8 Ways Overseas Drug Manufacturers Dupe the FDA

[bostonbro]

KATHERINE EBAN

SCIENCE

08.07.2019 07:00 AM

8 Ways Overseas Drug Manufacturers Dupe the FDA

From taking inspectors hostage to making stuff up, generic drug makers can try to look like they were following the regulations while actually subverting them.

 

QILAI SHEN/GETTY IMAGES

 

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NINETY PERCENT OF the prescription drugs consumed in the United States are generics, and the majority of them are produced overseas, mostly in India and China. Let’s say you’re a manufacturer looking to get in on America’s $104 billion generic drug market. You want to make the lowest-cost drugs possible and sell them at the highest possible price. How best to proceed?

To do things right, you’ll need approval from the world’s most feared regulator, the US Food and Drug Administration. But that requires that you comply with so-called current good manufacturing practices, which are complex and costly to implement. Who wants to keep a pristine record of every step in the production process and be ready to submit to detailed inspections and data reviews? Wouldn’t it be better if you were able to look like you were following the regulations while actually subverting them instead?

Katherine Eban is an award-winning investigative journalist and the author of two books about the pharmaceutical industry, Dangerous Doses and Bottle of Lies. Buy now.

HARPER COLLINS

 

FDA inspectors typically show up unannounced at domestic manufacturing plants. But overseas operators often get weeks, or even months, of advance notice. That forewarning has given rise to an intricate web of global deception. Here are some of the more innovative techniques the FDA has run into.

 

1. Serve Inspectors Contaminated Water

Allegation

 

In March of 2013, FDA investigators visited a facility in Maharashtra, India, operated by Wockhardt Ltd.

During the inspection, they noticed that an employee seemed to be attempting to smuggle a black bag out of the plant. They chased him down a hallway and saw him hurl the bag into a stairwell. When the inspectors retrieved the bag, they found roughly 75 torn manufacturing records inside.

The records concerned the company’s insulin products. They showed that many of the vials Wockhardt had tested contained black metallic particles—which came from defective sterilizing equipment and were potentially deadly—and had failed visual inspection. As the investigators followed the paper trail, they uncovered a formulation area that Wockhardt hadn’t disclosed to the FDA, where the company was using corroded sterilizing equipment to make both insulin and injectable adenosine, used to treat an irregular heartbeat. (The adenosine was destined for the US market.)

Wockhardt’s plant operators also served them “unsealed water bottles,” the report notes, “and each investigator developed stomach problems during the course of inspection.” The vice president of manufacturing “appeared to be threatening investigators” when they refused to remove a finding from their report. “It is suggested that an inspectional team perform the follow-up inspection with a clear emergency plan in place prior to arrival,” the investigators concluded.

Outcome

Two months after the inspection, the FDA restricted the import of drugs from this plant into the United States. With $100 million in drug sales at stake, Wockhardt’s CEO assured investors then that the company would bring the plant into compliance “in a month, or two months maximum.” Six years later, the restriction remains in place. Wockhardt did not respond to requests for comment.

2. Pretest Your Samples in Secret

Allegation

 

In January of 2013, FDA investigators visited a facility in West Bengal, India, that manufactured chemotherapy drugs for the German pharmaceutical company Fresenius Kabi Oncology.

At the plant’s quality-control laboratory, an investigator scrutinized the results of high-performance liquid chromatography tests, which measure the impurities in a drug sample and display them as a series of peaks in a record called a chromatogram. Toggling back and forth between computer files, the investigator determined that the official chromatograms were stored in the appropriate folders. But in other folders, marked “MISC” and “DEMO,” he discovered what looked like earlier tests of the same drug samples, some a day apart, some a month apart. Not all of the plant’s files moreover, were stored on its main server.

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The technicians, it turned out, had apparently used these hidden, offline tests as a kind of dress rehearsal, tinkering with their instrument settings until they obtained the outcome they wanted. When they retested the samples in the plant’s official system, they were guaranteed a passing result. According to the FDA, the plant’s managing director had overseen the scheme.

Outcome

Fresenius Kabi claimed not to have realized what was happening in its own offshore plant until the FDA investigators uncovered it. In a subsequent probe, the company found that the plant had been blending poor-quality active ingredients with higher-quality ingredients and creating false manufacturing records. Fresenius Kabi halted production at the plant, fired the entire management, and recalled all the medicine made with reblended ingredients. A Fresenius Kabi spokesperson confirmed that the plant has resumed operations today.

3. Change Any Data You Don’t Like

Allegation

In January of 2014, FDA investigators visited a facility in Punjab, India, where Ranbaxy Laboratories made atorvastatin calcium, a generic version of the cholesterol fighter Lipitor.

 

Although Ranbaxy expected the inspection on a Monday, the investigators arrived unannounced the day before. According to the FDA’s inspection report, in the quality-control laboratory, they found dozens of workers hunched over documents and backdating them. On one desk, they found a notebook that appeared to list all the records the employees planned to falsify. There were Post-It notes stuck to numerous surfaces, apparently noting what data to change—employee trainings, laboratory analyses, cleaning records.

In the plant’s computer systems, investigators discovered even more consequential falsifications. The FDA requires plants to investigate failing, or “out-of-specification,” test results. But in the gas chromatography laboratory, technicians were retesting failing drug samples and “over-writing raw data files ... until acceptable results are achieved,” according to the investigators’ account.

Outcome

The FDA issued a warning letter to the plant and restricted its drugs from being imported into the United States. That restriction remains in place today under the plant’s current owner, Sun Pharma. Ranbaxy no longer exists.

4. Make Stuff Up

Allegation

In June of 2014, FDA investigators showed up unannounced at an Akorn India facility in Himachal Pradesh.

As a manufacturer of sterile drugs—including injectable forms of the antibiotics cephalosporin and meropenem—the plant was required to test its environment, including its air, water, and surfaces, to ensure they were free of microbial contamination. Investigators reported that the testing data appeared to be in perfect order; data worksheets in the microbiology laboratory showed that samples had been prepared, incubated, and examined. But the samples weren’t presented to the investigators. As an FDA inspection report noted, “According to the QC Microbiologist, these samples were never prepared/incubated, and the documentation had been falsified.” Much of the laboratory, it seemed, was fake.

 

Outcome

The plant did not get approval to market its drugs, and its products were restricted from being imported into the United States. A company spokesperson said that when Akorn learned of the issues at its Indian plant, it worked “tirelessly” to resolve them and, under a new management team, is exploring “strategic alternatives to exit its India facility.” The company, under a new CEO, is committed to “the highest standards of quality and compliance.”

5. Use a Secret Lab

Allegation

In August of 2016, FDA investigators visited a facility in Punjab, India, run by Parabolic Drugs.

During the inspection, an investigator claims to have found a filthy, small, locked laboratory, its entrance partially blocked by a piece of bulky equipment. Plant officials claimed that the laboratory had been decommissioned some six years earlier. But the FDA investigator demanded it be opened. After a lengthy and unsuccessful effort to find the key, the firm’s president broke in the door.

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Inside, the investigator found a computer running tests on ingredients for cephalosporin, an oral antibiotic used to treat bacterial infections. Some of those test results were not entered into the plant’s official data system, which, the inspectors wrote, was “necessary to assure compliance.”

Outcome

 

The plant was not approved to sell its drugs in the United States. Parabolic Drugs did not respond to requests for comment.

6. Allow Your Software to Crash

Allegation

In September of 2016, FDA investigators visited a Mylan Laboratories facility in Nashik, Maharashtra, after a whistleblower claimed that employees were deliberately corrupting data.

Upon inspection, the investigators discovered that the plant’s software system was riddled with error messages—“instrument malfunction,” “power loss,” “connection to chromatography system lost.” Plant managers had apparently conducted no investigation into the repeated crashes: one error message appeared 150 times in seven days, another 42 times. According to the FDA, they had simply retested the samples.

This led the FDA to suspect that the crashes had been intentional, just as the whistleblower had alleged. Instead of deleting unwelcome data, which would have left a trail of metadata, it appeared that Mylan had crashed its system, as though technicians had literally pulled the computer plug from the wall. The technique was so notable that FDA officials gave it a name: “crashing files.”

The company offered various explanations for the error messages. In confidential written responses to the FDA, it attributed some of the errors to “Ethernet cable disconnection, some of which were a result of a power interruption.” Mylan then added, “It is not evident through retrospective review whether these disconnection events were caused by manual intervention of cables (accidental knocking of cables), or through an electronic loss of signal.” The company assured the FDA that “there was no resultant impact to the integrity and appropriateness of the results.”

Outcome

 

In April 2017, the FDA issued a warning letter to the plant, restricting review of its drug applications. A Mylan spokesperson “absolutely and vehemently” denied allegations that the company was manipulating data, and added, “any explicit or implicit suggestion that Mylan or Mylan employees altered data or circumvented computer systems and jeopardized the quality of the medications we manufacture is false.” Last year, the FDA reinspected the plant, and lifted the warning letter.

7. Don’t Leave a Trail

Allegation

In March of 2015, FDA investigators visited a facility in northeastern China run by Zhejiang Hisun, the country’s largest exporter of pharmaceutical ingredients to the US. At the time, the company had a joint venture with Pfizer.

At the plant’s quality-control laboratory, an investigator searched the grid of computer audit trails, using his rudimentary college Mandarin. He figured out that the plant was secretly pretesting its drug samples and masking the results. In one instance, the FDA claims, technicians had disabled the audit trail, run 80 covert tests, then turned the trail back on two days later. The investigator found the telltale evidence in the software’s metadata.

On the third day of the inspection, as the investigator was returning from a lunch break, he saw an analyst quickly remove a thumb drive from one of the chromatography machines and slip it into his lab coat. The investigator asked that he hand over the thumb drive, but the man “began running and fled the laboratory premises,” according to the inspection report. Fifteen minutes later, a manager returned to offer him the thumb drive, but the investigator had no idea whether it was the same one. He noted the incident—a refusal to share records—as import-ending conduct.

Outcome

In the wake of the inspection, the FDA issued an import alert and blocked the plant from sending its drug ingredients to the United States. However, facing a shortage of the active ingredient for the chemotherapy drug daunorubicin, the US allowed the plant to continue shipping that drug. Two and a half years later, Pfizer ended its partnership with Zhejiang Hisun.

 

 

 

8. When in Doubt, Take the Investigator Hostage

 

Allegation

In July of 2017, an FDA investigator visited a facility in northeastern China where Zhejiang Bangli Medical Products manufactured lidocaine and capsaicin skin patches for treating pain.

According to internal emails reviewed by WIRED, soon after the investigator and her translator began their work, worried company officials started interrogating them and questioning their authority to inspect. After the firm’s general manager became visibly upset, the inspectors went to gather their things in the conference room. The GM refused to let them leave, effectively imprisoning them, and called the police, who, according to the FDA, claimed their credentials were fake. More than an hour later, after the intercession of Chinese drug regulators, the FDA employees were finally freed.

As FDA officials grappled with the incident, one deputy director wrote in an email to her colleagues, “It is our belief that [the general manager]quickly understood that the inspection was not going to go well and resorted to appalling intimidation tactics to try to get out of the inspection.” However, the agency declined to classify the incident as refusing an inspection—grounds for an automatic import ban—because it wasn’t clear whether the plant manager who’d imprisoned the investigators “was making a specified refusal,” one senior FDA official noted.

Outcome

In a follow-up inspection the next month, an investigator discovered that the plant was not actually testing any of its products or ingredients to ensure their purity or strength and didn’t have cleaning procedures for its manufacturing equipment. The plant was placed on an import alert, which meant that its products were banned from entering the United States. Zhejiang Bangli did not respond to requests for comment.

In response to this reporting, Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation, wrote, “Whether a drug is made in the U.S. or overseas, manufacturers must undergo the same rigorous application process, and the information must be fully reviewed by our highly trained scientific staff.” She added that in recent years the FDA has “conducted a number of unannounced inspections at foreign manufacturing facilities—a critical approach when we have information from a whistleblower or when the FDA is investigating a drug safety issue."

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Adapted from Bottle of Lies: The Inside Story of the Generic Drug Boom, by Katherine Eban. Copyright © 2019 by Katherine Eban. Reprinted courtesy of Ecco, an imprint of HarperCollins Publishers.

 

 

 

 

 

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