Medical Device Daily Washington Editor
The Dec. 3, 2009, warning letter to Z-Medica (Wallingford, Connecticut), maker of hemostatic devices, including the QuikClot combat gauze, was another instance in which FDA quickly hammered out a warning letter in what would have been record time in years gone by. The inspection commenced in late October and ended Nov. 3, but a Nov. 20 response from the company to the inspectional findings was not enough to stave off the warning letter, which FDA issued in exactly one month after the inspection closed out.
The 30-day turn-around on this warning beats by five days the elapsed time between the agency's inspection of Guidewire Technologies (Salem, New Hampshire), which was the recipient of a Feb. 26 warning letter addressing findings during an inspection that was completed by Jan. 22 (Medical Device Daily, March 11, 2010). The foreshortened time between inspections and warning letters suggests that the agency's emphasis on safety, especially as it relates to sterility, is one of the prime drivers of the agency's regulatory activity. Sterility was an issue in the Guidewire warning letter as well, and was cited by FDA in it's action against Steris (Mentor, Ohio), which had to recall all of its SS1 sterilizers over changes made to the system since its inception, even those units that bore the original cleared configuration (MDD, Dec. 7, 2009).
In the case of Z-Medica, the agency managed to rapidly turn around a re-inspection as well. Denny Lo, senior VP of Z-Medica, told MDD that FDA sent an investigator back out to review the proposed corrections between Jan. 27 and Feb. 2, the results of which earned the company a close-out letter.
The warning letter to Z-Medica included a citation stating that the firm's gamma sterilization of the QuikClot gauze, which the company's procedures indicate was pegged to ISO 11137, failed to hew resolutely to the ISO standard. According to FDA, ISO 11137 Part 2 "requires that [redacted] separate lots of product . . . be used in the validation of the product manufactured on a frequency of more than one lot per quarter." The warning letter says that the company's procedure for initial sterilization validation "identifies one lot of product consisting of [redacted] units is to be used in the validation of the product." FDA also asserted that the protocol "does not require and your firm does not place dosimeters or biological indicators in routine production runs sent to [redacted] for gamma sterilization," which apparently also does not align with ISO 11137.
FDA was not mollified by the corrections proposed for this finding in the company's Nov. 20 letter, noting that Z-Medica promised to complete its revalidation by Dec. 31 last year. FDA said nothing specific about that proposed fix other than to ask for "a copy of the sterilization re-validated data for our review."
FDA also says that Z-Medica's validation of sealing machines "lacks documentation of monitoring of periodic burst testing of in-process or finished product during periodic manufacturing." The agency redacted the pressure used for burst testing, which apparently was acceptable, but the warning letter says that the company had "no formal program to monitor (e.g. annually, weekly, daily) production to assure the [redacted] sealer meets the finished product specification for the seal integrity."
According to FDA, Z-Medica "changed the testing for seal integrity from burst testing to a peel test performed by . . . a contract vendor in 2008 on the recommendation of the vendor. However, FDA asserted that Z-Medical lacked a "formal approved protocol changing the test procedure from the burst test to the peel test" that identified "the frequency of testing to assure the sealer maintains the finished product peel test parameter." Again, FDA does not specify what fault it might have found with the firm's proposed correction, saying only that it would like to see "a copy of the approved procedure [redacted] and evidence that all employees have been trained on this procedure." FDA also cited the firm for complaint handling and management review procedures, the former of which was related to packaging issues.
FDA's close-out letter of March 1 says that the second inspection resulted in another form 483, although the agency goes into no detail on the matter other than to say that the proposed corrections should suffice. Lo told MDD, "we received a close-out letter dated March 1," and he added, "the issues addressed in the warning letter have been addressed to FDA's satisfaction."
G3's contract sterilization cited in warning
The Oct. 13, 2009, warning letter to G3 Medical (Asheville, North Carolina) set no records for warning letter issuance, given that the inspection had closed out on Aug. 24, but G3 as the target of the warning letter is again suggestive of the agency's emphasis on sterility, given that the company is described in the warning letter as "a contract sterilizer and a contract packager of various medical devices," including spinal and epidural needles as well as catheters and convenience kits.
Once again, the company managed to respond to the inspectional findings, although not within the now-mandatory 15-day deadline, but G3's Sept. 17, 2009, response apparently missed on most of the points described in the warning letter.
According to FDA, G3's validation of an ethylene oxide (EtO) gas diffusion process came up short on several points, including that the company "failed to adequately establish the amount of ethylene oxide needed for the sterilization process" and "failed to monitor the amount of ethylene oxide delivered in each sterilization bag" for contract sterilization procedures.
The warning letter says also that G3 "failed to adequately establish the relative humidity needed for the sterilization process" because of a failure to "monitor the adequacy of the [redacted] during each sterilization validation." There were three other points in this section of the warning letter as well.
Company officials apparently informed FDA that it was "developing written agreements" with its customers regarding validation of the sterilization processes, and the agency corroborated that it expects the company "to have written agreements which specify exactly who is responsible for each aspect of the sterilization, sterility testing, sterilization validation," and other procedures. However, the warning letter says that G3 "did not indicate what corrective actions will be taken with regard to the sterilization validations in which you did not monitor critical parameters such as the quantity of ethylene oxide and the relative humidity."
According to the warning letter, G3 at the time followed the "overkill method" as described in ISO standards 11135 and 14161 and it was the firm's practice to vary the exposure only by time and not by the volume of EtO, humidity or temperature. However, FDA says that the company's reliance on "either pre-metered Certificate-of-Conformance based cartridge and/or by pre- and post-weight analysis," an approach the company apparently adopted in 2008, "is not adequate."
The agency asserted that processing records had disclosed variances in the quantity of EtO "delivered from the cartridges," and claimed that G3 did not establish "requirements for the humidification chips to demonstrate the relative humidity parameters identified in your various processes have been met." Another point of validation where FDA felt the firm fell down was in demonstrating that the process challenge device was located "at the most difficult to sterilize/worst case location" during validation.
FDA also alleged that G3 exceeded the number of allowed sterilization bags in two loads in a validation citation, although the agency states that the firm's response to this finding "appears adequate pending the proper implementation of the updated procedures provided along with your response." The warning letter also cites G3 for issues with corrective and preventive action and device history records. The company did not respond to a call for comment.
Mark McCarty, 703-268-5690