When the FDA tells you to clean up your act, it’s best not to make the regulator ask twice. Now, one Chinese drugmaker is learning that lesson the hard way.
The FDA has scolded Zhejiang Tianyu Pharmaceutical in the wake of an inspection at the company’s plant in the Chinese province of Zhejiang between Feb. 28 and March 4, 2022. In FDA’s warning letter, dated Aug. 17, the regulator laid out a laundry list of complaints tied to lapses in Tianyu’s active pharmaceutical ingredient (API) production, which the company failed to amply address in its response to an earlier Form 483.
Making matters worse, the FDA raised similar concerns more than three years back. Now, it’s urging Tianyu to summon outside help to get its manufacturing operations in order.
Up top, the FDA critiqued Tianyu’s investigation into impurities found in an unnamed drug ingredient. While the company identified four lots that failed to meet impurity standards, the company didn’t extend its investigation to all lots manufactured after August 2018, when Tianyu determined a certain impurity “had a higher risk of forming,” FDA said.
Instead, the company’s investigation was limited to testing of eight lots manufactured that same year “using the non-optimized manufacturing process,” the regulator continued. Further, FDA alleges there was a three-month stretch during which Tianyu continued to distribute the suspect API lots “without implementing mitigating controls” related to the potential impurity.
Tianyu did perform retrospective testing, which turned up another four lots from 2018 exceeding impurity specifications.
“You did not perform your investigative testing in a timely manner and API lots manufactured as early as 2017 using the non-optimized process were not considered and included within the scope of your investigation,” the FDA added.
More broadly, Tianyu “failed to conduct a comprehensive evaluation of the manufacturing process to identify all potential impurities,” the FDA said in its second observation. The regulator points out that last July, the presence of an unnamed impurity was flagged via customer complaint, which resulted in Tianyu receiving a deficiency letter from the European Directorate for the Quality of Medicines & HealthCare.
Further investigations by the company revealed unacceptable levels of the impurity, which the FDA alleges “is a byproduct of [the company’s] manufacturing process.”
This oversight kept Tianyu from pinpointing 39 suspect lots intended for U.S. markets, the FDA said.
Separately, Tianyu last November received a customer complaint alerting it to the presence of an impurity in a starting material intended for API manufacturing. Once again, Tianyu’s investigation into the matter was subpar, the FDA claims.
The FDA’s final rebuke centered around equipment cleaning, which Tianyu failed to do often enough to prevent “build-up and carryover of contaminates and degradants.” The FDA’s hygiene concerns were specifically linked to equipment used for continuous production or campaign production of successive batches of the same intermediates and drug ingredients.
Meanwhile, this isn’t the first time Tianyu has entered the FDA’s crosshairs. In its warning letter, the U.S. regulator pointed out that it cited similar manufacturing concerns during an inspection in April 2019.
“Repeated failures to address deficient operations demonstrate that executive management oversight and control is inadequate,” the FDA said.
Tianyu was given 15 days to respond to the FDA’s concern from the time it received the warning letter earlier this summer. Given the scope of the company’s problems, the FDA has recommended Tianyu tap a manufacturing consultant to help guide remediation efforts.