Editor’s note: This story has been updated to include a statement from Integra LifeSciences about the FDA warning letter.

Last month Integra LifeSciences initiated a global recall and production hold on all products manufactured at the company’s Boston, MA facility. So, it comes as no surprise that FDA has now hit the company with a warning letter addressing several violations at that plant.

The warning letter requirements do, however, raise questions about the company’s projected timeline for resuming sales of its tissue products.

FDA inspected the company’s Boston, MA facility from March 1 through May 17, and issued the company a Form 483 at the end of the inspection listing all the inspectional observations that need to be addressed. Integra responded to the Form 483 on June 8, however FDA found some of the company’s responses lacking.

“Integra is dedicated to patient safety and product quality,” Laurene Isip, a company spokesperson told MD+DI.

Isip said the company takes this commitment seriously and is working closely with FDA to fully address the agency’s concerns related to Integra’s manufacturing facility in Boston, MA.

“We have suspended production in the Boston plant and are accelerating upgrades to our quality manufacturing system there. We will not resume production until we have addressed the FDA concerns and are confident the facility meets the strictest regulatory and product quality standards, which we anticipate will occur by the end of the calendar year,” Isip said.

The FDA warning letter notes that Integra failed to establish and maintain procedures to control product that does not conform to specified requirements. For example, in June 2019 Integra released a lot of Durepair containing elevated levels of endotoxin. A second violation notes that Integra failed to establish and maintain procedures for implementing corrective and preventive actions (CAPA), including requirements for analyzing processes, work operations, concessions, quality audit reports, quality records, service records, complaints, returned product, and other sources of quality data to identify existing and potential causes of nonconforming product, or other quality problems.

According to the FDA warning letter, during the inspection, Integra initiated a health hazard evaluation (HHE) to address the endotoxin concerns and the potential health risk. This evaluation, completed on April 12, was not comprehensive and did not include all complaints that may have been associated with the issue, according to FDA. For example, two complaints of meningitis associated with Integra’s Durepair product were not included in the HHE assessment that concluded a field action was not recommended.

“We understand that you have taken a series of corrective actions, including a recall and production hold, however your response does not indicate how you will prevent such errors from recurring when you resume operations,” FDA noted in the warning letter.

The warning letter also states that Integra failed to validate with a high degree of assurance, a process whose results cannot be fully verified by subsequent inspection and test. Specifically, the company failed to adequately validate its test method for testing bacterial endotoxin of finished medical devices.

“We will need to review this CAPA to ensure it is comprehensive and will be effective in preventing similar failures from recurring when you resume distribution,” FDA said in the warning letter, adding that Integra will need to provide evidence that it has reviewed all its operations to ensure that the facility has validated processes in place.

Finally, the warning letter notes the company’s failure to store devices in a manner to facilitate proper stock rotation and to assess its condition as appropriate. On March 2, the FDA investigator observed sterile lots of implantable devices on an unsecure open shelf located in the QC quarantine area and were labeled as “non-sterile.” FDA said the company’s procedure does not adequately prevent mix-ups of sterile/non-sterile material.

FDA noted that it is aware that Integra received a complaint on Oct. 20, 2022, that described an example where non-sterile product was being handled in the same area as sterile product. According to the agency, a CAPA was not initiated at the time to address this issue and to prevent its recurrence.

The warning letter requires Integra to remedy several violations and to certify an outside consultant’s findings by the end of March 2024, with additional observations and certifications by the end of March 2025, and March 2026.

“Given these requirements, we wonder if [Integra LifeSciences’] tissue sales could still resume under the prior timeline,” Ryan Zimmerman, a medtech analyst at BTIG, noted in a report Wednesday.