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Radiopharma CDMOs navigate supply chain, raw material challenges as demand goes nuclear

Novartis recently said that sales of its radiopharmaceutical Pluvicto came in lower than expected in the third quarter as a result of manufacturing issues,…

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Novartis recently said that sales of its radiopharmaceutical Pluvicto came in lower than expected in the third quarter as a result of manufacturing issues, underscoring the tension between the explosive growth in the burgeoning market and the challenges to making these radiotherapies.

There were shortages of Pluvicto after “quality issues” were found at two manufacturing sites, and the Big Pharma had to switch production to an Italian facility and then ship the product to the US. With short half-lives of the raw materials, it only had five days to ship the therapy to patients.

“We continue to believe Pluvicto is going to be a multibillion-dollar medicine,” CEO Vas Narasimhan told investors on Oct. 24.

Pluvicto’s manufacturing woes are just one example of the challenges facing the radiopharmaceutical manufacturing sector. There are 55 FDA-approved drugs, diagnostics and imaging assets in the market, with over 400 radiopharma therapies either in clinical trials or awaiting regulatory approval.

Stephen Belcher

“It is just an absolute explosion … just an immense amount of drugs and new radioisotopes,” said Stephen Belcher, CEO of Radioisotope Life Sciences (RLS).

“The demand is drastically increasing as we speak to a point where the industry is dealing with different types of bottlenecks,” AtomVie CEO Bruno Paquin added.

According to six radiopharma CDMOs interviewed by Endpoints News, these bottlenecks come in two forms: figuring out the best supply chain approach, and ensuring consistent access to raw materials.

Across the industry, CDMOs are reviewing their supply chains to see if they are fit for purpose for the biopharmas they count as clients. What might work in a clinical trial setting may not work for commercial distribution. What might work for a radiopharma ingredient that decays within 24 hours might not be optimal for one with a longer half-life.

Bruno Paquin

Manufacturers are also in competition for the same raw materials. “For the next three or four years, there will be a shortage on the supply of isotopes,” NorthStar Medical Radioisotopes CEO Frank Scholz noted.

But the same insiders agree that these are simply growing pains. As Belcher describes it, it’s an opportunity for radiopharma CDMOs “to shape what manufacturing looks like going into the future.”

Centralized versus decentralized

Radiopharma CDMOs need to be strategic when thinking of their supply chains. Radioisotopes have finicky half-lives, which is a measure of how quickly it takes for the raw material to decay. Some radiotherapies may have very short shelf lives, making them impossible to stockpile. In some ways, it’s like trying to transport melting ice.

Certain CDMOs like AtomVie and NorthStar currently take a more centralized approach, in that they have a main hub for their manufacturing services. For example, Northstar is mainly at its five facilities within a single campus at Rock County, WI. In contrast, CDMOs like RLS and SpectronRx have a decentralized model. Those manufacturers have a variety of locations that manufacture radiopharmaceuticals so that they are produced closer to where they are used.

Frank Scholz

The beauty behind a centralized approach is that it can ease cost pressures. “You have a greater economy of scale,” Scholz added.

Having a single site can make it easier for quality control, AtomVie’s Paquin added. AtomVie has two facilities in Hamilton, Canada, with one near the Hamilton airport and less than an hour’s drive from the US border.

But a centralized model makes it harder to cater to patients much farther from the manufacturing site. To take the radioisotope’s half-life into account, manufacturers may have to ship more product than needed so that the right volume arrives onsite, Scholz noted. “The shorter the half-life is, the more you’re challenged by your centralized model,” he added.

The alternative is a decentralized model. This approach is more suited for large volumes and de-risks the supply chain by having multiple manufacturing locations, SpectronRx CEO John Zehner said. In a centralized model, the manufacturer may end up being too reliant on third-party distributors, Zehner added.

John Zehner

SpectronRx has three facilities in Indiana and one in Connecticut, with plans for a new facility in Belgium. Meanwhile, according to PharmaLogic general manager Scott Holbrook, it has been expanding to serve 100% of Canada and 85% of the US.

There needs to be “a national manufacturing network and distribution established in order to be able to make short shelf life radiotherapies available everywhere,” Holbrook added.

However, a decentralized supply chain makes maintaining compliance and quality throughout each facility difficult, as the FDA is “used to traditional pharma where you’ve got one centralized location,” Belcher noted. The agency is “looking for a very high level of consistent quality to ensure that the products are made at a certain level.”

And this can be expensive, Belcher noted. RLS, which only recently expanded to provide CDMO services, purchased GE Healthcare’s 31 radiopharmacy sites in 2020. “We benefit from the fact that GE spent the money to take all 31 sites in the US and make them look exactly the same from a cleanroom perspective,” he added.

With an increasing number of therapies potentially hitting the market in the future, insiders say that a decentralized approach is likely in the cards.

“We are considering opening other facilities, whether it’s in the US or Europe to get decentralized as well and to help with redundancy,” AtomVie’s Paquin said. “Our default is we want to centralize, but when it doesn’t make sense economically to ensure reliability for patients, we have to decentralize,” NorthStar’s Scholz noted.

While there is an ongoing debate about centralized versus decentralized models, it will ultimately be driven by the reality of the half-life of isotopes, Scholz added.

Competition for raw materials

Also, due to challenging half-lives, there is increasing competition for raw materials, which are already in shortage. “The key to being successful is to be aware of those [raw material challenges] and to come up with multiple strategies,” Holbrook said.

Scott Holbrook

Actinium is one example of an isotope in shortage. There is an insufficient supply for clinical trials, which may be a bottleneck for such radiopharmaceuticals from getting to market, Scholz added.

Not only are radioisotopes difficult to produce due to short half-lives, but being too reliant on a single raw material provider is also an issue. For example, Russia is the main, if not the predominant, source for lutetium, Holbrook noted. “Having a single-country source of raw material is kind of scary, and you could see how that could be an issue.”

The key is for CDMOs to diversify their sources. It is about partnering with multiple radioisotope providers so that “if one goes down, we have another avenue to bring those isotopes,” Belcher said. Charles Conroy, CEO of Nucleus RadioPharma, added it is looking to be “an aggregator of supply, working with many great producers of isotopes” as it offers the lowest risk and widest breadth of options for patients.

There is the option for CDMOs to produce their own raw materials, Belcher added. Companies like Northstar and SpectronRx not only have CDMO abilities, but they also each manufacture radioisotopes to use internally and to supply externally.

While in-house raw material production could sidestep shortage risk, this is not an easy feat. “The production of isotopes is very unique. It is a somewhat small business, so the staff is much more difficult to get,” Zehner said.

“It can be done but with a lot of caution,” Paquin added. “Only in limited circumstances would we become an isotope manufacturer,” Conroy noted.

Nevertheless, to move forward, manufacturers need to address these shortfalls to support the radiopharma therapies that are in or on the way to the commercial market. “This [radiopharmaceuticals] will ultimately be another leg of cancer treatment, next to the classical cancer treatments. We will make a huge difference for patients with cancers, which are right now hard to treat,” Scholz added.

Additional reporting by Reynald Castañeda.

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There will soon be one million seats on this popular Amtrak route

“More people are taking the train than ever before,” says Amtrak’s Executive Vice President.

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While the size of the United States makes it hard for it to compete with the inter-city train access available in places like Japan and many European countries, Amtrak trains are a very popular transportation option in certain pockets of the country — so much so that the country’s national railway company is expanding its Northeast Corridor by more than one million seats.

Related: This is what it's like to take a 19-hour train from New York to Chicago

Running from Boston all the way south to Washington, D.C., the route is one of the most popular as it passes through the most densely populated part of the country and serves as a commuter train for those who need to go between East Coast cities such as New York and Philadelphia for business.

Veronika Bondarenko captured this photo of New York’s Moynihan Train Hall. 

Veronika Bondarenko

Amtrak launches new routes, promises travelers ‘additional travel options’

Earlier this month, Amtrak announced that it was adding four additional Northeastern routes to its schedule — two more routes between New York’s Penn Station and Union Station in Washington, D.C. on the weekend, a new early-morning weekday route between New York and Philadelphia’s William H. Gray III 30th Street Station and a weekend route between Philadelphia and Boston’s South Station.

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According to Amtrak, these additions will increase Northeast Corridor’s service by 20% on the weekdays and 10% on the weekends for a total of one million additional seats when counted by how many will ride the corridor over the year.

“More people are taking the train than ever before and we’re proud to offer our customers additional travel options when they ride with us on the Northeast Regional,” Amtrak Executive Vice President and Chief Commercial Officer Eliot Hamlisch said in a statement on the new routes. “The Northeast Regional gets you where you want to go comfortably, conveniently and sustainably as you breeze past traffic on I-95 for a more enjoyable travel experience.”

Here are some of the other Amtrak changes you can expect to see

Amtrak also said that, in the 2023 financial year, the Northeast Corridor had nearly 9.2 million riders — 8% more than it had pre-pandemic and a 29% increase from 2022. The higher demand, particularly during both off-peak hours and the time when many business travelers use to get to work, is pushing Amtrak to invest into this corridor in particular.

To reach more customers, Amtrak has also made several changes to both its routes and pricing system. In the fall of 2023, it introduced a type of new “Night Owl Fare” — if traveling during very late or very early hours, one can go between cities like New York and Philadelphia or Philadelphia and Washington. D.C. for $5 to $15.

As travel on the same routes during peak hours can reach as much as $300, this was a deliberate move to reach those who have the flexibility of time and might have otherwise preferred more affordable methods of transportation such as the bus. After seeing strong uptake, Amtrak added this type of fare to more Boston routes.

The largest distances, such as the ones between Boston and New York or New York and Washington, are available at the lowest rate for $20.

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The next pandemic? It’s already here for Earth’s wildlife

Bird flu is decimating species already threatened by climate change and habitat loss.

I am a conservation biologist who studies emerging infectious diseases. When people ask me what I think the next pandemic will be I often say that we are in the midst of one – it’s just afflicting a great many species more than ours.

I am referring to the highly pathogenic strain of avian influenza H5N1 (HPAI H5N1), otherwise known as bird flu, which has killed millions of birds and unknown numbers of mammals, particularly during the past three years.

This is the strain that emerged in domestic geese in China in 1997 and quickly jumped to humans in south-east Asia with a mortality rate of around 40-50%. My research group encountered the virus when it killed a mammal, an endangered Owston’s palm civet, in a captive breeding programme in Cuc Phuong National Park Vietnam in 2005.

How these animals caught bird flu was never confirmed. Their diet is mainly earthworms, so they had not been infected by eating diseased poultry like many captive tigers in the region.

This discovery prompted us to collate all confirmed reports of fatal infection with bird flu to assess just how broad a threat to wildlife this virus might pose.

This is how a newly discovered virus in Chinese poultry came to threaten so much of the world’s biodiversity.

H5N1 originated on a Chinese poultry farm in 1997. ChameleonsEye/Shutterstock

The first signs

Until December 2005, most confirmed infections had been found in a few zoos and rescue centres in Thailand and Cambodia. Our analysis in 2006 showed that nearly half (48%) of all the different groups of birds (known to taxonomists as “orders”) contained a species in which a fatal infection of bird flu had been reported. These 13 orders comprised 84% of all bird species.

We reasoned 20 years ago that the strains of H5N1 circulating were probably highly pathogenic to all bird orders. We also showed that the list of confirmed infected species included those that were globally threatened and that important habitats, such as Vietnam’s Mekong delta, lay close to reported poultry outbreaks.

Mammals known to be susceptible to bird flu during the early 2000s included primates, rodents, pigs and rabbits. Large carnivores such as Bengal tigers and clouded leopards were reported to have been killed, as well as domestic cats.

Our 2006 paper showed the ease with which this virus crossed species barriers and suggested it might one day produce a pandemic-scale threat to global biodiversity.

Unfortunately, our warnings were correct.

A roving sickness

Two decades on, bird flu is killing species from the high Arctic to mainland Antarctica.

In the past couple of years, bird flu has spread rapidly across Europe and infiltrated North and South America, killing millions of poultry and a variety of bird and mammal species. A recent paper found that 26 countries have reported at least 48 mammal species that have died from the virus since 2020, when the latest increase in reported infections started.

Not even the ocean is safe. Since 2020, 13 species of aquatic mammal have succumbed, including American sea lions, porpoises and dolphins, often dying in their thousands in South America. A wide range of scavenging and predatory mammals that live on land are now also confirmed to be susceptible, including mountain lions, lynx, brown, black and polar bears.

The UK alone has lost over 75% of its great skuas and seen a 25% decline in northern gannets. Recent declines in sandwich terns (35%) and common terns (42%) were also largely driven by the virus.

Scientists haven’t managed to completely sequence the virus in all affected species. Research and continuous surveillance could tell us how adaptable it ultimately becomes, and whether it can jump to even more species. We know it can already infect humans – one or more genetic mutations may make it more infectious.

At the crossroads

Between January 1 2003 and December 21 2023, 882 cases of human infection with the H5N1 virus were reported from 23 countries, of which 461 (52%) were fatal.

Of these fatal cases, more than half were in Vietnam, China, Cambodia and Laos. Poultry-to-human infections were first recorded in Cambodia in December 2003. Intermittent cases were reported until 2014, followed by a gap until 2023, yielding 41 deaths from 64 cases. The subtype of H5N1 virus responsible has been detected in poultry in Cambodia since 2014. In the early 2000s, the H5N1 virus circulating had a high human mortality rate, so it is worrying that we are now starting to see people dying after contact with poultry again.

It’s not just H5 subtypes of bird flu that concern humans. The H10N1 virus was originally isolated from wild birds in South Korea, but has also been reported in samples from China and Mongolia.

Recent research found that these particular virus subtypes may be able to jump to humans after they were found to be pathogenic in laboratory mice and ferrets. The first person who was confirmed to be infected with H10N5 died in China on January 27 2024, but this patient was also suffering from seasonal flu (H3N2). They had been exposed to live poultry which also tested positive for H10N5.

Species already threatened with extinction are among those which have died due to bird flu in the past three years. The first deaths from the virus in mainland Antarctica have just been confirmed in skuas, highlighting a looming threat to penguin colonies whose eggs and chicks skuas prey on. Humboldt penguins have already been killed by the virus in Chile.

A colony of king penguins.
Remote penguin colonies are already threatened by climate change. AndreAnita/Shutterstock

How can we stem this tsunami of H5N1 and other avian influenzas? Completely overhaul poultry production on a global scale. Make farms self-sufficient in rearing eggs and chicks instead of exporting them internationally. The trend towards megafarms containing over a million birds must be stopped in its tracks.

To prevent the worst outcomes for this virus, we must revisit its primary source: the incubator of intensive poultry farms.

Diana Bell does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

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This is the biggest money mistake you’re making during travel

A retail expert talks of some common money mistakes travelers make on their trips.

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Travel is expensive. Despite the explosion of travel demand in the two years since the world opened up from the pandemic, survey after survey shows that financial reasons are the biggest factor keeping some from taking their desired trips.

Airfare, accommodation as well as food and entertainment during the trip have all outpaced inflation over the last four years.

Related: This is why we're still spending an insane amount of money on travel

But while there are multiple tricks and “travel hacks” for finding cheaper plane tickets and accommodation, the biggest financial mistake that leads to blown travel budgets is much smaller and more insidious.

A traveler watches a plane takeoff at an airport gate.

Jeshoots on Unsplash

This is what you should (and shouldn’t) spend your money on while abroad

“When it comes to traveling, it's hard to resist buying items so you can have a piece of that memory at home,” Kristen Gall, a retail expert who heads the financial planning section at points-back platform Rakuten, told Travel + Leisure in an interview. “However, it's important to remember that you don't need every souvenir that catches your eye.”

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According to Gall, souvenirs not only have a tendency to add up in price but also weight which can in turn require one to pay for extra weight or even another suitcase at the airport — over the last two months, airlines like Delta  (DAL) , American Airlines  (AAL)  and JetBlue Airways  (JBLU)  have all followed each other in increasing baggage prices to in some cases as much as $60 for a first bag and $100 for a second one.

While such extras may not seem like a lot compared to the thousands one might have spent on the hotel and ticket, they all have what is sometimes known as a “coffee” or “takeout effect” in which small expenses can lead one to overspend by a large amount.

‘Save up for one special thing rather than a bunch of trinkets…’

“When traveling abroad, I recommend only purchasing items that you can't get back at home, or that are small enough to not impact your luggage weight,” Gall said. “If you’re set on bringing home a souvenir, save up for one special thing, rather than wasting your money on a bunch of trinkets you may not think twice about once you return home.”

Along with the immediate costs, there is also the risk of purchasing things that go to waste when returning home from an international vacation. Alcohol is subject to airlines’ liquid rules while certain types of foods, particularly meat and other animal products, can be confiscated by customs. 

While one incident of losing an expensive bottle of liquor or cheese brought back from a country like France will often make travelers forever careful, those who travel internationally less frequently will often be unaware of specific rules and be forced to part with something they spent money on at the airport.

“It's important to keep in mind that you're going to have to travel back with everything you purchased,” Gall continued. “[…] Be careful when buying food or wine, as it may not make it through customs. Foods like chocolate are typically fine, but items like meat and produce are likely prohibited to come back into the country.

Related: Veteran fund manager picks favorite stocks for 2024

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