How a critical cancer drug became hard to find in the U.S.

 In Health

Cisplatin, a crucial chemotherapy drug, has been in short supply since February. NBC News mapped the drug’s journey across the globe to show how the shortage came to be.

A shortage of a critical cancer drug that’s left doctors and patients in the U.S. scrambling for other treatment options began halfway around the world, at a drug manufacturing plant in Gujarat, India.

In December, a Food and Drug Administration investigation prompted Intas Pharmaceuticals to suspend the production of cisplatin because of concerns over the quality of the drug. The company supplies about 50% of the cisplatin used in the U.S., and by February, the drug — which is used to treat cancers of the bladder, brain, throat, cervix, lung, ovaries and testicles — had fallen into shortage, with other suppliers unable to fill the gap.

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In June, the FDA said that it would temporarily allow imports of the drug from China. The move will offer some relief but is not a long-term solution.

The disruption in India shows how one kink in a drug’s manufacturing process can throw the entire supply chain into disarray. But cisplatin — and many other drugs used here and around the world — isn’t simply imported from India to hospitals in the U.S. India is just one of several stops the drug makes in its manufacturing process.

Working with the United States Pharmacopeia Medicine Supply Map, a database that provides insights into the international drug supply chain, NBC News mapped cisplatin’s global journey, from the mines where a key component is extracted from the earth, to the distribution centers where it can be sent on its way to reach patients in need.

Step 1: Mining the raw material

Location: South Africa and Russia

Long before cisplatin can be used to treat cancer patients, its raw ingredient — platinum — needs to be mined.

Platinum is highly potent as a drug, and in certain forms, it can be used to slow or stop cancer cells, said Stephen Schondelmeyer, the director of the PRIME Institute, which researches topics related to pharmaceuticals. Cisplatin is just one platinum-based chemotherapy drug; carboplatin and oxaliplatin are two others.

But platinum is rare, and only sourced from a few countries — mainly South Africa and Russia.

That raises several potential issues, said Frank Gupton, the department chair of chemical and life science engineering at Virginia Commonwealth University, including supply vulnerabilities if disruptions in mining occur and potentially high prices, because the resource is controlled by only a handful of countries.

“There’s a general issue with sourcing this material because it’s all produced overseas,” he said.

The metal is first mined as ore deep underground and then refined to remove impurities.

Matt Christian, director of supply chain insights at United States Pharmacopeia (USP), said that refining platinum requires a special facility, because heavy exposure to the metal and the substances used to refine it can be dangerous.

Step 2: Manufacturing the API

Location: India and Germany

After the platinum has been refined, it’s sent to a manufacturing facility, where it is chemically converted into cisplatin, the active pharmaceutical ingredient, or API, Christian said.

The API is the part of the drug that’s responsible for the drug’s intended effect — in cisplatin’s case, that effect is killing cancer cells. (Another example is semaglutide, the API in the popular medications Ozempic and Wegovy.)

Alongside the API, drugs can also contain other ingredients, like preservatives that keep the medication stable or dyes that make it easier to identify.

The USP Medicine Supply Map has identified FDA-approved cisplatin API manufacturing facilities in Germany and India, though the group notes that it hasn’t done a comprehensive analysis of every cisplatin facility in the world.

Turning platinum into cisplatin is a challenging process, Gupton said. It involves synthesizing the metal with two other chemicals, ammonia and chlorine, which are also risky to work with.

As in all drug manufacturing, workers need to be careful not to expose themselves to the compounds, Gupton said, while also making sure they don’t contaminate the compounds.

“The problem you have is whenever you’re handling these materials in an open environment you can generate dust particles that are really difficult to contain,” he said.

The process is highly regulated, and the FDA will shut down a facility if it suspects there are contamination issues.

“Most of our shortages are due to a manufacturing interruption or a quality issue, something that either happened during the manufacturing process or something that’s at the site,” said Valerie Jensen, the associate director of the FDA’s drug shortage program.

Step 3: Fill finish

Location: Germany, Italy, India, the Netherlands and the United States

After the active ingredient is created, the final step is what’s known as “fill finish,” which involves packaging, labeling and preparing the drug for distribution, Christian said.

For cisplatin, the process occurs in FDA-approved facilities in Germany, Italy, India, the Netherlands and the United States, according to the USP Medicine Supply Map.

The drug is first put in its container — such as vials, syringes, or cartridges — and then sealed, Gupton said, adding that this step usually occurs under very controlled conditions to prevent contamination. The product is then inspected for any defects and a label is added.

The fill-finish facility may also distribute the drug, or it could be sent to a distribution center, Gupton said.

“Most have very complex distribution channels,” he said. “It’s just one level of complexity after another.”

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A ‘really significant challenge’

It was during these last two phases — API manufacturing and fill finish — that Intas Pharmaceuticals in India ran into problems with the FDA, pressuring it to suspend production last year, said Erin Fox, a supply chain expert and senior pharmacy director at the University of Utah.

“They had some quality problems that they needed to remediate, and they were not insignificant,” Fox said. What’s more, Intas workers appeared to be trying to conceal the problems. The FDA report noted that the company, using acid, destroyed documents related to the sterility and quality of the products ahead of the inspection. The agency also slammed the company over poor cleaning practices as well as failure to take measures to prevent microbial contamination.

Intas did not respond to a request for comment.

With Intas out of commission, however, the FDA couldn’t easily switch to another manufacturer or find an existing one willing to ramp up production.

Cisplatin is not an expensive drug; it’s sold for about $16 per dose, Fox said. Making the API, on the other hand, is expensive as well as complicated. The low profitability means that not many drugmakers are willing to do it, she said.

It’s not “worth it for them to go to all the trouble of manufacturing,” she said.

Even if another drugmaker is willing to make the drug, they can’t simply switch on production.

Producing drugs like cisplatin is a “really significant challenge,” Gupton said. “They’re highly regulated, highly inspected, and there are a lot of places that can’t meet the specifications.”

Schondelmeyer noted that “it probably takes two years at least from the time that we know we need a drug to get FDA approval and get a factory up and get production started again.”

The difficulty highlights how a single problem in the supply chain can disrupt access to necessary treatment.

“It’s a matter of public health and a matter of national security,” Schondelmeyer said.

Michael Thompson, 60, of Iowa, was diagnosed with stage 3 throat cancer in May. Two months later, in July, he learned he would not be able to get cisplatin because of the ongoing shortage and would instead be given carboplatin. While the drugs are similar — both are platinum-based — carboplatin is less effective in treating his condition, his doctors told him. (Carboplatin, also made by Intas, is also in shortage, according to the FDA.)

“You can’t prepare yourself for that kind of news,” Thompson said. “Dealing with cancer is hard enough. But then, man, you don’t want to be hit with the news that the treatments that you need aren’t available, because that is really tough to swallow.”

The FDA says it’s doing everything possible to address the shortage.

In June, the agency said it would work with the Chinese drugmaker Qilu Pharmaceutical to import cisplatin. The cisplatin from Qilu is marketed and manufactured in China, but is not approved by the FDA in the U.S., although the import strategy is expected to increase the U.S. supply of the chemotherapy drug.

“That is a temporary measure,” the FDA’s Jensen said. “That import will continue until all the approved manufacturers are able to meet all patient needs.”

Jensen also said that the FDA is expediting its review of anything that another company would need to ramp up productionor begin manufacturing cisplatin. The agency will also allow Intas Pharmaceuticals to distribute to the U.S. some cancer drugs that are in shortage, including cisplatin. However, a third party will need to verify the quality of the products before they are distributed, the agency said in a document.

The FDA’s moves are helpful, Fox said, but added they don’t solve the extensive supply chain issues.

“Clinicians are just really nervous about making plans for patients because there are a lot of unknowns right now,” she said.

In the meantime, Thompson hopes that the treatment he does receive will be effective. If not, his doctors are advising a total laryngectomy, or surgical removal of his larynx, which would leave him unable to speak.

“It’s an emotional struggle because you know you’re facing a life and death battle,” he said.


Source: NBC News

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