exposures. After Ensifer meliloti were exposed to temperatures up to 50° Celsius, the researchers found that they were still able to form symbiotic nodules on plant roots and convert nitrogen to ammonia. They also found that their formulation of E. coli Nissle 1917 was able to inhibit the growth of Shigella flexneri, one of the leading causes of diarrhea-associated deaths in low- and middle-income countries, when the microbes were grown together in a lab dish. “We further show, in live animals and plants, that synthetic extremophiles remain functional against enteric pathogens and as nitrogen-fixing plant supplements even after exposure to elevated temperatures.”

Last year, several strains of these extremophile microbes were sent to the International Space Station, which Jimenez described as “the ultimate stress test. He said “Even just the shipping on Earth to the preflight validation, and storage until flight are part of this test, with no temperature control along the way.” The samples recently returned to Earth, and Jimenez’ lab is now analyzing them. He plans to compare samples that were kept inside the ISS to others that were bolted to the outside of the station, as well as control samples that remained on Earth.

Concluding on their reported work, the team stated, “We develop a high-throughput pipeline to define species-specific materials that enable survival through drying, elevated temperatures, organic solvents and ionizing radiation…This synthetic, material-based stabilization enhances our capacity to apply microorganisms in extreme environments on Earth and potentially during exploratory space travel.”

Further improvements in microbial stability and dosage form design may involve genetic approaches, or single-cell encapsulation techniques, they wrote. “Our bulk material stabilization approach is orthogonal to and could be combined with these approaches to make microbial materials with more advanced robustness and pharmacokinetic release profiles.”

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Adeno-associated viral (AAV) gene therapy products, which contain a DNA transgene packaged into a protein capsid, have shown tremendous therapeutic potential in recent years for a range of diseases. Technologies like imaged capillary isoelectric focusing (icIEF) are designed to help scientists make these products a reality by providing an orthogonal, fast, and high-resolution method for AAV charge species collection and characterization. Addressing charge heterogeneity is crucial as it can affect the stability and biodistribution of AAV-based biotherapeutics.

In this GEN webinar, our speakers will discuss icIEF technology and its application to protein charge analysis in AAV gene therapy development. During the webinar, you’ll learn about the MauriceFlex icIEF system, a protein fractionation solution the enables fraction collection for charge variant analysis and eliminates the need for mobilization after separation while providing data in 10-15 minutes. You’ll also hear about recent innovations that enable the direct characterization of charge isoforms by icIEF separation by mass spectrometry (MS) including a novel methodology for AAV viral protein species separation by icIEF and characterization by MS.

Key learnings for this webinar include:

• How the protein fractionation capabilities of MauriceFlex enable fraction collection for charge variant analysis
• A methodology for AAV viral protein species separation by icIEF and characterization by MS
• The advantages of using icIEF fractionation over traditional ion-exchange chromatography (IEX)-based fractionation

A live Q&A session will follow the presentation, offering you a chance to pose questions to our expert panelist.

Webinar produced with support from:

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Launched in May 2023, Constellation combines automation robotics with aseptic fluid-handling technologies in a scalable system. The platform physically and digitally reportedly integrates with a wide range of existing bioprocessing equipment, “enabling users to adopt its use without requiring significant changes to either the workflow or equipment, alleviating the risks and time that come with process redevelopment,” continued Stone.

Autologous cell therapy manufacturing

The ACTIA Platform is focused on the autologous cell therapy manufacturing and allows for massively multiplex and distributed industrial automation, noted a company spokesperson, who added that with this technology, users can selectively increase capacity to target process bottlenecks, typically the expansion step, alongside random access to any process step or patient dose.

“The acquisition of the ACTIA Platform IP shows Cellular Origins’ continued dedication to creating the most efficient, cost effective and scalable solution to cell therapy manufacturing,” said Stone. “Combined with ongoing R&D, this expansion of our technology and IP portfolio underpins our commitment to develop Constellation to solve the challenge of affordable, large-scale production of cell therapies that meets the needs of our customers and ensures we can offer the right solution for long-term success.”

“The approach of stringing together sequential unit ops, as we did to manufacture recombinant proteins, does not meet the unique needs of autologous cell therapy,” explained Hodge, now a scientific adviser at Cellular Origins.

“Constellation has already demonstrated its capabilities to transform manufacturing of cell therapies, offering an easily accessible route to cost- and space-efficient, large-scale production. ACTIA further augments Constellation, and the ambition to revolutionize cell therapy manufacturing and deliver life-saving therapies to more patients than ever before.”

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