Medical Device Daily Washington Editor

It's no secret that FDA takes process validation seriously, likewise the qualification and installation of processing equipment. What is perhaps not always obvious is that FDA will not just allow a contract manufacturer to replicate a process from the client firm's plant without conducting its own validation and qualification studies.

A Nov. 20 warning letter to Contract Medical Manufacturing (CMM; Oxford, Connecticut) indicated problems with the company's sterilization of customized cranial implants that were sufficient to prompt the company to place a hold on the implants "until further notice," according to the warning letter.

The implants were apparently designed by and manufactured for Stryker (Kalamazoo, Michigan), given the mention of Stryker in a passage that refers to post-inspection correspondence sent to FDA by both companies. Pat Anderson, a spokesman for Stryker, declined to comment for the record, but he confirmed that CMM is a vendor for Stryker's customized cranial implants.

According to FDA, the September inspection disclosed that CMM could not document that the company had validated the package sealing process or the sterilization process for the implants. The letter states that the company suspended shipments on Sept. 16 and that it would initiate a recall of "all sterile custom cranial implants manufactured by CMM." FDA noted that it "look[s] forward to reviewing the completed documentation process" for the sterilization validation, but indicated that the company's response to the inspectional form 483 "did not address ... the seal integrity process."

FDA cited the company for monitoring the humidity in the room in which ethylene oxide (EtO) sterilization was taking place rather than the humidity in the autoclave. This citation for environmental monitoring also notes that CMM "was not maintaining or reviewing the temperature recording charts" generated during sterilization procedures.

The company's response apparently included an updated standard operating procedure, but FDA asserted that CMM had to "assure that the validation is successful and then confirm that all the proper procedures are in place."

The warning letter states in a separate citation that CMM could not document "review and acceptance of sterilization validation activities conducted by [redacted] on the sterile cranial implants" made by CMM. This citation also notes that CMM was provided with operational and performance qualification data on two sterilization chambers as well as with "accelerated aging studies" for the implants. This citation states, "There was no documentation that CMM personnel reviewed or accepted these ... reports."

Further into this citation, the agency states that CMM's quality plan lists a redacted entity — presumably Stryker — "as being responsible for [the] manufacturing and/or assembly process" used to manufacture and sterilized the product at CMM's plant.

The warning letter does not explicitly state that CMM is responsible for its own validation work on the processes in question, but FDA indicates in a subsequent passage that further clarification of the matter "will clearly define your responsibilities as a finished device manufacturer," which would seem to imply the necessity of conducting its own validation and qualification work.

The warning letter states that a complaint file opened in November 2007 "noted a patient infection," but that the file did not document further attempts to obtain additional information. This file was still open when the inspection commenced, according to FDA. Another complaint was opened for a patient who had three implants for the same surgical site, with infections following the first two. According to FDA, the firm's analysis was that "the implant was shipped before CMM started performing sterilization and there was not sufficient evidence to take the investigation further." FDA acknowledged the changes made to the company's current complaint-handling procedures, but suggested that CMM "may need to revisit these procedures again."

FDA also noted that the firm's records for medical device reports (MDRs) did not include information on the complaints described previously, but that they did have information on four MDRs for which there were no associated complaint files. The agency states that this was not noted on the 483.

At press time, the company had not responded to a call for comment.

Incoming components trip up Steritec

An Oct. 17 warning letter to Steritec Products (Castle Rock, Colorado) once again highlighted the hazards of contract manufacturing. The agency mentioned the firm's withdrawal of three lots of a component known as a flash integrator used in sterilization procedures because of the use of a faulty component made by a third party.

The withdrawal action was noted in connection with a citation for a lack of procedures for testing of incoming components, and while FDA states in the warning letter that the firm's response to the 483 "appears to be addressing our concerns," the agency states in the warning letter that it will review the situation upon the next inspection.

FDA also cited the company for conducting no quality audits in 2005 and for failing to appropriately document the company's quality audit for the following year. As was the case with the preceding citation, FDA deemed the response to the 483 adequate, but promised to check on the situation in the next inspection.

The warning letter also states that Steritec had not established "a complete quality system, including management controls, design controls, process validation, acceptance activities and corrective and preventive action," but went into no details and did not cite a company response to this finding. In a separate citation, the letter states that Steritec could not document that management had reviewed any corrective action for the flash integrator situation, but states that the company's June 16 response to the 483 appeared to cover the situation.

Linda Nelson, Steritec's quality control and regulatory affairs manager, told Medical Device Daily that the company had responded to the warning letter and that "we haven't heard anything since the response." She said that the warning letter "made it sound like we have no quality system," but said the company sees its compliance framework as now being in good form.