NoneFORT WASHINGTON, Pa., Dec. 11, 2024 (GLOBE NEWSWIRE) -- Toll Brothers, Inc. TOL ( TollBrothers.com ), the nation's leading builder of luxury homes, today announced that its Board of Directors has approved a quarterly cash dividend to shareholders. The dividend of $0.23 per share will be paid on January 24, 2025 to shareholders of record on the close of business on January 10, 2025. ABOUT TOLL BROTHERS Toll Brothers, Inc., a Fortune 500 Company, is the nation's leading builder of luxury homes. The Company was founded 57 years ago in 1967 and became a public company in 1986. Its common stock is listed on the New York Stock Exchange under the symbol "TOL." The Company serves first-time, move-up, empty-nester, active-adult, and second-home buyers, as well as urban and suburban renters. Toll Brothers builds in over 60 markets in 24 states: Arizona, California, Colorado, Connecticut, Delaware, Florida, Georgia, Idaho, Indiana, Maryland, Massachusetts, Michigan, Nevada, New Jersey, New York, North Carolina, Oregon, Pennsylvania, South Carolina, Tennessee, Texas, Utah, Virginia, and Washington, as well as in the District of Columbia. The Company operates its own architectural, engineering, mortgage, title, land development, insurance, smart home technology, and landscape subsidiaries. The Company also develops master-planned and golf course communities as well as operates its own lumber distribution, house component assembly, and manufacturing operations. In 2024, Toll Brothers marked 10 years in a row being named to the Fortune World's Most Admired CompaniesTM list and the Company's Chairman and CEO Douglas C. Yearley, Jr. was named one of 25 Top CEOs by Barron's magazine. Toll Brothers has also been named Builder of the Year by Builder magazine and is the first two-time recipient of Builder of the Year from Professional Builder magazine. For more information visit TollBrothers.com. Toll Brothers discloses information about its business and financial performance and other matters, and provides links to its securities filings, notices of investor events, and earnings and other news releases, on the Investor Relations section of its website (investors.TollBrothers.com). From Fortune, ©2024 Fortune Media IP Limited. All rights reserved. Used under license. CONTACT: Gregg Ziegler (215) 478-3820 gziegler@tollbrothers.com © 2024 Benzinga.com. Benzinga does not provide investment advice. All rights reserved.
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FORT WASHINGTON, Pa., Dec. 11, 2024 (GLOBE NEWSWIRE) -- Toll Brothers, Inc. (NYSE:TOL) ( TollBrothers.com ), the nation's leading builder of luxury homes, today announced that its Board of Directors has approved a quarterly cash dividend to shareholders. The dividend of $0.23 per share will be paid on January 24, 2025 to shareholders of record on the close of business on January 10, 2025. ABOUT TOLL BROTHERS Toll Brothers, Inc., a Fortune 500 Company, is the nation’s leading builder of luxury homes. The Company was founded 57 years ago in 1967 and became a public company in 1986. Its common stock is listed on the New York Stock Exchange under the symbol “TOL.” The Company serves first-time, move-up, empty-nester, active-adult, and second-home buyers, as well as urban and suburban renters. Toll Brothers builds in over 60 markets in 24 states: Arizona, California, Colorado, Connecticut, Delaware, Florida, Georgia, Idaho, Indiana, Maryland, Massachusetts, Michigan, Nevada, New Jersey, New York, North Carolina, Oregon, Pennsylvania, South Carolina, Tennessee, Texas, Utah, Virginia, and Washington, as well as in the District of Columbia. The Company operates its own architectural, engineering, mortgage, title, land development, insurance, smart home technology, and landscape subsidiaries. The Company also develops master-planned and golf course communities as well as operates its own lumber distribution, house component assembly, and manufacturing operations. In 2024, Toll Brothers marked 10 years in a row being named to the Fortune World’s Most Admired CompaniesTM list and the Company’s Chairman and CEO Douglas C. Yearley, Jr. was named one of 25 Top CEOs by Barron’s magazine. Toll Brothers has also been named Builder of the Year by Builder magazine and is the first two-time recipient of Builder of the Year from Professional Builder magazine. For more information visit TollBrothers.com . Toll Brothers discloses information about its business and financial performance and other matters, and provides links to its securities filings, notices of investor events, and earnings and other news releases, on the Investor Relations section of its website (investors.TollBrothers.com). From Fortune, ©2024 Fortune Media IP Limited. All rights reserved. Used under license. CONTACT: Gregg Ziegler (215) 478-3820 gziegler@tollbrothers.com
Alabama A&M's Medrick Burnett Jr. dies after head injuryOpen boss sends clear message to Donald Trump as decision made on Turnberry futureZach Sieler earns AFC Defensive Player of the Week after tormenting Aaron Rodgers and the Jets
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COLUMBUS, Ohio (AP) — A fight broke out at midfield after Michigan stunned No. 2 Ohio State 13-10 on Saturday as Wolverines players attempted to plant their flag and were met by Buckeyes who confronted them. Police had to use pepper spray to break up the players, who threw punches and shoves in the melee that overshadowed the rivalry game. Ohio State police said in a statement “multiple officers representing Ohio and Michigan deployed pepper spray.” Ohio State police will investigate the fight, according to the statement. After the Ohio State players confronted their bitter rivals at midfield, defensive end Jack Sawyer grabbed the top of the Wolverines’ flag and ripped it off the pole as the brawl moved toward the Michigan bench. Eventually, police officers rushed into the ugly scene. Ohio State coach Ryan Day said he understood the actions of his players. “There are some prideful guys on our team who weren’t going to sit back and let that happen,” Day said. The two Ohio State players made available after the game brushed off questions about it. Michigan running back Kalel Mullings, who rushed for 116 yards and a touchdown, didn’t like how the Buckeyes players involved themselves in the Wolverines’ postgame celebration. He called it “classless.” “For such a great game, you hate to see stuff like that after the game,” he said in an on-field interview with Fox Sports. “It’s just bad for the sport, bad for college football. But at the end of the day, you know some people got to — they got to learn how to lose, man. ... We had 60 minutes, we had four quarters, to do all that fighting.” Michigan coach Sherrone Moore said everybody needs to do better. “So much emotions on both sides,” he said. “Rivalry games get heated, especially this one. It’s the biggest one in the country, so we got to handle that better.” ___ Get poll alerts and updates on the AP Top 25 throughout the season. Sign up . AP college football: andNiger proposes N1.2tr for 2025 fiscal yearBy JOSH BOAK WASHINGTON (AP) — Donald Trump loved to use tariffs on foreign goods during his first presidency. But their impact was barely noticeable in the overall economy, even if their aftershocks were clear in specific industries. The data show they never fully delivered on his promised factory jobs. Nor did they provoke the avalanche of inflation that critics feared. This time, though, his tariff threats might be different . The president-elect is talking about going much bigger — on a potential scale that creates more uncertainty about whether he’ll do what he says and what the consequences could be. “There’s going to be a lot more tariffs, I mean, he’s pretty clear,” said Michael Stumo, the CEO of Coalition for a Prosperous America, a group that has supported import taxes to help domestic manufacturing. The president-elect posted on social media Monday that on his first day in office he would impose 25% tariffs on all goods imported from Mexico and Canada until those countries satisfactorily stop illegal immigration and the flow of illegal drugs such as fentanyl into the United States. Those tariffs could essentially blow up the North American trade pact that Trump’s team negotiated during his initial term. Chinese imports would face additional tariffs of 10% until Beijing cracks down on the production of materials used in making fentanyl, Trump posted. Democrats and business groups warn of risks from Trump’s tariff threats Business groups were quick to warn about rapidly escalating inflation , while Mexican President Claudia Sheinbaum said she would counter the move with tariffs on U.S. products. House Democrats put together legislation to strip a president’s ability to unilaterally apply tariffs this drastic, warning that they would likely lead to higher prices for autos, shoes, housing and groceries. Sheinbaum said Wednesday that her administration is already working up a list of possible retaliatory tariffs “if the situation comes to that.” “The economy department is preparing it,” Sheinbaum said. “If there are tariffs, Mexico would increase tariffs, it is a technical task about what would also benefit Mexico,” she said, suggesting her country would impose targeted import duties on U.S. goods in sensitive areas. House Democrats on Tuesday introduced a bill that would require congressional approval for a president to impose tariffs due to claims of a national emergency, a largely symbolic action given Republicans’ coming control of both the House and Senate. “This legislation would enable Congress to limit this sweeping emergency authority and put in place the necessary Congressional oversight before any president – Democrat or Republican – could indiscriminately raise costs on the American people through tariffs,” said Rep. Suzan DelBene, D-Wash. But for Trump, tariffs are now a tested tool that seems less politically controversial even if the mandate he received in November’s election largely involved restraining inflation. The tariffs he imposed on China in his first term were continued by President Joe Biden, a Democrat who even expanded tariffs and restrictions on the world’s second largest economy. Biden administration officials looked at removing Trump’s tariffs in order to bring down inflationary pressures, only to find they were unlikely to help significantly. Tariffs were “so new and unique that it freaked everybody out in 2017,” said Stumo, but they were ultimately somewhat modest. Trump’s first term tariffs had a modest impact on economy Trump imposed tariffs on solar panels and washing machines at the start of 2018, moves that might have pushed up prices in those sectors even though they also overlapped with plans to open washing machine plants in Tennessee and South Carolina. His administration also levied tariffs on steel and aluminum, including against allies. He then increased tariffs on China, leading to a trade conflict and a limited 2020 agreement that failed to produce the promised Chinese purchases of U.S. goods. Still, the dispute changed relations with China as more U.S. companies looked for alternative suppliers in other countries. Economic research also found the United States may have sacrificed some of its “soft power” as the Chinese population began to watch fewer American movies. The Federal Reserve kept inflation roughly on target, but factory construction spending never jumped in a way that suggested a lasting gain in manufacturing jobs. Separate economic research found the tariff war with China did nothing economically for the communities hurt by offshoring, but it did help Trump and Republicans in those communities politically. When Trump first became president in 2017, the federal government collected $34.6 billion in customs, duties and fees. That sum more than doubled under Trump to $70.8 billion in 2019, according to Office of Management and Budget records. While that sum might seem meaningful, it was relatively small compared to the overall economy. America’s gross domestic product is now $29.3 trillion, according to the Bureau of Economic Analysis. The total tariffs collected in the United States would equal less than 0.3% of GDP. Trump wants much more far-reaching tariffs going forward The new tariffs being floated by Trump now are dramatically larger and there could be far more significant impacts. If Mexico, Canada, and China faced the additional tariffs proposed by Trump on all goods imported to the United States, that could be roughly equal to $266 billion in tax collections, a number that does not assume any disruptions in trade or retaliatory moves by other countries. The cost of those taxes would likely be borne by U.S. families, importers and domestic and foreign companies in the form of higher prices or lower profits. Former Biden administration officials said they worried that companies could piggyback on Trump’s tariffs — if they’re imposed — as a rationale to raise their prices, just as many companies after Russia’s invasion of Ukraine in 2022 boosted food and energy costs and gave several major companies the space to raise prices, according to their own earnings calls with investors. But what Trump didn’t really spell out is what might cause him to back down on tariffs and declare a victory. What he is creating instead with his tariff threats is a sense of uncertainty as companies and countries await the details to figure out what all of this could mean. “We know the key economic policy priorities of the incoming Trump administration, but we don’t know how or when they will be addressed,” said Greg Daco, chief U.S. economist at EY-Parthenon. AP writer Mark Stevenson contributed to this report from Mexico City.Adam Titlbach had the only goal for Vancouver Giants – his eighth tally of the season – as Everett Silvertips scored two power play goals and two shorthanded goals in a 7-1 win on Friday night, Nov. 30 at the Langley Events Centre. Giants Head Coach Manny Viveiros apologized to the fans. "We just got outclassed," Viveiros said. "Completely outclassed. Credit to Everett. They're good. They work. They know their identity. They know how to play. Even if they don't have their game, they stick with it. We don't do that. Our group doesn't do that. When things get tough sometimes, guys do individual things instead of staying with the system or giving ourselves an opportunity to at least compete. We didn't do that tonight. I'm just sorry for the fans that had to watch that tonight. It was not a good effort from our group at all tonight." The Giants' record drops to 10-9-4 this season, while the first place Silvertips improve to 20-3-2-1. Everett has a league best 12 road wins and have one regulation loss in their last 18 games (14-1-2-1). Julius Miettinen scored a pair for Everett, who also got goals from Dominik Rymon, Carter Bear, Clarke Schaefer, Jesse Heslop and Tyler McKenzie. The final shots on goal in the game were 40-19 for Everett. Silvertips got things started with a shorthanded goal 6:31 into the first period, after McKenzie stole the puck on the forecheck and found Rymon for a one-timer. The visitors extended their lead to 2-0 with 31 seconds left in the first period when Bear got the last touch at the far post following a tremendous pad save from Carter Capton. Less than five minutes into period two, Vancouver got some life thanks to an Everett turnover where Brett Olson fed a pass to Titlbach in front of the goal. Several minutes later, however, Everett went back ahead by two thanks to Schaeffer's first career WHL goal, off a good shot pass from defenceman Eric Jamieson from the left circle. Miettinen would get on the board with another shorthanded goal when he beat two Giants defenders to a loose puck at centre ice and broke in alone, firing home his eighth of the season to make the score 4-1 after 40 minutes. Heslop scored 29 seconds into the third period to stretch the Silvertips lead to 5-1, before Miettinen and McKenzie added goals as well, making it a 7-1 final. Everett outshot Vancouver 40-19. Next, Giants host the Seattle Thunderbirds Sunday, Dec. 1 at LEC. Puck drops at 4 p.m.
The connections are clear between the Tampa Bay Buccaneers and Carolina Panthers, longtime NFC South rivals. The teams get together for a meeting on Sunday in Charlotte and showed recent signs they can play with any team. "It's an NFC South battle," Buccaneers coach Todd Bowles said. "All of them are going to be hard, none of them (are) going to be easy. ... They're playing pretty good football. They missed some games here and there, but they're playing very good football. It's going to be a tough battle." Few introductions are needed on Sunday, as first-year Panthers coach Dave Canales came to Carolina after serving as Buccaneers offensive coordinator a season ago. Canales' prized pupil last season, Tampa Bay quarterback Baker Mayfield was with the Panthers for part of the 2022 campaign. "There's some familiarity," Canales said of his connection to the Buccaneers. "Knowing coach Bowles, he's got a really sophisticated system and he attacks each team with a specific game plan. There's some principles that carry over. I know that he's going to have some things up his sleeve." The Buccaneers (5-6) playing a division opponent for the first time since an Oct. 27 loss to the Atlanta Falcons. The goal will be notching back-to-back wins for the first time since the first two weeks of the season. Four different ball-carriers, including Mayfield, found the end zone on the ground during a 30-7 drubbing of the New York Giants last Sunday. Mayfield also completed 24 of 30 passes for 294 yards. "For me, the biggest thing was blocking and tackling," Bowles said of what his team did well last weekend. "We cleaned up the fundamental and technique part of it." Star wideout Mike Evans was back in action for Tampa Bay following a three-game absence due to a hamstring injury. He finished with five receptions for 68 yards against the Giants and now gets a crack at a Carolina team allowing a league-high 30.9 points per game this season. However, the Panthers have tightened up their play as of late, winning two games in a row before hanging with the two-time defending champion Kansas City Chiefs in a 30-27 setback last Sunday. The outing against Kansas City may have been the most efficient performance of Panthers quarterback Bryce Young's two-year career. Young completed 21 of 35 passes for 263 yards and one score without throwing a pick. "It's not all Bryce, it's the whole unit," Canales said. "It's a collective effort, but he certainly needs to be the voice and driver of that." Wide receiver Jalen Coker (quadriceps), tight end Ja'Tavion Sanders (neck) and safety Lonnie Johnson (personal) were all missing from practice on Wednesday for Carolina. Defensive end LaBryan Ray is dealing with a hand issue and was among those limited. Safety Jordan Whitehead (pectoral) was one of four Buccaneers to miss practice on Wednesday. Evans practiced in full. Carolina and Tampa Bay might as well get used to each other, as the two teams will collide again in Week 17. --Field Level MediaNo secrets as Bucs visit Dave Canales, Panthers for NFC South showdown
WASHINGTON (AP) — Donald Trump loved to use tariffs on foreign goods during his first presidency. But their impact was barely noticeable in the overall economy, even if their aftershocks were clear in specific industries. The data show they never fully delivered on his promised factory jobs. Nor did they provoke the avalanche of inflation that critics feared. This time, though, his . The president-elect is talking about going much bigger — on a potential scale that creates more uncertainty about whether he’ll do what he says and what the consequences could be. “There’s going to be a lot more tariffs, I mean, he’s pretty clear,” said Michael Stumo, the CEO of Coalition for a Prosperous America, a group that has supported import taxes to help domestic manufacturing. The president-elect posted on social media Monday that on his first day in office he would impose 25% tariffs on all goods imported from Mexico and Canada until those countries satisfactorily stop illegal immigration and the flow of illegal drugs such as fentanyl into the United States. Those tariffs could essentially blow up the North American trade pact that Trump’s team negotiated during his initial term. Chinese imports would face additional tariffs of 10% until Beijing cracks down on the production of materials used in making fentanyl, Trump posted. Business groups were quick to warn about , while said she would counter the move with tariffs on U.S. products. House Democrats put together legislation to strip a president’s ability to unilaterally apply tariffs this drastic, warning that they would likely lead to higher prices for autos, shoes, housing and groceries. Sheinbaum said Wednesday that her administration is already working up a list of possible retaliatory tariffs “if the situation comes to that.” “The economy department is preparing it,” Sheinbaum said. “If there are tariffs, Mexico would increase tariffs, it is a technical task about what would also benefit Mexico,” she said, suggesting her country would impose targeted import duties on U.S. goods in sensitive areas. House Democrats on Tuesday introduced a bill that would require congressional approval for a president to impose tariffs due to claims of a national emergency, a largely symbolic action given Republicans’ coming control of both the House and Senate. “This legislation would enable Congress to limit this sweeping emergency authority and put in place the necessary Congressional oversight before any president – Democrat or Republican – could indiscriminately raise costs on the American people through tariffs,” said Rep. Suzan DelBene, D-Wash. But for Trump, tariffs are now a tested tool that seems less politically controversial even if the mandate he received in November’s election largely involved restraining inflation. The tariffs he imposed on China in his first term were continued by President Joe Biden, a Democrat who even expanded tariffs and restrictions on the world’s second largest economy. Biden administration officials looked at removing Trump’s tariffs in order to bring down inflationary pressures, only to find they were unlikely to help significantly. Tariffs were “so new and unique that it freaked everybody out in 2017,” said Stumo, but they were ultimately somewhat modest. Trump imposed tariffs on at the start of 2018, moves that might have pushed up prices in those sectors even though they also overlapped with plans to open washing machine plants in Tennessee and South Carolina. His administration also levied tariffs on steel and aluminum, including against allies. He then increased tariffs on China, leading to a trade conflict and a limited 2020 agreement that failed to Still, the dispute changed relations with China as more U.S. companies looked for alternative suppliers in other countries. also found the United States may have sacrificed some of its “soft power” as the Chinese population began to watch fewer American movies. The Federal Reserve kept inflation roughly on target, but factory construction spending never jumped in a way that suggested a lasting gain in manufacturing jobs. found the tariff war with China did nothing economically for the communities hurt by offshoring, but it did help Trump and Republicans in those communities politically. When Trump first became president in 2017, the federal government collected $34.6 billion in customs, duties and fees. That sum more than doubled under Trump to $70.8 billion in 2019, according to Office of Management and Budget records. While that sum might seem meaningful, it was relatively small compared to the overall economy. America’s gross domestic product is now $29.3 trillion, according to the Bureau of Economic Analysis. The total tariffs collected in the United States would equal less than 0.3% of GDP. The new tariffs being floated by Trump now are dramatically larger and there could be far more significant impacts. If Mexico, Canada, and China faced the additional tariffs proposed by Trump on all goods imported to the United States, that could be roughly equal to $266 billion in tax collections, a number that does not assume any disruptions in trade or retaliatory moves by other countries. The cost of those taxes would likely be borne by U.S. families, importers and domestic and foreign companies in the form of higher prices or lower profits. Former Biden administration officials said they worried that companies could piggyback on Trump’s tariffs — if they’re imposed — as a rationale to raise their prices, just as many companies after Russia’s invasion of Ukraine in 2022 boosted food and energy costs and gave several major companies the space to raise prices, according to their own earnings calls with investors. But what Trump didn’t really spell out is what might cause him to back down on tariffs and declare a victory. What he is creating instead with his tariff threats is a sense of uncertainty as companies and countries await the details to figure out what all of this could mean. “We know the key economic policy priorities of the incoming Trump administration, but we don’t know how or when they will be addressed,” said Greg Daco, chief U.S. economist at EY-Parthenon.He's been helping Donald Trump’s most contentious Cabinet picks try to win confirmation in the Senate.
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Biomanufacturing might appear to be centered around the cell line, which does enjoy a certain pride of place, ensconced as it is in the bioreactor, where conditions are carefully monitored and exquisitely controlled. Yet the cell line exists to generate a product. So, one might argue that biomanufacturing is in fact centered around the product, whether it is an antibody, a recombinant protein, or a vaccine. Admittedly, the product suffers various indignities during downstream processing, such as being transferred from one unit operation to the next, enduring capture, intermediate purification, and polishing. But in its own way, the product is quite as pampered as the cell line. The product must not be unduly diminished in quantity—and certainly not in quality, not at all. The product’s integrity must be preserved. To accommodate the product, biomanufacturers can take advantage of tools, such as chromatography columns and membrane filters, that can smooth the product’s downstream processing journey. Choosing the appropriate columns and filters can expedite purification, improve recovery, and increase productivity. Other tools include design of experiment (DOE) studies, which can improve the management of processing parameters, either through a traditional trial-and-error approach or through machine learning, which can predict how specific parameters may affect the entire process at different times under various conditions. Finally, the product may follow the usual downstream itinerary, a series of synchronized steps, or it may have the luxury of a single, integrated, end-to-end process—or something in between. So, let the cell line have its bioreactor throne. The product may soon travel the royal road of purification on the way to fill and finish. To see how the product’s path is becoming smoother and more continuous, read about the advances discussed in this article, which conveys the insights of a retinue of downstream processing experts. Large biotherapeutic molecules originate from a variety of sources—plasma, supernatant, or cell lysate, for example—with differing requirements for chromatographic separation. Size matters. But so do factors such as hydrodynamic radius, sensitivity to shear stress, propensity to aggregate or fragment, and the presence of closely related impurities, to name but a few. However, all of them, “suffer from slow diffusion and mass transfer kinetics and, as a result, low binding capacity,” Artur Stanczak, application specialist, process chromatography, Bio-Rad Laboratories, said in a recent webinar. This need not always be the case. Dealing with large molecules requires modern resins that are fit for purpose. Stanczak discussed aspects of Bio-Rad’s Nuvia resin family members, such as a narrow distribution range, optimized ligand density, and rigid hydrophilic phase matrix. For example, he said that with Nuvia resins, even high flow rates “won’t impact DBC [dynamic binding capacity] dramatically because of the rigid polymer structure.” The idea is to reduce nonspecific binding and free up some binding sites. Some of the resins, such as Nuvia HP-Q, offer properties such optimized pore structure and surface extenders. These allow for high DBC at high flow rates, and thus an improved recovery of the target product and an increase in productivity. DOE studies should be conducted to determine ideal conditions, including testing factors such as pH and conductivity. Understanding critical process parameters is also important for optimizing the filtration process. For example, parameters such as concentration, crossflow, and transmembrane pressure (TMP) determine transmembrane flux, which directly impacts filter performance. Ordinarily, these parameters are assessed via TMP excursions, which involve measuring volume flow through a membrane at specific time points. “This approach, however, only provides snapshots; it’s not predictive,” explains Mark Duerkop, PhD, CEO of Novasign. “The current setup relies heavily on trial and error, lacking a straightforward, systematic method.” Novasign’s intuitive software studio leverages machine learning to derive insights from an automated TMP excursion. From that training run, it automatically builds a model to simulate various scenarios in silico, guiding operators on optimizing their chosen parameters—whether the operators are interested in minimizing production time or managing diafiltration volume, pH, and excipient concentration. “Our digital twin tells you how to set up your process at laboratory scale and how to transition smoothly to pilot or manufacturing scale,” Duerkop asserts. The smart machine learning tool removes the need for repeated validation runs for each parameter change by simulating different scenarios digitally. It assists in decisions about membrane selection and optimal operation, indicating the ideal switching points between ultrafiltration, diafiltration, and a second ultrafiltration stage. It also provides insights into performance within continuous single-pass tangential flow filtration. According to Duerkop, the studio delivers significant savings in time, labor, and product compared with traditional trial-and-error or DOE approaches. Chromatography and filtration steps in a downstream process are employed to separate the desired product from host cell proteins and other process-related impurities. During process development, each step is optimized for removal of impurities, typically by quantifying them via affordable and easy-to-use commercial kits. The end goal is the serial diminution of impurities through the purification process until they are undetectable, or at least within acceptable limits. One exception has been the presence of viruses, which should not be detectable in the first place except as a contaminant. Instead, during scaled-down process validation, viruses are spiked in at each stage of the process and their removal tracked. This is typically carried out by a contract research organization using live virus under BSL2/3 conditions, which is expensive and can have long turnaround times. Regulatory agencies require data demonstrating the efficacy of the process to remove viruses before the product can be introduced into humans during clinical trials and commercial release. There is an option to disrupt that paradigm, says David Cetlin, senior director, R&D, MockV products, Cygnus Technologies. “The MockV approach replaces live viruses with noninfectious particles that mimic the same properties of that original virus,” he says. “They’re physiochemically similar, meaning that analyses can be straightforward. For example, the data you generate from a MockV MVM [minute virus of mice] kit should align pretty well with the data that you would generate from a live MVM study.” “Historically our customers were applying the kits predominantly for process development, resin screening, process optimization, and things like that,” Cetlin points out. But he adds that newly revised regulatory guidelines “enable customers to use our RVLP [retrovirus-like particle] kit product to actually validate their process and put that data into a regulatory submission.” At most biomanufacturers, downstream processing is performed one step at a time, with deliberate transfers of the product from one intermediate stage, accomplishing tasks such as protein A affinity purification and viral inactivation. But at some biomanufacturers, downstream processing is semicontinuous or even continuous. “Typically, end users connect different chromatography and filtration systems to get all steps of the process running at the same time,” says Joanna Pezzini, CEO, PAK BioSolutions. “And to do that, you need to build automation to have the different steps talk to each other, to make sure that they’re running at the same rate.” PAK BioSolutions offers a continuous end-to-end solution at three different scales from process development to commercial scale, allowing for purification of 2 to as many as 20,000 L per day. The company can connect multiple different steps of a biopharmaceutical purification process in a single system. “We can do diafiltration, chromatography, virus inactivation, inline concentration and filtration,” Pezzini remarks. “You can perform up to four unit operations simultaneously on a single system, and inline process analytical control technology assures that they run at the same rate.” “If you can do four different purification steps at the same time, you can produce four times more product or run four times faster,” she adds. The other benefit she touts is resin savings: “We run a lot of chromatography cycles on very small columns instead of a few chromatography cycles on very big columns, so you’re purchasing smaller volumes of resin for products that only require a few batches each year.” According to Pezzini, some companies that offer continuous manufacturing provide individual systems that perform one step in the process and leave it to the end user to build the automation that connects these different systems together. She says that unlike those companies, PAK BioSolutions is “creating a turnkey solution.” Upstream and downstream processes can be connected to form an end-to-end continuous platform as well, helping to bring down manufacturing costs along the way. Such platforms have been constructed by Enzene Biosciences, a contract development and manufacturing organization focused on biologics production. Enzene Biosciences has set out to reduce the cost of goods for innovative biologics manufacturing, aiming to reach $40 per gram by 2025. Until recently, the predominant technology for developing biologics has been—and largely remains—a fed-batch process. “With fed-batch, the only way to lower costs is by achieving a higher-titer clone or using an exceptionally large bioreactor,” explains Russell Miller, vice president of sales and marketing, Enzene Biosciences. “But even that may not be enough. We knew we needed to explore a different, more innovative technological basis.” “The EnzeneX platform is a fully connected, continuous manufacturing platform from start to finish,” Miller asserts. Specifically, the “start” is a bioreactor step that incorporates perfusion technology, and the “finish” is the step just before nanofiltration. The company’s website indicates that the Enzene platform “harnesses the power of intensified perfusion using alternate tangential flow and automated multicolumn chromatography to achieve continuous production of biologics.” Miller elaborates, “When you take the perfusion technology and you’re able to couple it with the elimination of hold tanks and run the process continuously [for 30 days], you enhance the opportunity to maximize productivity, which gives a commensurate reduction in cost of goods.” The company has facilities in Pune, India, and in Hopewell, NJ, and it has started a phased rollout of its EnzeneX 2.0 technology. Among the innovations is an enhanced cell line capable of producing a titer of 8–10 g/L—double the previous cell line’s titer. According to Miller, the new technology will enable Enzene to scale up the bioreactor to 1,000 L. The next phase will bring online artificial intelligence–powered process analytical technology, with the final phase centered around optimization of culture media to further boost productivity and efficiency.
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