| Public Health Service Food and Drug Administration |
Waterview Corporate Center |
Department of Health and Human ServicesTelephone (973) 331-4906
May 11, 2010
WARNING LETTER
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
Mr. Richard Gibson
President
Artegraft, Inc.
220 North Center Drive
North Brunswick, NJ 08902
Dear Mr. Gibson:
10-NWJ-10
During an inspection of your firm located in North Brunswick, New Jersey, on February 22, 2010 through March 8, 2010, an investigator from the United States Food and Drug Administration (FDA) determined that your firm is a manufacturer for Artegraft (vascular graft) and D-Clot (thrombectomy catheter system). Under section 201(h) of the Federal Food, Drug, and Cosmetic Act ("the Act") [21 U.S.C. § 321(h)] these products are devices because they are intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or are intended to affect the structure or function of the body.
At the close of the inspection, an FDA Investigator discussed with you objectionable conditions observed during the inspection. A Form FDA-483 was issued to you. We received a response from Laurence A. Potter, Vice President, Scientific Affairs, on March 22, 2010 concerning our investigator's observations noted on the Form FDA 483, List of Inspectional Observations. The violations and Mr. Potter's response are discussed below.
The FDA inspection revealed that your devices are adulterated within the meaning of section 501(h) of the Act (21 U.S.C. § 351(h)) in that the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with the Current Good Manufacturing Practice (CGMP) requirements of the Quality System (QS) regulation found at Title 21, Code of Federal Regulations (CFR), Part 820. We address your firm's March 19,2010 response below, in relation to each of the noted violations. These violations include, but are not limited to, the following:
1. Failure to identify the action(s) needed to correct and prevent recurrence of nonconforming product and other quality problems. 21 CFR § 820.100(a)(3). Specifically, your firm has failed to address numerous complaints received
concerning leaking Artegraft products (natural collagen vascular grafts). Your firm has failed to establish and maintain procedures for control and action to be taken on devices distributed, and those not yet distributed, that are suspected of having potential nonconformities. For example:
A) Your firm received a customer complaint (080021) on July 21, 2008 concerning a leaking Artegraft product. Your firm determined that the possible root cause was customer handling or operator error during the capping process. Your firm's corrective action to the compliant was to add a process check after the culture tubes are (b)(4). However, this action was not effective since your complaint tracking log documents additional complaints that were received by your firm for leaking products in 2009. No Corrective Action Request (CAR) was opened at the time of this inspection to identify the actions needed to correct and prevent recurrence of nonconforming product and other quality problems.
B) Engineering Change Notice (ECN 0333), dated December 23, 2008 was initiated by your firm to address complaints received concerning leaking Artegraft products. An additional manufacturing step (b)(4) was executed as a result of this ECN. However, additional complaints were received by your firm after this engineering change notice was initiated, and your firm has failed to correct and prevent recurrence of nonconforming product and other quality problems.
C) In-Process Non-Conformance Report, NCR N09-007, dated July 17, 2009 states that one Artegraft was found to have a leaking culture tube. As a result, your firm decided to change the design of the cap (add a second liner to the cap). However, your firm determined that there was no significant difference between the single layer cap and double layer cap where the single layer cap continues to be used by your firm. You have failed to control and take action on devices distributed, and those not yet distributed, that are suspected of having potential nonconformities.
We have reviewed your response pertaining to FDA-483 observation three and have concluded that your response was not adequate because of the following:
a. Your firm stated in your response that you have purchased equipment in order to provide consistent specified (b)(4) for your threaded cap processing (included as attachment 5 to your response). However, your firm needs to verify or validate your proposed corrective and preventative actions for the possible elimination of package leaking in order to ensure that such action is effective and does not adversely affect the finished device.
b. Your firm states that you have initiated a Corrective Action Request (CAR- 2010-3); however, no CAR was provided in your response to show that you will be able to identify the action(s) needed to correct and prevent recurrence of nonconforming product and other quality problems.
c. Your response states that you will develop proper process procedures, specifications, and test requirements in order to eliminate future package leaking. However, no procedures were provided in your response to show that you're promised corrective actions will be effective at eliminating future package leaking. There is no assurance (based on your written response) that your firm will be able to establish and maintain procedures for control and action to be taken on devices distributed, and those not yet distributed, that are suspected of having potential nonconformities.
2. Failure to verify or where appropriate validate according to § 820.75 changes to a specification, method, process, or procedure before implementation, and failure to document these activities. 21 CFR § 820.70(b). Specifically, your firm failed to verify or validate the impact of extending the time of the sterilization process for Artegraft products. It was documented that they were removed from your heat chamber during the sterilization process do to operator error and equipment failure. For example:
A) In-process Non-Conformance Report # N09-002 dated March 19,2009 documents batch/lot numbers 09A014, 09A015, and 09A016 were removed after (b)(4) of a (b)(4) heat chamber sterilization cycle due to a manufacturing technician error. The batches were outside of the heat chamber for a period of three days and your firm's current sterilization process (WI-MFG-003, dated May 14, 2007) and you're production work order requires Artegraft products to be held in the heat chamber at (b)(4). Your firm's corrective action was to place the three batches back into the heat chamber for an (b)(4) without any validation documentation to support these deviations from the normal sterilization process.
B) In-process Non-Conformance Report # N08-004, dated May 23, 2008 documents that the heat chamber temperature indicator was showing that the heat chamber temperature fell below (88 degrees Fahrenheit) the requirements of (b)(4) degrees Fahrenheit on April 8, 2008. According to your Non-Conformance Report #N08-004, the lots that were affected in the heat chamber at the time of the non-conformance were 08C047, 08C048, 08C049,and 08C050. Your compliance team calculated a sterilization extension time of seven days for these grafts. In addition, your 2008 Sterilization log shows that batches 08C051, 08C052, 08C053, and 08C054 were in your heat chamber on April 4, 2008. As a result, your Non-Conformance report # N08-004 documents that sterilization fluid currently in the culture tubes for batches 08C051, 08C052, 08C053, and 08C054 were drained out and new sterilization fluid was placed in the culture tubes. These batches were placed back into your heat chamber for sterilization. However, no validation documentation to support these deviations from the normal sterilization process was performed by your firm prior to implementation.
We have reviewed your response pertaining to FDA-483 observations two and four,and have concluded that your response was not adequate because of the following:
a. No evidence was provided to show that validation will be performed prior to your firm making changes to a production process that would require validation activities. If manufacturing changes (deviations) may influence a validation process, the process must be revalidated as described in 21 CPR § 820.75.
b. No worse case formal sterilization validation study was provided for review as an attachment to your written response.
3. Production processes were not adequately developed, conducted, controlled, and monitored to ensure that devices conform to their specifications. 21 CPR §820.70(a). Specifically, you have failed to adequately develop, monitor, and control production processes in order to ensure reliability and repeatability of the manufacturing process. For example:
A) Your firm's procedure for testing the quality of your water (SOP 036, Revision F) which is used to process products requires root cause investigations and re-testing to be performed immediately for water samples that fail action limits. On December 24, 2009, your contract laboratory reported to you that the conductivity test result (198 uS at 25 degrees Celsius) for port 10 did not conform to specifications. Your firm failed to perform a retest or investigate the OOS result as per your written procedure.
B) Your firm's Routine Product Bioburden Testing SOP 046, Revision B. describes random sampling (b)(4). However, your firm has no documentation to show that (b)(4) final samples were taken from a (b)(4) manufacturing technician during the January 11, 2008, July 15, 2008, and July 31, 2009 bioburden testing as required by your written procedure.
C) Your Routine Product Bioburden Testing SOP 046, Revision B, specifies jncreased limits when compared to your 2008 and 2009 quarterly Artegraft product bioburden test results. There was no scientific data provided during the inspection to demonstrate the appropriateness for the limits set in your written procedure.
We have reviewed your response pertaining to FDA-483 observation 5 (A2, B, C) and have concluded that your response was not adequate because of the following:
a) Your response does not provide any evidence that the failing water results for port 10 were erroneous. Your firm has failed to follow your own written procedure which requires root cause investigations and re-testing to be performed immediately for water samples that fail action limits. It is your responsibility to ensure that manufacturing processes remain in a state of control in order to produce devices that conform to their specifications.
b) No evidence of training was provided to show implementation of routine sampling which would include quarterly bioburden samples to be submitted per operator.
c) No evidence was provided in your response to support your new alert and action limits for bioburden.
4. Failure to establish and maintain adequate procedures to control environmental conditions that could reasonably be expected to have an adverse effect on product quality and failure to periodically inspect environmental control systems to verify that the system is adequate and functioning properly. 21 CFR§ 820.70(c). For example:
A) Your firm's "Environmental Monitoring, Sampling and Corrective Action for the manufacturing Facility and Personnel", Revision H, does not require your firm to monitor the positive pressure even though your validation report for Artegraft's manufacturing facility, dated May 3, 1999, requires positive pressurization in (b)(4) from the (b)(4) and to (b)(4).
B) Your firm's "Environmental Monitoring, Sampling and Corrective Action for the manufacturing Facility and Personnel", Revision, H, requires swab sampling of the Artegraft and D-Clot manufacturing rooms and personnel sampling to determine the microbial burden within the manufacturing , environment and on the operator's gloves. However, at the time of this inspection no alert and action limits had been established by your firm for swab sampling and personnel sampling.
C) Your firm's "Environmental Monitoring, Sampling and Corrective Action for the Manufacturing Facility and Personnel", Revision H, requires trend analysis to be performed on all resultant data in order to determine increases in all areas for microbial and non-viable particulate activity. However, at the time of this inspection no trend analysis was performed by your firm.
We have reviewed your response pertaining to FDA-483 observation 5 (A2, B, C) and have concluded that your response was not adequate because of the following:
a) No evidence was provided to support that you will be able to adequately monitor continuous positive pressure in your Artegraft manufacturing facility (Requirement per your Artegraft's manufacturing validation report). Manufacturers are required to establish and maintain adequate procedures to control environmental conditions that could reasonably be expected to have an adverse effect on product quality. As a part of the requirement, manufacturers are required to periodically inspect environmental control systems to verify that the system, including necessary equipment, is adequate and functioning properly and these activities are documented and reviewed.
b) No evidence was provided in your response to support your alert and action limits for swab sampling and personnel sampling.
c) No evidence of training was provided in your response to support implementation of your QA Data Trending and Analysis (SOP 51) procedure.
5. Failure to ensure that all equipment used in the manufacturing process meets specified requirements and is appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use. 21 CFR § 820.70(g). Specifically, your firm failed to provide the FDA investigator with procedures for inspecting, monitoring, and maintaining a (b)(4) Refrigerator, ID # 00059, that is used for the temporary storage of raw materials and in-process vascular graft materials used for manufacturing.
We have reviewed your response pertaining to FDA-483 observation 7 and have concluded that your response was not adequate because of the following:
a) Your proposed written procedure for transporting grafts in and out of the (b)(4) refrigerator, WI-MFG-011, Revision A, is not adequate since this procedure does not require maintenance schedules for the adjustment, cleaning, and other maintenance of your refrigerator in order to ensure that manufacturing specifications are met. Manufacturers must also conduct periodic inspections in accordance with established procedures to ensure adherence to applicable equipment maintenance schedules. When maintenance activity is required, the manufacturer must document and follow procedures for inspection of maintenance activities to ensure that such activity is conducted according to schedule, that all activities have been completed, and that equipment specification requirements continue to be met.
b) Your firm must ensure that all equipment that is used in manufacturing meets specified requirements and it must be appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use. Your response does not provide us with any evidence that the (b)(4) refrigerator is suitable for the temporary storage of raw materials and in-process vascular graft materials which are used for manufacturing products. By not adequately maintaining and inspecting the refrigerator, products that do not meet specifications may be used in the manufacture of the devices, which could ultimately lead to the finished devices not meeting specifications.
You should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action being initiated by FDA without further notice. These actions include, but are not limited to, seizure, injunction, and/or civil money penalties. Also, federal agencies are advised of the issuance of all Warning Letters about devices so that they may take this information into account when considering the award of contracts. Additionally, premarket approval applications for Class ill devices to which the Quality System regulation deviations are reasonably related will not be approved until the violations have been corrected. Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected.
Please notify this office in writing within fifteen (15) working days from the date you receive this letter of the specific steps you have taken to correct the noted violations, including an explanation of how you plan to prevent these violations, or similar violations, from occurring again. Include documentation of the corrective action you have taken. If your planned corrections will occur over time, please include a timetable for implementation of those corrections. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed.
Your response should be sent to: Robert J. Maffei, Compliance Officer, U.S. Food and Drug Administration, 10 Waterview Boulevard, 3rd Floor, Parsippany, New Jersey, 07054. If you have any questions about the content of this letter, please contact Mr. Maffei at 973-331-4906.
Finally, you should know that this letter is not intended to be an all-inclusive list of the violation(s) at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations noted in this letter and in the FDA-483 issued at the closeout of the inspection may be symptomatic of serious problems in your firm's manufacturing and quality assurance systems. You should investigate and determine the causes of the violations, and take prompt actions to correct the violations and to bring your products into compliance.
Sincerely yours,
/s/
Diana Amador-Toro
District Director
New Jersey District Office
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