Lilly Plant Making Covid Therapy Drug Flagged Again by Inspectors

By Anna Edney, Bloomberg, Oct 20, 2020.

U.S. drug-safety inspectors have found continuing quality-control problems at a New Jersey plant Eli Lilly & Co. is using to help produce its Covid-19 antibody therapy, posing a potential obstacle to the company meeting its goal of producing 1 million doses by year-end.

In an Oct. 2 memo, Food and Drug Administration compliance officers wrote that findings from an inspection of the facility in July and August “support a major failure of quality assurance.” They noted that Lilly planned to make its antibody therapy at the plant and said the inspection group “feels it is still imperative that FDA take action.”

The assessment was based on a four-week site inspection at the Branchburg, New Jersey, facility that ended on Aug. 21, the details of which haven’t previously been reported.

The compliance officers recommended that the company receive a warning letter, one of the agency’s strongest enforcement measures, according to documents reviewed by Bloomberg News. Agency inspectors found that in some cases Lilly employees didn’t investigate potential quality problems and routinely overrode testing systems, according to the documents.
A warning letter could complicate plans to boost production of Lilly’s experimental coronavirus therapy, which is part of a class of drugs that disease experts including Anthony Fauci have called a bridge to a vaccine. Lilly is seeking an emergency-use authorization from the FDA for its treatment, which is similar to a Regeneron Pharmaceuticals Inc. therapy given to President Donald Trump after he was diagnosed with Covid-19.

In a statement published on its website after Bloomberg asked about the inspection, Lilly said it hadn’t received a warning letter or other enforcement letter.

“The issues raised during the Branchburg inspections have our full attention and we have been working closely with FDA on remediation efforts,” the company said, adding it was confident the issues didn’t affect drug quality or patient safety, and it is working to address them.

Lilly said the Branchburg facility is one of five sites worldwide where it makes the antibody therapy, which is called bamlanivimab. An independent consultant has been hired to review manufacturing and quality records from Branchburg for the treatment, the company said.

The inspection this summer followed a visit in November first reported by Reuters. At that time, inspectors found the company’s system for tracking manufacturing quality wasn’t secure and could be accessed and modified by anyone, according to the documents reviewed by Bloomberg.

“As part of the FDA’s review process for applications and emergency-use authorizations, one of the factors we consider is the facility’s recent inspection history,” said Jeremy Kahn, a spokesman for the FDA. “The FDA uses a risk-based scientific approach when evaluating a facility, and takes all scientific evidence into account when making decisions.”

Kahn didn’t comment on whether the agency plans to send Lilly a warning letter.

Notice Warranted
Industrywide, the capacity for making antibody therapies remains somewhat limited.

Regeneron said early this month it has 50,000 doses of its antibody cocktail on hand, and it could have 300,000 more doses in the next few months. Regeneron is also seeking an emergency-use authorization from the FDA. Lilly previously said it could have 100,000 doses available of its antibody on hand this month and as many as a million doses by year-end.

At the same time, U.S. coronavirus infection rates have been climbing. Over the seven days through Tuesday, new cases averaged 59,400 a day, according to Johns Hopkins University data.
Both companies say they plan to ramp up production next year with the help of agreements they’ve made with other drugmakers to expand manufacturing capacity.

Before they can do that, they will need authorization from the FDA.

At Lilly, the FDA compliance officials said in their memo that the inspection warranted an Official Action Indicated notice. The designation means that regulatory or other actions will be recommended following an inspection. Lilly said in its statement that it had received an OAI notice from the agency.

FDA officials didn’t test any products made at the facility, but the compliance officers said in the letter the incidents they described “leave room for significant potential impact on product quality.”

In one case described by FDA inspectors, a Lilly employee allegedly used the wrong material in a critical purification step. In another, after routine checks revealed a potential impurity in a drug product, an employee retested it to get a passing result, according to the documents, instead of attempting to figure out why there were signs of an impurity in the sample.

Lilly managers downplayed quality missteps in a data-management system FDA has access to during inspections called TrackWise, according to inspection documents. Drugmakers use such workflow tracking systems to record the outcomes of quality checks during the manufacturing process.

A confidential informant told the FDA that Lilly managers documented more details of quality concerns that required personnel action in the company’s human resources system, according to the Oct. 2 memo. Agency inspectors said in their report that they repeatedly asked to review the human-resources records, but said Lilly refused to grant them access.

“We are not in receipt of any of the documents you reference in your email and thus cannot confirm their authenticity nor comment on the specifics outlined in your questions,” Mark Taylor, a spokesman for Lilly, said in a statement after Bloomberg asked about the contents of the inspection reports and the Oct. 2 memo. “FDA’s practice is to keep such documents confidential during the pendency of its investigation and review.”

Cancer Drugs
Lilly makes ingredients for the migraine drug Emgality at the New Jersey facility, as well as three cancer drugs, according to FDA documents. Lilly has also asked FDA to approve the site to make ingredients for one of its best-selling drugs, Trulicity, for the U.S. market, according to the documents. The type 2 diabetes drug accounted for $4.1 billion in revenue last year, according to data compiled by Bloomberg.

Lilly began reconfiguring the Branchburg plant in the spring to be able to produce active pharmaceutical ingredients for the experimental Covid-19 therapy. The technology transfer, which can typically take up to a year, was completed in 90 days, according to Darin Moody, a senior vice president of manufacturing. Production of the antibody began in July.

Enrollment in a government-sponsored clinical trial of Lilly’s antibody therapy was paused due to a potential safety concern last week, at the recommendation of an independent data safety monitoring board. Lilly has said its other trials of the antibody are continuing.

The FDA’s leadership doesn’t always follow the advice of its staff. It overruled an inspector who raised red flags about potential contamination of drug ingredients made at a facility in China in 2017. The inspector recommended the company receive a warning letter, but instead top FDA officials allowed the company to attempt to fix the problems itself.

A little more than a year later, blood-pressure drugs made at the Chinese firm were found to be contaminated with a chemical that can cause cancer, setting off a recall of millions of pills.

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