Audit of dura mater firm yields warning, recall. Was TRF a 'distributor'? (Medical Devices).

Transplantation Research Foundation, Bellaire, TX, Dallas District

Confusion about its status as a distributor coupled with a voluntary recall of over 200 dura mater allografts were likely motivators for Transplantation Research Foundation (TRF) to revise its processing agreement with its unnamed contract manufacturer.

Following a March 2001 inspection by investigators Ellen Kleintop and Lillie Young, the duo issued an eight-item 483, which cited TRF for not having "clearly defined or complete" procedures to ensure all dura mater allografts received from its outside contract manufacture "conform to specified quality requirements, and the type and extent of control to be exercised."

Specifically, the investigators noted that the processing data and test results that the outside con-tract manufacture was required to provide to TRF "was not clearly defined (i.e. verification and/or validation data for the specified attributes)," nor was there a "clear agreement from the contract manufacturer ... that they will notify your firm (TRF) of changes in the product or service."

In the meantime, before a warning letter could be issued or before TRF could respond to the 483, FDA sent the firm a June 15, 2001, letter stating that, based upon the inspection, the agency had determined that the firm was sponsoring a study investigating the clinical significance of residual endotoxins in dura mater allografts. The letter stated that the dura mater devices used in the study had levels of endotoxin in excess of 0.06 EU/ml and required an investigational device exemption and institutional review board approval to continue.

Ten days later, TRF was hit with a June 25, 2001, warning letter (Doc. 10596W), which stated the firm "would only be exempt from the premarket notification requirements if it acted solely as a distributor of dura mater ... or as a repackager."

Before responding to the warning letter or the 483, TRF fired off three letters.

The first letter, dated June 29, 2001, stated TRF was voluntarily instituting a recall of 243 allografts, which by July 3, 2001 got bumped up to 249.

According to the letters announcing the recall, TRF told FDA that the agency misunderstood the firm "regarding its distribution of dura mater allografts," and that the company had never sponsored any such clinical study.

TRF had determined that 249 allografts it had released for distribution had contained residual levels of endotoxin above the recommended 0.06 EU/ml level. TRF also said it was initiating a voluntary recall, although a certain number of the grafts had already been implanted.

The next letter from Executive Director Weldon Guest, M.D., to FDA on July 18, 2001, re-quested extension for addressing the warning letter "in order to clarify the future role of our company as a distributor and not a manufacturer of the dura mater allografts." He also said TRF needed to finalize its contract with its outside manufacturer.

The firm finally began to explain itself in a 23-page, response to the warning letter on Aug. 20, 2001. Guest stated that in response to the warning letter, "TRF intends to revise its Dura Mater Processing Agreement" with an outside firm "in a manner that limit's TRF's role strictly to the recovery of cadaveric dura mater, the shipment of all TRF-recovered dura mater to [the outside firm] for processing, and the distribution of [the outside firm's] processed and released dura mater allograft."

In response to the above citation by Klein-top and Young, Guest stated that under its revised agreement with the outside firm it would become a vendor to the outside firm and not a contract manufacturer.

"Under this arrangement, [the outside firm] will establish and maintain the specification for TRF-recovered dura mater and its acceptance for processing." In addition, Guest said that the outside firm would be responsible for "testing inprocess materials and the packaging, labeling, testing and re-leasing of finished dura mater allografts for human transplantation."

Clearing the air, TRF addresses 483

Responding to the warning letter allowed Guest to address other citations from the 483. For example, the investigators stated that TRF had not defined procedures "for the control of dura mater that does not conform to specifications, including the documented identification, authority for disposition and investigation of non-conforming product."

Backing up this citation, Kleintop and Young wrote: "Disposition records (electronic) did not clearly document the destruction of unsuitable dura mater, and there were no disposition procedures addressing the segregation and disposition activities for unsuitable dura mater."

Guest responded that other than the allografts that were found to have excess endotoxin and covered by the recall, the outside firm had never returned any processed allografts to TRF.

However, to address the 483 observation, Guest stated TRF would "revise the procedures for handling the recovered dura mater it ships" and that the outside firm would have "sole responsibility for establishing and maintaining procedures to control the disposition and destruction of TRF-recovered dura mater that does not meet ... acceptance criteria" under the new agreement.

The FDAers also wrote up TRF for not establishing document and change control procedures to assure change records "include a full description and justification of the change, validation (or verification with justification) of a product or process change, identification of affected documents, and that all documents used for manufacturing activities are controlled."

As examples, the duo stated the firm did not validate the new arbitrary endotoxin (pyrogen) limit, or justify the change to a postmortem time interval for tissue procurement to [a given value].

Guest agreed that TRF did not validate the endotoxin limits or the postmortem time interval for finished allografts. He said TRF was handling these deficiencies via the recall and that in the future, the outside firm would be responsible for "the final disposition and destruction of such material."

FDA did not release the EIR stating it was presently being reviewed to determine whether it could be disclosed. Calls into TRF requesting comment were not returned as of press time.

Transplantation Research Foundation, Bellaire, TX, 3/9, 12, 13 & 19/01, Doc. 109358M, $21.50 plus retrieval.