Musculoskeletal Transplant Foundation 4/11/13
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Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
Waterview Corporate Center
10 Waterview Blvd., 3rd Floor
Parsippany, NJ 07054
Telephone (973) 331-4911
April 11, 2013
UNITED PARCEL SERVICE
Mr. Bruce W. Stroever
President/Chief Executive Officer
Musculoskeletal Transplant Foundation
125 May Street, Suite 300
Edison, NJ 08837-3264
Dear Mr. Stroever:
The Food and Drug Administration conducted an inspection of your firm located at 125 May Street, Edison, NJ from September 17 to November 30, 2012. During the inspection, FDA investigators found significant deviations from the regulations for human cells, tissues, and cellular and tissue-based products (HCT/Ps), set forth in Title 21, Code of Federal Regulations, Part 1271 (21 CFR 1271) and issued under the authority of Section 361 of the Public Health Service Act (42 USC 264).
The deviations documented on a Form FDA 483, Inspectional Observations, were presented to and discussed with you at the conclusion of the inspection. The items of concern include, but are not limited to the following:
1. You must not make available for distribution of a HCT/P that is in quarantine, is contaminated, is recovered from a donor who has been determined to be ineligible or for whom a donor eligibility determination has not been completed,or that otherwise does not meet release criteria designed to prevent communicable disease transmission [21 CFR 1271.265(c)(2)].
For example, sterility testing of Trinity products from donors 0031108715 and 0671107306 failed due to the presence of Clostridium perfringens and Clostridium sordellii, respectively. According to your release criteria, these positive sterility tests should have resulted in the gamma irradiation of the fresh tissue allografts, frozen/freeze dried bone, and soft tissue allografts from the same donors following processing.
However, these allografts were only processed aseptically and not gamma irradiated, yet were released and distributed.
2. Failure to establishand maintain procedures appropriate to meet core current good tissue practice (CGTP) requirements for all steps that you perform in the manufacture of HCT/Ps. You must design these procedures to prevent circumstances that increase the risk of the introduction, transmission, or spread of communicable diseases through the use of the HCT/Ps [21 CFR 1271.180(a)]. For example:
a) You failed to follow the procedure, WI-335, Quality Assurance First and Second Review for Whole Donor Musculoskeletal Tissue, Rev. 8, during the release of musculoskeletal allografts from donors 0031108715 and 0671107306. The procedure requires that the results of sterility testing for Trinity products be reviewed to verify they are negative for Clostridium and Group-A Strep, and that the Work Order be reviewed for special requirements. If the sterility test results are positive for Clostridiumor Group-A Strep, the procedure requires gamma irradiation of bone and soft tissue allografts associated with the same donor. The sterility testing of Trinity products from donors 0031108715 and 0671107306 failed due to the presence of Clostridium perfringens and Clostridium sordellii, respectively. The musculoskeletal allografts from both donors were released without post-processing gamma irradiation and without a review of sterility testing results for Trinity products and the special requirements on the Work Orders.
b) WI-335, Quality Assurance First and Second Review for Whole Donor Musculoskeletal Tissue,was not revised to reflect the following critical changes:
i. Engineering Memo 40, dated October 19, 2011, included the change in the disposition of whole donor work orders when the donor had partial positive sterility cultures; Engineering Memo 50, dated December 1, 2011, included a change to the QA release criteria for frozen bone; and Engineering Memo 56, dated December 28, 2011, included the rework process for bone donors with <1000 CFUs on post process bioburden cultures. The changes described in these Engineering Memos were not added to the procedure until Revision 9, effective July 13, 2012.
ii. Post-treatment of tissue with gamma irradiation was discontinued beginning with Donor 0831201642, processed July 19, 2012; however, the procedure was not updated to reflect this change until October 08, 2012.
iii. Revision 10 of the procedure, effective October 09, 2012, instructs quality assurance analysts to verify that in-process bioburden samples were taken and to determine sterility path designation for first review.
The revision only includes instructions for the Edison location and not the Jessup location; quality assurance analysts conduct the same functions at both sites.
iv. Revision 10 of the procedure, effective October 09, 2012, states that frozen bone and freeze-dried bone can have three ATP re-works; however only one re-work is currently approved, per OP-229, MTF Tissue Handling and Processing Procedures, Rev. 29, Section 31.4.
c) WI-680, In-Process Bioburden Sampling for Frozen Donors states that each cortical/cancellous sample be individually rinsed and then placed into the sample bag. However, on September 18, 2012, investigators observed the cortical and cancellous samples being rinsed, placed on a drape until all the pieces of the sample were rinsed, and then placed into the sample bag.
d) WI-185, Clean Room Code of Conduct/Edison, Rev. 1, was not followed. For example, during the inspection, investigators observed the following:
i. Section 5.6.4 states, "Apply this universal rule: 'another zone-another glove' when working in the clean room." However, during in-process bioburden sampling on September 08, 2012, investigators observed that the person collecting the samples did not consistently change gloves when moving to each zone.
ii. Section 5.6.4 states that a "HCT/P is never in contact with the outer surface of any package." However, during in-process bioburden sampling on September 08, 2012, investigators observed that when attempting to place the bulk tissue into a bag after collection of the sample, the tissue draped over the bag, coming into contact with the outside of the bag.
3. Failure to establish and maintain procedures for cleaning, sanitizing, and maintaining equipment to prevent malfunctions, contamination or cross-contamination, accidental exposure of HCT/Ps to communicable disease agents, and other events that could reasonably be expected to result in the introduction, transmission, or spread of communicable diseases [21 CFR 1271.200(b)].
For example, during the inspection, FDA investigators observed the cleaning of band saws used for cutting of HCT/Ps and in-process bioburden samples from various HCT/Ps. There is no assurance that the band saws are adequately cleaned to remove debris from all contact surfaces.
4. Failure of the quality program to establish and maintain appropriate monitoring systems as necessary to comply with the requirements of 21CFR 1271 Subpart D [21 CFR 1271.160(b)(5)].
For example, you did not track sterility results for HCT/Ps processed since September 28, 2011, as required by your procedure, "WI-245, Procedure for Addressing Alert and Action Levels Reported in SPC Trend Analysis for HCTIP," Revision 1, effective September 13, 2011.
We have reviewed your written response, dated December 21, 2012. We cannot determine the adequacy of all of your responses based on the information provided, however, we acknowledge the corrective actions you have implemented to improve your procedures for reviewing manufacturing records pertaining to each HCT/P to verify that the release criteria have been met. However, we remain concerned about your release and distribution of HCT/Ps from donors when these release criteria were clearly not met. We are also very concerned about the many lapses that occurred and about your ability to establish and maintain procedures.
We also acknowledge the changes you have made to your procedures and record review requirements, as well as the re-training of staff involved in these activities, however, your December 21, 2012 response does not address how you intend to ensure these corrective actions are effective to prevent recurrence. In addition, we expect that your quality program will closely monitor release and distribution activities to ensure that all requirements under 21 CFR 1271 are met and that your periodic quality audits will verify compliance with the regulatory requirements. Finally, we note that you are implementing changes to your computer software used to determine the sterility path of donor tissue based on the in-process bioburden results. If you rely upon this software to comply with core CGTP requirements and the software is custom or customized, you must validate the performance of the software for its intended use.
The above identified violations are not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to ensure that your establishment complies with all applicable requirements of the federal regulations. You are responsible for reviewing your firm's operations to assure you are in compliance with all applicable FDA regulatory requirements. You should take prompt action to correct these deviations and prevent their recurrence. Failure to do so may result in additional regulatory action. Such action may include, but is not limited to, an order to retain, recall, destroy, or cease manufacture of HCT/Ps.
We request that you 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 violation(s), or similar violation(s), from occurring again. If corrective action cannot be completed within 15 working days, state the reason for the delay and the timeframe within which the corrections will be completed.
Your response should be sent to the following address: U.S. Food and Drug Administration, 10 Waterview Boulevard, 3rd Floor, Parsippany, NJ 07054, Attn: Stephanie Durso, Compliance Officer. If you have any questions about the content of this letter, please contact Ms. Durso at 973-331-4911
New Jersey District