The COVID Vaccines Are Approaching. Is the FDA Ready to Inspect the Plants Where They’re Made?

Arie Menachem faced an overwhelming task when he arrived in Durham, North Carolina, to inspect a sprawling vaccine plant operated by Merck Sharp & Dohme, a subsidiary of the drugmaker Merck, on October 22, 2018. The facility, the Maurice R. Hilleman Center for Vaccine Manufacturing, makes an array of vaccines, including ones to fight chickenpox and shingles, and to prevent mumps, measles, and rubella, known as M-M-R_II, given to children starting at age one. Menachem, a consumer safety officer with the U.S. Food and Drug Administration, estimated that the plant was roughly the length of 13 football fields. Yet he had been sent alone and given only nine days to inspect it.

Menachem, whose experience at the Merck plant has not been previously disclosed, was part of a specialized FDA division called Team Biologics, an elite unit comprised of 14 investigators who inspect the 280 manufacturing plants that make vaccines and blood products for U.S. patients and ensure manufacturers follow the detailed rules such work requires.

In the world of drugmaking, there is little as critical as the safe operations of a manufacturing plant that makes sterile injectable drugs, where potential contamination can prove deadly. Employees must move slowly and deliberately, so as not to disturb airflow. They must wear sterile gowning and cannot move from a less to a more restricted area without regowning, so as not to introduce contaminants. The rules, known as current good manufacturing practices, become more stringent the closer one gets to the sterile core of the plant, where vials of medicine may sit open.

On his first afternoon at Merck’s Durham plant, Menachem’s concern deepened when his FDA supervisor belatedly emailed him a 19-page document, sent to the agency from a confidential informant at the facility. The allegations described a biohazard nightmare. Workers appeared to be defecating and urinating in their uniforms, and feces had been found smeared on the floor of the plant’s production area, the letter alleged. In a sterile manufacturing plant, bathroom breaks can be difficult to take because they require additional time, which could serve as one possible explanation for the events inside the Merck plant. Ungowning can take 15 minutes, regowning can take 15 minutes, and on a night shift, there may be no one else to cover an essential worker during that time, Menachem said.

The problem was so serious that Cintas, which supplied and laundered uniforms for the plant’s technicians, had complained to Merck about the unsanitary condition of the gowning, the letter stated. “I was shocked and incredibly scared,” Menachem recalled of the complex inspection that lay before him. “I felt such a heavy burden of responsibility.”

But perhaps even more troubling, the document included an 11-page letter that the informant had first sent to the FDA in January 2016, which did not seem to have been forwarded to investigators. That letter included similar allegations: Fecal matter had been found on sterile garments and on the floor of controlled areas; a urine-filled glove had been tied up and placed in a trash container in a critical production area; technicians had been caught on video dancing in clean room suites, thus sending potentially dangerous particulates into the air. The allegations suggested a manufacturing plant that was out of control, and that prioritized production at the expense of patient safety.

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The informant wrote in the 2018 letter, “How is it that a company that is so heavily regulated due to the criticality of what we manufacture, these VIOLATIONS are allowed to take place year-after-year-after-year.” Until the plant’s managers started firing employees, the letter went on, “this facility will never change. Hopefully, it will change before the death of a child or adult from one of our vaccines.”

In a written statement, a Merck spokesperson told Vanity Fair, “Merck’s top priorities are patient safety, employee safety, and product quality.”

Given the severity of the allegations, Menachem again asked his supervisor for backup. For the agency’s previous three inspections of the Merck plant, the FDA had sent at least two investigators. That approach allowed them to fan out across the facility and question staff separately, to ensure they got a candid picture of the manufacturing plant’s operations. It was also recommended FDA procedure to have two investigators present when dealing with a whistleblower. Menachem said his supervisor not only denied his request for help, but blocked him from pursuing an adequate investigation, even after he was able to corroborate key aspects of the whistleblower’s allegations. That obstruction put the public at risk, he contended.

Vanity Fair confirmed this account of Menachem’s Merck inspection, and events inside Team Biologics, through interviews with four current or former FDA employees, including Menachem, a detailed review of documents, and an analysis of Team Biologics inspection data. One person with knowledge of the Merck investigation described it as “malfeasance” by the FDA.

Menachem—who holds a master’s degree in biochemistry and worked for 13 years in quality assurance and compliance at several pharmaceutical companies before joining the FDA in 2014 as a drug specialist—was so troubled by what unfolded that he became a whistleblower himself. In November 2018, one month after the Merck inspection, he filed a complaint with the U.S. Office of Special Counsel, an independent federal agency that protects government whistleblowers. Claiming that the FDA was failing to properly regulate vaccine- and biologics-manufacturing plants, Menachem alleged that after inspections at Merck, and three other manufacturing plants, his supervisor and other FDA compliance officials improperly downgraded his findings and allowed the facilities to escape regulatory enforcement.

In May 2019, Menachem resigned from the FDA and today works as a vice president for quality and regulatory compliance at a major European pharmaceutical company. “If the FDA’s responsibility is to ensure that everything is done correctly,” he said, “the FDA is not doing its job.”

In a statement, an FDA spokesperson said the agency’s goal, “is ensuring the American public has access to safe, effective medical products manufactured in compliance with current good manufacturing practice.”

Merck said in its statement, “Assertions that any act by Merck personnel at any of our facilities endangered the safety or lives of those who took Merck’s vaccines is patently and demonstrably false.” It noted, “The Hilleman site operates in a state of continuous compliance with [good manufacturing practice] requirements and has a long, successful inspectional history that reflects this.”

It added, “From time to time, we have been made aware of isolated occurrences involving extraneous material in gowns sent for cleaning. No such incident posed any threat to patients or product quality.”

A Cintas spokesperson did not respond to repeated phone calls and emails for comment.

As we stand at the threshold of one of the largest mass-vaccination campaigns in human history, we need the public to trust vaccines. Without millions of Americans willing to roll up their sleeves for a COVID-19 vaccine—which could be approved within weeks—there appears to be no exit from the devastating SARS-CoV-2 pandemic, which is growing worse by the day. Its uncontrolled spread, fueled by the Trump administration’s disinterest and catastrophic mismanagement, has so far sickened over 13 million in the U.S. and killed close to 270,000.

Amid this carnage, vaccine development has stood out as a bright spot of concerted government effort. Under a public-private partnership launched by the Health and Human Services Department and the Department of Defense, a program called Operation Warp Speed has invested more than $12 billion in developing COVID-19 treatments and vaccines. Several of those are now in Phase III clinical trials, typically the last stage of development before approval. Moderna announced that its vaccine, funded by Operation Warp Speed, appears to be almost 95% effective against COVID-19, according to preliminary testing data. Pfizer, which has not received Operation Warp Speed development money, but has presold 100 million doses to the federal government, has announced similar results. (Merck is also developing two COVID-19 vaccines, though they are still in an early phase and have not received government funding.)

There is no reason to think, from the alleged events at Merck’s Durham plant or lapses in FDA inspections, that vaccines pose an underlying threat to health and safety, or that so-called anti-vaxxers are onto something. Their movement, which often posits a link between childhood vaccines and autism, has relied on debunked science riddled with ethical conflicts, promulgated by a British doctor who has since been drummed out of the medical profession. To the contrary, vaccines stand out as one of the world’s great public health achievements, all but eradicating fearsome diseases from smallpox to polio.

“Vaccines have saved millions of lives, there is no doubt about it,” said Dr. Stuart Blume, emeritus professor of science and technology studies at the University of Amsterdam in the Netherlands. “We’re not aware of what it was like before [vaccines]…and that’s fed into a kind of complacency.”

This fall Donald Trump’s public bullying of the FDA to approve a pre-election COVID vaccine–which sparked fears of a politically tainted drug-approval process—had a devastating impact on public confidence. In September a Kaiser Health News poll of over a thousand people found that 6 in 10 Americans would not take a COVID-19 vaccine if it were approved before the election. “When it comes to building public confidence, don’t mix up vaccination campaigns and elections,” said Heidi Larson, director of the Vaccine Confidence Project at the London School of Hygiene & Tropical Medicine. “It’s 101 in global health.” To reassure a jittery public, Dr. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, has pledged that he and his staff will be driven only by science in deciding whether to approve a COVID-19 vaccine, a pledge echoed by FDA Commissioner Stephen Hahn.

As for any drug, the safety and efficacy of vaccines lie not just in their development, but in how they’re manufactured. But as the FDA’s impending vaccine-approval decisions have dominated public discussion, the unprecedented effort to actually make the more than 300 million doses that a successful national vaccination effort will require has gotten less attention. Vital questions about the FDA’s inspections of vaccine plants have slipped under the radar. “Oversight of the manufacturing process is a very important part of what the FDA does,” said Dr. Joshua Sharfstein, vice dean for public health practice and community engagement at the Johns Hopkins Bloomberg School of Public Health. While expressing confidence in FDA oversight, he added, “There is not a lot of room for error on a COVID vaccine.”

Menachem’s experience inside Team Biologics is critical now because it raises questions about the FDA’s oversight of the manufacturing plants that will be producing COVID-19 vaccines. Because such facilities face financial and production pressures that are often at odds with safety, regulatory oversight is essential. As well, shifting any drug in development from a controlled laboratory setting to the manufacturing floor, and scaling up production from thousands to millions of doses, can present a minefield of hazards, leading drugs to become unstable or impure.

The FDA’s Team Biologics investigators work to ensure that vaccine manufacturing plants–which are fundamentally perilous environments ripe for human error—operate safely. The work is “mentally exhausting and physically exhausting,” said a person who has inspected vaccine plants for the FDA. “It’s the hardest work I’ve ever done for the agency. [To] fully go in” and inspect the large number of highly technical manufacturing steps, the source explained, “you’re there 12 hours a day.”

Four people familiar with its operations told Vanity Fair that Team Biologics, staffed with only 14 investigators, is riven by conflict, dissent, personnel complaints, and low morale, and overseen by inexperienced supervisors. Supervisors routinely downgrade investigators’ recommendations that plants make urgent changes to their operations, those four people said. From 2015 to 2019, despite serious findings by investigators, not a single inspection performed by Team Biologics resulted in a warning letter, the FDA’s principal method for forcing a drug plant to comply with manufacturing rules, an analysis of FDA inspection data revealed. This permissive attitude toward vaccine and biologics plants has allowed manufacturing plants with quality deficits to continue operating unimpeded, said Menachem.

In its statement, an FDA spokesperson said that the FDA uses “ongoing interactions with manufacturers to help resolve process and compliance issues. Open communication often achieves more timely and effective corrective action to inspectional findings than does the regulatory process.”

Even before a COVID-19 vaccine has been approved, manufacturing plants are already churning them out in advance, to be ready if and when the FDA grants emergency approval. But so far those plants are not undergoing full FDA inspections, which the agency often performs before approving a new drug, one person familiar with the process told Vanity Fair. Instead, this person said, Team Biologics investigators are making site visits and submitting their findings in internal memos, rather than typical public inspection reports. “They won’t be publicly released, which is the reason they’re doing it,” the person told Vanity Fair. “It’s not really a good process. It seems like a lot of people are trying to dilute any findings, if there are some.”

An FDA spokesperson stated that the FDA relies on data from manufacturers, record reviews, site visits, and an evaluation of compliance history to assess manufacturing plants making products approved under emergency authorization, and has conducted “two such investigations of manufacturers of COVID-19 vaccines to date.”

Though Menachem’s inspection at Merck involved but one plant, and one nine-day period, the events there became infamous within Team Biologics and stood out as a “colossal disaster” that “never should have happened,” said one person familiar with the issues involved. It seemed to crystallize the crisis of regulation gripping Team Biologics.

That October, as Menachem began his inspection at Merck’s Durham plant, he caught clear glimmers of the problems captured in the informant’s letter. Typically, a highly controlled sterile plant will make it difficult for workers to violate protocols. It will limit entry to sterile areas of the plant and configure doorways so workers have to follow the unidirectional airflow. Gowning for sensitive production areas known as clean rooms may be a different color to ensure that workers change into unique garb when entering those zones. But at the Merck plant, the sterile gowning for different areas was the same color, and Menachem saw that placement of the door handles allowed staff to move from uncontrolled to more controlled rooms without regowning. (Merck contended that door handles were positioned to comply with North Carolina’s building code and that personnel were trained to observe unidirectional airflow. Since then, the company said it has further distinguished between less and more controlled areas by adding signs for workers, a door alarm, and requiring different-colored hair nets between the two areas.)

Menachem made contact with the whistleblower, who shared a photo of a trash bin with a sign for workers to discard gowning that contained feces, urine, or blood. The whistleblower’s letter said that the trash bins had been set outside men’s and women’s dressing rooms near production areas in May 2018, after Cintas had complained of receiving five garments contaminated with blood, urine, or fecal matter over the course of a month. But the bins had been removed during Menachem’s inspection, the whistleblower told him. “They were hiding evidence quicker than I could find it,” Menachem recalled of the plant’s management.

Merck denied that it was hiding evidence from the FDA.

When Menachem asked to see any complaints made against the plant by gown provider Cintas, plant officials redacted 13 of the 15 they shared with Menachem, stating they were financial in nature. They had uttered “the magic word,” said Menachem. “I can’t ask them about financial stuff.” Though manufacturing plants are required to give the FDA all materials related to product quality, they don’t have to share information related to their business operations.

While workers failing to get to a bathroom at a sterile manufacturing plant might seem uniquely horrifying, it’s not unprecedented. In 2011, the FDA found urine in a 10-gallon can in the plant of a cancer-drug manufacturer, Ben Venue Laboratories in Bedford, Ohio, which was ultimately forced into a consent decree with the agency. “They were pushing the workers so hard, they couldn’t get out to go to the bathroom,” recounted Steven Lynn, a former FDA regulator who oversaw the agency’s issuance of a consent decree against Ben Venue Laboratories, and now consults for pharmaceutical companies.

Vanity Fair asked Lynn to review the Merck whistleblower’s allegations, to assess whether he deemed them credible and how the FDA should have responded. “Even if only a few of the allegations noted in the letter are factual and true, it could represent a clear and present danger to the quality of the vaccines manufactured at that site,” he said, adding of the allegations’ severity, “This is a ‘show up unannounced during the night shift with a team of vaccine, steriles, and lab experts’ type of investigation.”

Responding to the photograph of the waste bin, Lynn added, “In all the manufacturing plants I’ve been in, I’ve never seen a sign like this. Why is that there? Why are you telling people to throw away urine and feces?”

Merck stated that biohazard bins had been placed in the plant several years ago “so that in rare circumstances when they may be necessary, it is clear where personnel must dispose of gowns that cannot be relaundered.” It added, “The presence of these bins does not indicate that they are needed on a regular basis—they are not.”

Merck is no stranger to vaccine-related whistleblower allegations. In 2010, two Merck virologists filed a whistleblower lawsuit in the U.S. District Court for the Eastern District of Pennsylvania, alleging that company scientists, with the knowledge of Merck executives, used improper testing techniques and manipulated data to falsely claim that its M-M-RI_I vaccine had an efficacy rate of 95%. It did so, the lawsuit suggested, so that the vaccine could be relicensed by the FDA, and also bundled with a chickenpox vaccine to create a new vaccine product called ProQuad. The lawsuit claimed that Merck’s M-M-RII vaccine had a lower efficacy rate, which might have led to a resurgence of mumps. The case is still being litigated, and both sides have moved for summary judgment.

The Merck spokesperson described the lawsuit as “completely baseless” and said, “Merck is confident that it will prevail in court.”

Though the FDA tries to inspect every manufacturing plant that makes drug ingredients or finished doses for the U.S. market roughly every few years, it prioritizes high-risk products like vaccines. The agency also typically inspects plants before approving a new drug, or if it learns of dangerous conditions.

The FDA’s investigators document any problems they find, known as observations, in a report called a Form 483. They also classify their inspections, by recommending one of three different outcomes. “No action indicated” means the plant is operating safely. “Voluntary action indicated” means the plant should make corrections, but on a nonurgent basis. “Official action indicated,” the most serious finding, means that the FDA is likely to restrict a plant’s manufacturing and require immediate changes. If the plant still falls short, then it could receive a warning letter. That can lead to further sanctions and be catastrophic for a company’s bottom line.

The FDA’s observations and warning letters are typically made public, which serves a vital function: “It helps keep companies honest,” said former FDA regulator Lynn. “Eventually they know that if they’re not doing it right, it will get out in the public domain and they may have to answer to it.”

But that transparency has been notably absent in Operation Warp Speed. Because the program has funded the development of vaccine candidates that may or may not be approved, millions of vaccine doses have already been manufactured. If the FDA grants what is called an emergency use authorization for a COVID-19 vaccine, under a standard that falls short of the requirement for a full approval, it is not even clear whether the FDA will require full inspections of the manufacturing plants, a possibility first reported by Bloomberg.

Philip Russ, president of IcGXP, a pharmaceutical-compliance consulting firm, said of concerns regarding manufacturing quality, “I don’t know if there’s going to be any issue with [good manufacturing practices] that’s going to be as dangerous as not having any vaccine at all.”

But the very function of vaccines–to protect healthy people–requires greater vigilance, said Dr. Peter Hotez, a vaccine researcher and dean of the National School of Tropical Medicine at the Baylor College of Medicine. “The bar for COVID vaccines is higher, because you are injecting people who are generally well to prevent them from getting sick, and the margin for error is lower,” he said. With a COVID-19 vaccine, “you are potentially infecting the entire population of the United States, and if you get it wrong, it’s amplified by 330 million.”

To examine the FDA’s track record in policing vaccine-manufacturing plants, Vanity Fair asked Redica Systems (formerly known as Govzilla), which says it has the largest cache of publicly available FDA inspection records, to examine the observations and outcomes of inspections done by Team Biologics. The results were striking. From 2015 to 2019, Team Biologics investigators documented problems, or observations, at 86% of their inspections. And yet, not a single one of those inspections resulted in a warning letter. (Redica excluded 2020 from its analysis, as warning letters resulting from those inspections may not have been filed yet.)

This is in striking contrast to inspections of human-drug plants under the FDA’s Center for Drug Evaluation and Research. Over the same five-year period, its inspectors documented problems, or observations, at 51% of their inspections, the analysis found. Nonetheless, this lower rate resulted in warning letters almost 4% of the time. That is more in line with Team Biologics’ track record from 2010 through 2014, when 77% of its inspections led to observations, and over 3% of its inspections resulted in warning letters.

Asked about this, the FDA provided evidence that the Office of Regulatory Affairs’ biologics program had issued 26 warning letters to facilities since May 2017—2020 included. That office’s purview, however, is broad and includes many facilities less specialized than vaccine plants, such as blood and sperm banks. Presented with this number, Redica Systems stood by its analysis. 

Michael de la Torre, CEO of Redica Systems, told Vanity Fair that based on the data he analyzed, “it certainly looks like there was a change of policy [inside Team Biologics], because the investigators are finding very similar things, but it’s not leading to warning letters like it was before.”

Though it is not exactly clear why Team Biologics supervisors have opted to let vaccine and biologics plants off the hook, an analysis by Science magazine in July 2019 found that under President Trump, the FDA’s issuance of warning letters fell by one third.

Menachem spent nine long days at Merck’s North Carolina plant. He emerged with enough evidence to issue a 483 report, citing the plant for four manufacturing violations. The first and most consequential violation—which dealt partly with insufficient restrictions as workers moved from less to more controlled areas of the plant—was based, in part, on his having confirmed some of the whistleblower’s allegations. His report stated, “Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established and followed.”

Though Menachem recommended the inspection results be categorized as “official action indicated,” the most serious finding, his FDA supervisor ultimately downgraded the resolution to “voluntary action indicated,” which allowed Merck to make nonurgent changes.

Menachem said that although he asked his supervisor to be able to continue and expand the investigation by questioning Cintas, his supervisor refused. The resolution was typical of Team Biologics inspections. Four current or former FDA employees said it was well known inside the FDA that the Office of Compliance would rarely issue a warning letter to biologics plants. Though the reason why remains unclear, one of those employees suggested that a “very pro-industry” bent was the cause.

Menachem was so troubled by the FDA’s handling of the allegations that the following month, in November 2018, he filed an official complaint with the federal government’s Office of Special Counsel. But because of the government shutdown that December, the FDA was not notified of his complaint until February of 2019.

On March 11, 2019, Menachem said he was in Raleigh, North Carolina, traveling for work, when he got a call from his supervisor: Someone would be coming to his hotel within an hour to confiscate his government computer.

Menachem could only marvel at the irony. The agency had refused to send backup to a North Carolina manufacturing plant to help him question a confidential informant who’d alleged grave public health abuses. When it came to taking away his computer, the agency moved like a well-oiled machine.

Soon, Menachem said, he found himself being investigated for living part-time in Israel while doing his job, an arrangement that his supervisor had verbally approved. A lawyer with Health and Human Services’ Office of the General Counsel then offered him a deal: If he would withdraw his complaint against the agency, the FDA would halt its investigation, and Menachem would be able to return to government service in the future. Menachem instead resigned.

Spokespeople for both the FDA and Health and Human Services declined to comment on personnel matters. A spokesperson for the Office of Special Counsel said, “OSC is unable to comment on or confirm the status of pending investigations.”

On May 29, 2019, Menachem sent a resignation letter to his supervisor, noting the terms of the deal he was offered: “that any agreement with HHS would preclude me from continuing my [Office of Special Counsel] complaint against the substantial and specific danger to public health and gross mismanagement I encountered during my tenure in Team Biologics.” He added, “My conscience does not allow me to waive the OSC complaint I made in November and I refuse to violate the public trust by rescinding the complaint.”

Looking back on his experience, Menachem said, “I don’t claim brilliance...but I do have a good sense of empathy. That’s what really makes a difference at this job, [if] you can imagine your children or parents” taking the medicine.

In response to Menachem’s complaint, the FDA investigated itself. In a report completed by the FDA in June 2019 and obtained by Vanity Fair, the agency concluded that the four inspections Menachem flagged, for which his recommendations of “official action indicated” were downgraded, were “conducted per governing procedures.” Despite Menachem’s findings at the Merck plant, the report claimed that he had been unable to substantiate the whistleblower’s allegations, concluding, “there is no merit to these allegations.”

Additional reporting by Stan Friedman.

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