FDA blasts Toyobo for subpar particulate investigation and data integrity breaches

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Toyobo responded to an FDA form 483 back in March, but the regulator still has concerns. (FDA)

Particle contamination has proved a stumbling block for many drug manufacturers in recent years. Now, Japan's Toyobo is learning that lesson the hard way. 

The FDA has taken out its red pen to chide Toyobo—better known for textiles than pharmaceuticals—after it failed to suss out the source of particle contaminants in certain drugs. The company also dropped the ball on its investigation of data integrity breaches, the regulator said.

The U.S. regulatory agency handed down a warning letter after Toyobo attempted to right the ship at its Otsu, Shiga, Japan manufacturing plant earlier this year.

The company did not immediately respond to Fierce Pharma's request for comment.

The FDA inspected Toyobo’s plant between Feb. 15 and Feb. 19, then again on Feb. 22 and once more between Feb. 24 and Feb. 25. Toyobo attempted to correct its ways in March when it submitted its response to a form 483, but the regulator still has concerns.

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Born as a cotton-spinning outfit way back in 1882, Toyobo is predominantly a fiber and textile maker. The company’s pharmaceutical unit offers contract manufacturing for injectables, contract packaging, contract testing and formulation study for injections, according to Toyobo’s website.

“Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed,” the FDA said in its publicly posted letter.

Specifically, Toyobo didn’t do enough to investigate “significant” particulate defects in its sterile drugs, including “recurring incidents” of foreign particle contamination.

Over 2019 and 2020, multiple batches of an unnamed injectable were flagged for significant contamination with foreign particles. After Toyobo made this discovery, it failed to kick off an investigation in a timely manner, the FDA said.

“Our review revealed that your in-process quality standards, limits, categories and triggers for investigations do not sufficiently differentiate intrinsic from extrinsic particulate contamination,” the regulator added.

In June, Toyobo told the FDA it had improved its processes and was now performing supplier audits to get a handle on the problem. The company’s own investigation suggested it was “highly possible”—as quoted in the FDA’s letter—that its washing and sterilization methods could not remove certain particles stuck to stoppers or vials.

The company didn’t follow up properly on “multiple instances” of an iron contaminant that was spotted during visible particle identification studies. This type of particulate could cause serious side effects because of a person’s immunogenic response, the FDA said.

The company’s response to the FDA’s earlier complaint cited 12 batches from the regulator’s inspection that were found to contain visible particulates of cellulose fibers, glass fibers, black and white “particles” and “stain-" like particles in a range of colors.

Meanwhile, after Toyobo was alerted to data integrity breaches, the company’s investigation failed to root out the full scope of the problem at its facility, the FDA said.

Toyobo itself found on multiple occasions that its workers weren't using personnel and environmental monitoring plates properly when performing certain cleanroom activities.

The company's investigation into the breach issues lacked a comprehensive assessment into the extent of the “falsification of airborne particles measurement records” and other breaches of data integrity occurring in the facility,” the FDA said.

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Toyobo's environmental monitoring data linked to operators, equipment surfaces and nonviable particulate monitoring was “unreliable” and called the sterility of the company’s products into question, the regulator added.

The FDA also flagged “weaknesses in the reliability” of Toyobo’s documentation, citing “uncontrolled” testing documents and subpar systems for reconciliation of laboratory documents.

The agency has asked Toyobo to run an updated risk assessment of its marketed products, specifically to track down any foreign particulates. It also wants the company to update its testing procedures and examine the potential health fallout of iron contaminants in its drugs.

The company also needs to form a plan to ensure its employees follow proper cleanroom procedures and better supervise drug batches during production. Toyobo must also run an assessment of all contamination risk to its aseptic process, equipment and facilities, the FDA said. Toyobo is working with a consultant to settle the FDA’s complaints, the regulator added.

Toyobo isn’t the only drugmaker grappling with particulate problems. Hikma’s U.S. operations last year halted production of an injectable pain med as it worked to root out the source of black, oily and gelatinous particles in certain product vials. Fresenius Kabi has also pulled multiple lots of its anti-inflammation drug Ketorolac Tromethamine Injection on particulate concerns.

Just this week, Moderna received “several complaints on particulate matter” in vials of its mRNA-based COVID-19 vaccine, a company spokesperson confirmed with Fierce Pharma. The complaints are tied to a single product lot distributed in Japan, and Moderna said it believes the issue relates to a production line at a contract manufacturing facility in Spain.