Medical Device Daily Washington Editor

The need to detail the specifics of manufacturing operations, standard operating procedures (SOPs) and process validations — in past times known as "paperwork" — was highlighted by some of the recent warning letters to companies from the FDA.

A warning letter to Defibtech (Guilford, Connecticut), one of several issued by the agency to both U.S. and European companies in recent months, cited the automated external defibrillator (AED) manufacturer for failure to validate software used to display the charge status of the battery.

According to the April 24 letter, three AEDs failed a quarterly test in that the display indicated a charge that was sufficient to deliver the required shock, but which nonetheless possessed insufficient charge. The agency said all three AEDs "were then connected to patients in real life-saving emergencies and shut down because of low battery" charge.

The FDA stated that the company lacked documentation to indicate the number of AEDs that were sold with a certain type of transformer. It told Defibtech to "provide documentation of the validation that was performed, as well as the revised" SOPs, in addition to documentation indicating the "steps you have taken to prevent these issues from recurring."

Its Jan. 16 letter to Gynetics Medical (Hamont Achel, Belgium), maker of assistive reproductive technology, stated that a September 2006 inspection disclosed that the firm's procedures for corrective and preventive action did not specify an "exhaustive" list of data sources for determining "existing and potential causes of non-conforming product or other quality problems." Gynetics also was cited for failure to describe an appropriate statistical methodology for analysis of such data.

FDA said the firm's initial response to the finding was inadequate because the revised SOP "does not address work operations, concessions, quality audit reports and quality records within the translated document." The agency acknowledged that the procedures included a list of various sources of quality data, but that the response did not define the statistical methodology to be employed.

The response also was seen as inadequate because the firm did not indicate any training "to ensure that information related to quality problems or non-conforming product is disseminated to those directly responsible for assuring the quality of such product or the prevention of such problems."

The 11-page warning letter contained 14 other citations, including failure to identify actions needed to correct and prevent occurrences of non-conforming product, failure to validate corrective action, and failure to validate device design changes.

Diagnostics maker Medical Wire (Corsham, UK) received an April 26 warning letter that began with a citation for failure to validate filling, capping and sealing processes that are performed by semi-automated and automated equipment. FDA deemed the response inadequate because Medical Wire had not validated the software used to manage capping operations and because it did not specify which fluids "were used during the operational and performance qualification of the dispensers."

Another citation was for failure to validate the radiation dose for sterilization of the firm's Transwab to ensure that the dose level did not compromise the device or the product packaging. The response to this finding was deemed inadequate because the firm did not evaluate packaging and the swab for tolerance of a radiation dose.

FDA said that the company did not investigate an excursion of bioburden on media overlay plates that were "heavily contaminated … with gram positive rods, gram negative rods and/or gram positive cocci." Medical Wire's response failed to mollify the agency because the amended procedure did not "address … the method for determining verification or validation to ensure the corrective and/or preventive action is effective and does not have an adverse effect on the device."

The warning letter said that FDA would be in touch regarding a follow-up inspection.

FDA warning letters to foreign device makers typically include a warning that their devices may be detained upon entry to the U.S., but the letter to Gynetics noted that the agency was especially concerned about "the seriousness of the violation[s]."

An April 26 warning letter to Silimed (Dallas) cited the firm for several lapses in its sponsorship of a clinical trial, each of which the agency said was "a repeat violation cited in the last sponsor inspection in January 2003." The maker of cohesive-gel silicone implants was acquired by Sientra (Santa Barbara, California) in April (Medical Device Daily, April 19, 2007).

The first citation indicated that quarterly audits had not been conducted by a designated party, which was said to have handed off that responsibility to a contractor, but Silimed could not document that any such audits had been performed. The warning letter also stated that pre-study initiation visits took place at five sites for a continuing access study prior to approval by an institutional review board (IRB), and at two sites for a "second core study." FDA rejected the company's response to this finding because Silimed did not "provide any explanation and supporting documentation" as to how site monitors and clinical research associates would be trained in the appropriate SOPs.

The warning letter said that some clinical investigators had documented receipt of the study article prior to IRB approval, and that some subjects were implanted prior to signing consent forms.

Sun Biomedical (Blackwood, New Jersey) received an April 12 warning letter citing the company for not obtaining "clearance or approval from FDA before [it] began marketing" several of test kits for Oxycodone and alcohol use. The firm also was cited for failure to validate the use of "a new piece of equipment," the identity of which was purged, but which is used to evaluate the production of OraLine d-Meth RAB, an alcohol detection kit.

FDA also said that Sun did not establish quality requirements for purchased breath alcohol detectors. The letter said that Sun's response to the validation citation was inadequate, and that the response to qualification of third-party products "does not provide us with any assurance that your suppliers will be able to provide your firm with acceptable product." The agency added: "your response does not discuss what your corrective actions … will be concerning the distribution of unapproved devices by your firm."