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Agnes Shanley is senior editor of Pharmaceutical Technology.
A whistleblower’s complaint raises questions about FDA inspector training and support, as well as CGMP noncompliance patterns at biologics facilities.
Disclaimer: This article reflects an editor's views based on interviews and a review of documents. It in no way represents the official opinion of our magazine or company.
Like any organization, FDA has been criticized for political divisions and resistance to change.
In the late 2000s, the agency launched initiatives designed to hire more technical people with engineering backgrounds and better understanding of the scientific principles behind genomics and concepts such as biomarkers. Efforts were made to recruit more inspectors, improve inspector training, and to harmonize requirements and expectations. As Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research (CDER) noted in testimony to Congress in December 2019, inspector training and support remains a key area of focus for CDER and the agency.
But questions may remain about how well inspectors outside of CDER are keeping up with the quick pace of scientific and industry change. Team Biologics, a core group of 14 inspectors and managers, is responsible for ensuring the safety of vaccines, plasma derivatives, and other biologics.
Part of FDA’s Office of Regulatory Affairs’ Office of Biological Products Operations, the team faces a daunting task, at a time when technologies are constantly changing. In addition, their inspection activities can range widely. One day, a team inspector may be called upon to visit an advanced personalized medicine facility and the next a commodity vaccine plant, the type of installation that does not typically receive much in the way of upgrades or capital investment. Balancing responses so that they are not overly punitive, yet protect the public, is not easy.
On December 18, FDA Press Officer Jeremy Kahn issued the following statement affirming the agency’s commitment to its inspectors, and to supporting and continuing to build on the expertise of Team Biologics.
“…The agency’s investigators are essential to the FDA’s ability to help ensure the quality and safety of medical products. FDA’s investigators are experienced and trained professionals, and the agency provides its investigators with numerous resources to support inspections and investigations, including continuous advanced instruction and training… The Team Biologics Staff (TBS) currently has 14 investigators. The FDA plans to increase the number of investigators assigned to conducting surveillance inspections of biological products regulated as drugs (e.g., vaccines, recombinant therapeutic proteins and cellular and genetic therapies),” he wrote.
However, in early December, reports of a former FDA inspector’s whistleblower complaint in Vanity Fair (1) focused attention on the timelines, training, and support given to inspectors on Team Biologics.
The report focused on vaccine manufacturing, but when examined more broadly, the complaint also raises some fundamental questions about the benchmarks that are used to determine compliance with current good manufacturing practices (CGMPs) at biologics facilities, and whether there are unwavering standards for judging data integrity and aseptic conditions, overall manufacturing safety, and product quality.
On the corporate level, it also provokes questions of whether industry operators are receiving the basic respect required for them to solve problems and do their jobs properly, and whether changes in shift scheduling and better approaches to gowning and error prevention are needed. This is particularly important at commodity vaccine facilities, some of which are older and whose products may be essential for the public, but are not financially profitable to their manufacturers.
Near the end of 2018, former Team Biologics staffer Arie Menachem filed a complaint with the Office of Special Counsel (OSC), an independent agency established to address federal employee whistleblower complaints. He alleged that his supervisors had downplayed serious concerns that he had noted during facility inspections.
Plant inspection is by definition subjective, and results will vary depending on the training, background, and interests of the individual inspector. However, Menachem’s complaint would seem to demand clarification of the following questions:
The following is a brief summary of the story behind the complaint, without company names.
Menachem told Pharmaceutical Technology that he found a number of serious CGMP compliance problems during routine biopharma facility inspections in 2017 and 2018, a year that started off with furloughs at FDA and the US Health and Human Services and a government shutdown. In these cases, Menachem says, he had issued 483s with “official action indicated,” requiring that FDA take administrative action and suggesting that recipients address problems before a followup inspection could trigger a Warning Letter.
He says that he began to notice a trend of managers systematically downgrading OAIs to VAIs, even though the problems that he had seen could compromise fundamental aseptic quality and data integrity, and result in adverse effects in patients.
He began to correspond with an OSC attorney in late 2018. OSC requires that departments cited in the complaints resolve them independently, instead of sending them to a neutral third party, so Menachem’s complaints were returned to FDA, and Team Biologics leadership officially dismissed them and closed out their investigation of the matter in June 2019.
Knowing that his dismissal was imminent and that, if he withdrew his complaints, he would be banned from government service for “only” seven years instead of for life, Menachem chose instead to resign from a job that he had embraced with enthusiasm and energy, and now works in the private sector. He had joined Team Biologics after 2.5 years at FDA. “I was excited to join, because of the intellectual challenge, but also the motivation to protect and promote public health,” he says.
As he noted, the short deadlines for filing detailed reports posed significant challenges for field and team managers alike. For inspectors, an OAI designation requires that a full report be filed 10 days after the site inspection. “If we found something to be OAI, we had to tell our supervisor about it ahead of time, in order to write the report within the 10-day deadline. That was difficult, in and of itself, because it required coordinating with the different people involved in the inspection,” he says. Supervisors then had 30 days to review the report, discuss findings with the inspectors involved, and begin to prepare a response to the manufacturer.
Perhaps the most dramatic examples of noncompliance were seen at a vaccine manufacturing facility in North Carolina. Menachem was assigned to inspect the 450,000 square foot factory, which manufactures both API and finished drug product, by himself, a task that would normally be assigned to two people. “We’d never done a solo inspection of this facility, which makes both API and finished product. It was like doing two inspections in one, using half the resources and in less time,” he said. Then, at 3 PM on the first day of the inspection, he received an unexpected email with a 20-page long document, a confidential informant’s (CI’s) complaint about ongoing CGMP problems at the site, he said.
Menachem asked his supervisor for help, but was refused. When he contacted the informant, Menachem found that the employee was concerned about conditions at the facility and anxious for FDA to use the information he had reported, in order to perform a more comprehensive inspection.
As it turns out, a compliance officer at FDA had received the CI’s report 11 days before Menachem’s inspection started, but had not shared it with Team Biologics. In addition, the same informant had sent a similar complaint to FDA in 2016, before the agency was scheduled to inspect the facility that year, and yet the agency did not share the letter with the Investigators that performed the 2016 inspection.
While Menachem’s supervisor focused on the late transmittal of the informant’s report and procedural issues, he grappled with the content of the letter. “I was in the middle of an inspection, and now I had to follow up on this CI complaint and do a GMP inspection, which was inadequately staffed to begin with, all while protecting the informant and not revealing any hints that could clue the manufacturer to the fact that an informant had complained.”
According to the CI’s account, staffers were forced to remain in place for long shifts, foregoing bathroom breaks that would require their degowning and regowning, a process that can take more than 30 minutes, because there were no staffers to cover them while they were away from their stations.
The CI had included in his complaint a photo of a biohazards bin right in the middle of a gowning area, which he said had been removed before FDA inspectors arrived. In documentation, Menachem soon found the smoking gun that proved it had existed. “A deviation report referred to a technician who had cut himself but didn’t report it, and then threw a bloody glove in a regular waste bin. The report noted that the glove should have been put “in the ‘biohazards bin’“ he says, into which operators were also alleged to have deposited gowning soiled by urine and fecal matter.
The informant had also reported that staffers moved to differently graded classified areas in the facility, contrary to the required directional flow. They all wore the same color uniforms (contrary to best practices, in which staffers’ uniforms are color-coded or differentiated based on the level of classification of the area they work in) and one couldn’t tell where they had been, where they were going, or where they were supposed to be at any given time, Menachem recalls. He verified this, he says, by noting the way handles were installed on facility doors, which would allow staff to move in a direction opposite to the required flow. The company claimed that state building code required the handles to be installed that way.
He says that he looked into environmental monitoring and glove checks, but found multiple instances in which no indentation in the plates that would have suggested that staff fingertips were being checked for contamination. When he asked that plant employees save and show him plates that had actually recovered microbes, he was told that the plates had been thrown out, against his express request. Other problems included deleting footage from a cleanroom video and removal of documents from a shredder. Are these problems substantially different from the stonewalling tactics that some facilities in China have used when dealing with FDA inspectors?
But noting the problems was only the first hurdle. Menachem saw the key problem as adulteration of evidence, most flagrantly demonstrated by removal of the biohazards bin before the inspection. However, his supervisor wanted him to zero in on individual technicians and how well they followed gowning procedures. Doing this would be impossible, Menachem said, given the way that gowning procedures are set up. “It became clear that [my supervisor] had never performed a inspection of an aseptic manufacturing facility,” he says.
That was not the only problem noted in his complaint to the OSC. In another instance, Menachem noted that a facility that manufactured a treatment for hemophilia was fudging potency results, taking vials from various batches to achieve desired results. They were also averaging out-of-specification (OOS) results in stability testing. “Averaging OOS results meant that you had no idea when the product would expire,” he said. That OAI recommendation was also downgraded.
Another writeup was for tests that were licensed by FDA’s Center for Biologics Evaluation and Research and used to fractionate plasma to ensure that donors did not have diseases such as HIV or hepatitis. Menachem found data integrity problems, including one login for all analysts, preventing traceability, as well as the fact that alarm and other data could be easily deleted or changed without detection.
Time pressure and training issues
Menachem believes that time pressure and workload contributed to some problems that occurred during his tenure with Team Biologics. “Supervisors had to downgrade inspection findings, in part, because they didn’t react in time,” he says. “But whenever an inspector describes something as OAI, people’s lives are at stake.” Training was another problem, Menachem said. Few people on the supervisory chain of Team Biologics had been specifically trained in drug inspection, and a number of team members came from food and devices, he says, despite the fact that they are overseeing complex therapeutics, such as cell and gene therapies. The one time three-hour training program given in gene and cell therapy was not enough, he says.
Before taking his complaints to OSC, Menachem says, he had contacted everyone along the supervisory chain, even going to the head of operations, to alert them to potential dangers to patients. Even in his initial letter to OSC, he insisted that he had no personal grudges but was genuinely concerned about patients. FDA received the report in February and his computer was taken away from him, and from that point on, Menachem’s story follows the traditional whistleblower path.
One quirky note in the CI’s message to FDA noted that staff members at the vaccine manufacturing facility mentioned in Menachem’s complaint would sometimes dance during longer breaks, occasionally videotaping these activities. Strange behavior for people at a pharma plant. Definitely not regulated by CGMPs.
But is that behavior common in hospitals? In the Spring of 2020, when makeshift morgues were set up throughout New York City, households opened their windows every evening at 7 PM to make noise to recognize the heroism of healthcare workers treating patients with COVID-19. Physicians and nurses at hospitals around the world were videotaped dancing. One can only assume they did that to maintain spirit, despite few resources and unbelievable stress.
Not that pharma workers’ situations are in any way comparable to those of healthcare workers during this second, terrible COVID-19 surge. But nobody is making noise for, or can attest to the stress that some bio pharma operators (or regulatory agency inspectors) may be experiencing. That’s what makes accounts like Menachem’s important.
One former operator at the vaccine plant emailed Menachem after the Vanity Fair article came out in December, a note that Menachem shared with Pharmaceutical Technology, corroborating shift, gowning, and other problems and a grueling, exhausting job. Despite his respect for what the industry does, he has left pharma and is now working in a different industry.
There are no villains in this story. But whether or not FDA agreed with Menachem’s version of the truth, allegations in his complaint suggest problems that require communication and collaboration to resolve, and may be driving idealistic people out of bio/pharma. What are your thoughts?
1. K. Eban, “The COVID-19 Vaccines are Approaching: Is FDA Ready to Inspect the Plants Where They’re Made?” Vanity Fair, December 6, 2020.