FDA warns Integra LifeSciences over endotoxin testing, complaint investigations

This story was corrected on 22 August 2022 to clarify one of the violations listed in the warning letter*

The US Food and Drug Administration (FDA) recently issued a warning letter to TEI Biosciences, a unit of Integra LifeSciences, for releasing collagen-based products which failed bacterial endotoxin testing. The company was also cited for other violations of good manufacturing practices (GMPs) associated with its products, which are intended for wound care, soft tissue repair and reconstructive surgery.

FDA investigators said these problems were associated with the company’s Durepair product, which is a non-synthetic dura substitute to repair the dura mater for neurosurgical procedures.

The warning letter was issued on 17 July and posted on 15 August. FDA said the inspection revealed that devices were “adulterated” and not in conformance with the current good manufacturing practice requirements (cGMPs) under 21 CFR Part 820 of FDA’s Quality System Regulation (QSR).

After the inspection, the company initiated a recall of these products, and pledged not to distribute them until it is operating in “substantial conformity with Quality System regulations (QSR).”

FDA said the company released products that did not conform to specifications and exceeded acceptable endotoxin limits. The company attributed the out-of-specifications (OOS) result to a transcription error and that these endotoxin limits were for a different product.

FDA did not accept the response, and said the company failed to provide a copy of its corrective action and prevention action (CAPA). The agency said that “we remain concerned that your quality system will be capable of identifying similar OOS errors when you resume operations and will prevent the release of non-conforming products.”

The firm was also criticized for its handling of a non-comprehensive health hazard (HHE) evaluation to address endotoxin concerns. The warning letter states that “the HHE, completed on April 12, 2023, was not comprehensive and did not include all complaints that may have been associated with this issue. For example, two complaints of meningitis, complaint #’s 198786 and 198790, associated with your Durepair product were not included in your initial HHE assessment that concluded a field action was not recommended.”

Lastly, the firm was chastised for keeping sterile lots of implantable devices on an “unsecure” open shelf, and for a complaint that a non-sterile product was being handled in the same area as sterile products. The firm did not initiate a CAPA to address these issues and to prevent their recurrence.

FDA said these issues need to be addressed within 15 days, and that failure to do so “may result in regulatory action being initiated by the FDA without further notice.” Such actions include seizure, injunction, and civil money penalties.

FDA further advised the company to hire an outside expert to audit its manufacturing and quality assurance systems, and to submit a copy of the consultant's report, and certifications that corrective actions have been taken. An initial certification must be submitted by 31 March 2024 and subsequent certifications must be completed by 31 March 2025 and 31 March 2026.

In response to the warning letter, an Integra official told Focus that “we suspended production in the Boston plant and are accelerating upgrades to our quality manufacturing system there. We take our commitment to patient safety and product quality very seriously and are working closely with the Food and Drug Administration to fully address their concerns related to our manufacturing facility in Boston, Massachusetts. 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.”

*A previous version of this article incorrectly stated that Integra was faulted for inadequately responding to complaints of meningitis associated with its Durepair product. Instead, FDA objected to the company’s methodology for calculating the HHE, not for a failure to respond to complaints. The article has also been updated to incorporate Integra’s response. Regulatory Focus regrets the error.

Warning letter

FDA warns Integra LifeSciences over endotoxin testing, complaint investigations

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