HCT/P Deviations & Reporting. 13 th ANNUAL FDA & The Changing Paradigm for HCT/P Regulation February 13-15, 2017

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1 HCT/P Deviations & Reporting CASE STUDIES FROM TISSUE AND EYE BANKS AND CELLULAR THERAPY. 13 th ANNUAL FDA & The Changing Paradigm for HCT/P Regulation February 13-15, 2017

2 Tissue Bank Perspective Ashley Bilbo, BS, CTBS LifeNet Health

Tissue Case Study #1 Scenario Late arriving information was received from a recovery agency that reported a toxicology report was ordered by the Medical Examiner It was previously reported

3 Tissue Case Study #1 Scenario Late arriving information was received from a recovery agency that reported a toxicology report was ordered by the Medical Examiner It was previously reported that no toxicology was performed Bone grafts were found to be distributed The Medical Director reviewed the results of the toxicology and found the outcome acceptable Ashley Bilbo LifeNet Health

4 Tissue Case Study #1 Is this reportable? Why or why not? No. Why or why not? The New information did not impact the donor eligibility decision that was previously determined (acceptable for release). Ashley Bilbo LifeNet Health

5 Tissue Case Study #2 Scenario A notification was received informing the tissue bank that a graft packing slip stated the graft expiration date was 11/11/15, however the graft label stated 12/11/16. The (one) graft was implanted on 03/12/16. The graft was packaged on 11/11/10. Packaging validation supports a 5 year expiration The actual expiration date of the graft is 11/11/15 An investigation was launched and found this product line had 23 other grafts distributed with incorrect expiration dates 8 grafts remain in inventory Ashley Bilbo LifeNet Health

6 Tissue Case Study #2 Is this reportable? Why or why not? Yes. Why or why not? The validation does not support time greater than 5 years. Packaging degradation past 5 years is unknown, leaving a potential for product contamination risk. How many grafts are included in the report? 24. The one graft from the initial notification, and the 23 distributed. Ashley Bilbo LifeNet Health

7 Tissue Case Study #2 Which Core GTP applies? Facilities Environmental Control Equipment Supplies and Reagents Recovery Processing and Process Controls Labeling Controls Storage Receipt, Predistribution Shipment, and Distribution Donor Eligibility Ashley Bilbo LifeNet Health

Tissue Case Study #3 Scenario A patient infection notification was received The patient noted redness and tenderness at the healing incision site The patient waited a couple of days prior to coming

8 Tissue Case Study #3 Scenario A patient infection notification was received The patient noted redness and tenderness at the healing incision site The patient waited a couple of days prior to coming to the emergency department (which was 2.5 months after their tendon surgery) Patient tested positive for Staphylococcus aureus Immediate correction An investigation was launched and no deviations were identified for this donor 41 grafts were produced from this donor, 28 had already been distributed No additional complaints have been associated with this donor Ashley Bilbo LifeNet Health

9 Tissue Case Study #3 Is this reportable? Why or why not? No. Why or why not? No deviations were identified during the production of the donor. The Medical Director will review the results of the investigation. The case will be closed at this time. Ashley Bilbo LifeNet Health

10 Tissue Case Study #4 Scenario A review of the donor record was performed as part of an unrelated investigation The review revealed conflicting information regarding the donor s travel history The initial interview with the Next of Kin, asked the question if the donor ever traveled outside of the U.S. The Next of Kin answered no Later in the interview the Next of Kin answered that her husband possibly received blood in Sicily when he had a heart attack Immediate Correction The Next of Kin was contacted to receive clarification. The donor s travel history did not meet acceptance criteria. 273 grafts were produced on this donor; 63 grafts were distributed and holds have been placed on the remaining grafts in inventory. Ashley Bilbo LifeNet Health

11 Tissue Case Study #4 Is this reportable? Yes. Why or why not? Distribution of the 63 grafts did not meet eligibility criteria. Ashley Bilbo LifeNet Health

12 Tissue Case Study #4 Which Core GTP applies? Facilities Environmental Control Equipment Supplies and Reagents Recovery Processing and Process Controls Labeling Controls Storage Receipt, Predistribution Shipment, and Distribution Donor Eligibility Ashley Bilbo LifeNet Health

13 Cellular Therapy Perspective Erica Agy Seattle Cancer Care Alliance

14 Cellular Case Study #1 Scenario Syringe manufacturer issues a recall on 09/23/16 for 10 ml syringes Breach in the sterilization process during manufacturing The recalled lot was in use by Apheresis between 08/15/16 and 09/23/16 The recall affected the recovery of 63 HCT/Ps The lab processed those 63 products for either storage or infusion, which totaled 201 products Of the 201 HCT/Ps processed by the lab, 111 were distributed for infusion 90 HCT/Ps remain in storage, and may be distributed at a later date The processing lab did not use any of the recalled syringes. Erica Agy Seattle Cancer Care Alliance

15 Cellular Case Study #1 Is this reportable? YES! But only for the 111 products that have been distributed* *A report will be required if and when the remaining 90 products are distributed Why or why not? Potential product contamination Erica Agy Seattle Cancer Care Alliance

16 Cellular Case Study #1 Which Core GTP applies? Facilities Environmental Control Equipment Supplies and Reagents Recovery Processing and Process Controls Labeling Controls Storage Receipt, Predistribution Shipment, and Distribution Donor Eligibility Erica Agy Seattle Cancer Care Alliance

17 Cellular Case Study #2 Scenario Related allogeneic bone marrow product harvested and distributed for infusion 4 days after harvest, lab receives notification that a sample from the product tested positive for microbial contamination Preliminary results show Gram positive rods 7 days after harvest, the testing lab identifies the organism as Propionibacterium species No adverse events occurred during or immediately following infusion of the product Blood cultures from the patient are negative Erica Agy Seattle Cancer Care Alliance

18 Cellular Case Study #2 Is this reportable? NO! Why or why not? Minimally manipulated bone marrow products are not considered HCT/Ps Erica Agy Seattle Cancer Care Alliance

19 Cellular Case Study #3 Scenario Autologous mononuclear cell [MNC(A)] product recovered by Apheresis A CD34+ cell selection is performed and product is cryopreserved with 10% DMSO in vials Prior to culturing, product vials are thawed, transferred into tubes, and centrifuged During centrifugation, a small crack in one tube is observed prior to placing the cells in culture Crack is due to over-tightening the cap No apparent loss of product Product is genetically modified and cultured prior to distribution Distributed as a T-Cells(A) product Sterility samples all show no microbial growth Patient experienced mild hypertension and nausea during the infusion Erica Agy Seattle Cancer Care Alliance

20 Cellular Case Study #3 Is this reportable? NO*! * The IND/IDE Sponsor needs to be notified, who will appropriately report it to the FDA Why or why not? Product is more than minimally manipulated, making it a 351 product Erica Agy Seattle Cancer Care Alliance

21 Cellular Case Study #4 Scenario Related allogeneic donor is determined to be eligible, and donates an HPC(A) product that is distributed and infused A later review of donor records reveals the donor visited Florida within 6 months of donation The patient experienced mild nausea during infusion of the product All sterility samples show no microbial growth Erica Agy Seattle Cancer Care Alliance

22 Cellular Case Study #4 Is this reportable? YES! Why or why not? Potential product contamination by the Zika virus Erica Agy Seattle Cancer Care Alliance

23 Cellular Case Study #4 Which Core GTP applies? Facilities Environmental Control Equipment Supplies and Reagents Recovery Processing and Process Controls Labeling Controls Storage Receipt, Predistribution Shipment, and Distribution Donor Eligibility Erica Agy Seattle Cancer Care Alliance

24 Eye Bank Perspective Kristin Mathes, MA Lions VisionGift

25 Ocular Tissue Case Study #1 Scenario Eye bank identifies a trend of organisms growing in preoperative culture results reported by transplanting surgeons at one hospital. One is associated with an infectious keratitis that resolved without medical intervention. Eye bank investigates and finds no link to its processes. Eye bank is notified by another customer of multiple positive preoperative culture results with the same organisms and includes another eye bank reported to them that they discovered the same trends and linked it to a sterile eye rinse used during recovery. Eye bank investigates and links the positive preop culture results to the same eye rinse. Immediate correction Eye rinse is pulled from shelves and recovery kits, in-stock tissue recovered using the suspect eye rinse is quarantined, and surgeons receiving tissue for surgery that day what was recovered using the eye rinse are notified. Kristin Mathes Lions VisionGift

26 Ocular Tissue Case Study #1 Follow-up and Corrective Action Both eye banks file a MedWatch report with CDER with suspect lots. Both eye banks submit samples of the eye rinse for testing to a laboratory. Laboratory results return data that highly suggests the eye rinse from at least 6 different lots have been contaminated. Both eye banks file a complaint with the distributor, who begins their own investigation. Distributor files a voluntary recall of over 20 lots of sterile eye rinse due to microbial contamination. Bracket Eye bank determines the eye rinse with suspect lots from this distributor was used in recovery of eye tissue for 6 months. A total of 388 corneas were distributed for intermediate use (i.e., not irradiated). Reporting What do you think? Is this a reportable deviation? Kristin Mathes Lions VisionGift

27 Ocular Tissue Case Study #1 Is this a reportable deviation? YES. Why or why not? Potential and confirmed tissue contamination from a supply that was used in recovery of tissue. Kristin Mathes Lions VisionGift

28 Ocular Tissue Case Study #1 Which Core GTP applies? Facilities Environmental Control Equipment Supplies and Reagents Recovery Processing and Process Controls Labeling Controls Storage Receipt, Predistribution Shipment, and Distribution Donor Eligibility Kristin Mathes Lions VisionGift

29 Ocular Tissue Case Study #2 Scenario Eye bank uses environmental monitoring software to track temperature and humidity in a supply cabinet where PCDs/BIs and sterilized instrumentation are stored. The SOP states temp and rh criteria reflect ambient values and requires periodic monitoring. There is a communication error between the data logger and the software. Temperature and humidity data for 32 days is lost. There is data for the beginning of one month and the end of the next. It wasn t until the QA staff ran the monthly reports for all environments that the problem was discovered. Immediate Correction Eye bank investigated to determine if PCDs/BIs and instrumentation could have been exposed to extremes in temps and found no evidence of such. Temps and rh data before and after lost data show acceptable ranges. Investigation included evaluation of autoclave performance and maintenance. All equipment maintenance was up-to-date and no report of malfunctions. Staff did not report any external or internal indicators had not turned upon use of instruments. Kristin Mathes Lions VisionGift

30 Ocular Tissue Case Study #2 Follow-up and Corrective Action Eye bank discovered communication error was a result of a constellation of IT/IS changes and server upgrades. Changes resulted in replacement of a component of all loggers for the software to communicate with the loggers. The IS employee performing the switch missed a step in the configuration of one of the loggers. It was also discovered the IT/IS staff did not used a controlled method for making the changes. Reporting What do you think? Is this a reportable deviation? Kristin Mathes Lions VisionGift

31 Ocular Tissue Case Study #2 Is this a reportable deviation? Why or why not? No. No tissue was distributed that was suspected of being processed with instruments that were not sterile. Does it require Corrective and Preventive Action with verification that the actions taken were effective? Yes. What if the mistake happened with a logger that was used in a tissue storage refrigerator that requires continuous monitoring? 21 CFR (d) Computers requires validation of the performance of computer software for its intended use, and the performance of any changes to that software for the intended use, if that software is used to comply with core CGTP requirements. As such, equipment used to interact with that software (e.g., servers that host the software) require a qualification (e.g., IQOQPQ) and changes to the equipment need to be evaluated to confirm the changes did not adversely affect the functions they are expected to perform. Kristin Mathes Lions VisionGift

32 Ocular Tissue Case Study #3 Scenario Eye bank uses environmental monitoring software to track temperature in a blood bank refrigerator where tissue intended for and released for transplant is stored. The SOP states temperature in the refrigerator will be continuously monitored, and remain between 2-8 C. There is a communication error between the data logger and the software. As a result, temperature data is not communicated to software for 5 days. It wasn t until the QA staff ran the monthly reports for all environments that it was discovered there was a temperature excursion in the refrigerator on one day. The excursion lasted just over four hours and spiked at 15 C. Temperature during all other time frames meets SOP requirements. Immediate Correction Eye bank investigated to determine cause of temperature excursion. Investigation included determining bracket of any tissue stored in the refrigerator during that time and determine its location. Any tissue that was in storage during time of excursion that is still in stock is quarantined. Kristin Mathes Lions VisionGift

33 Ocular Tissue Case Study #3 Follow-up and Corrective Action Eye bank discovered communication error was a result of a constellation of IT/IS changes and server upgrades, which prompts its own investigation and CAPA actions as seen in prior case study. Investigation showed the temperature excursion was due to loss of power to the refrigerator due to power outage. No one was in the building to hear the device alarm, and the software did not detect a temperature excursion due to communication error and notifications were not sent. The power outage resolved before anyone returned to building and no one expected a problem. Bracket 17 corneas were stored in refrigerator during loss of power to refrigerator. 13 were distributed for transplant. The other 4 were moved to non-transplant/research uses due to donor eligibility issues. Reporting What do you think? Is this a reportable deviation? Kristin Mathes Lions VisionGift

34 Ocular Tissue Case Study #3 Is this a reportable deviation? Yes. Why or why not? Tissue exposed to temperatures outside of acceptable parameters and timeframes intended to reduce microbial growth. Kristin Mathes Lions VisionGift

35 Ocular Tissue Case Study #3 Which Core GTP applies? Facilities Environmental Control Equipment Supplies and Reagents Recovery Processing and Process Controls Labeling Controls Storage Receipt, Predistribution Shipment, and Distribution Donor Eligibility Kristin Mathes Lions VisionGift

36 Ocular Tissue Case Study #4 Scenario A QA audit of a recorded uniform donor risk assessment interview (UDRAI) finds that the interviewer did not ask one of the questions, but documented on the form a no answer. It was not caught on peer review. Eye bank Medical Director designees do not listen to UDRAI recordings as a part of eligibility determination. They only review the written documentation. Donor s COD was MVA, pronounced on scene. Referral came from coroner, donor never admitted to hospital. The question asks whether the donor had ever been diagnosed with malaria. Kristin Mathes Lions VisionGift

37 Ocular Tissue Case Study #4 Immediate Correction Eye bank recontacts historian to ask the question. The answer is yes, and the diagnosis had been in the last 3 years, but historian believed had resolved prior to death. Eye bank reviews all available medical records and confirms diagnosis was 18 months prior to death, but was resolved. History of malaria in 5 years prior to death is a contraindication for the eye bank. One cornea was transplanted 4 days after recovery. The other cornea was processed and irradiated, still in inventory, and quarantined and then discarded. Reporting What do you think? Is this a reportable deviation? Kristin Mathes Lions VisionGift

38 Ocular Tissue Case Study #4 Is this a reportable deviation? Why or why not? No. Malaria is not a relevant communicable disease agent or disease. Does it require Corrective and Preventive Action with verification that the actions taken were effective? Yes. Staff follow-up with interviewer and the peer reviewer needs to be performed. Why was the question missed, and why was the answer documented no? Trends in these findings should be evaluated to determine if it s common, which could prompt a change in procedure, e.g., the Medical Director Designee may be required to listen to all interviews prior to eligibility determination. Kristin Mathes Lions VisionGift

39 Ocular Tissue Case Study #5 Scenario Eye bank recovers corneas on a donor shared with a tissue bank. Eye bank does not perform recovery/preprocessing cultures. Donor is screened and tested, and tissue is determined eligible for transplant. Both corneas are distributed and transplanted within 4 days of recovery. Tissue bank performs recovery cultures and reports positive growth for Pseudomonas on 20 out of 22 bone cultures. The tissue bank Medical Director determines all tissue will be discarded as results indicate a likely sepsis. Tissue bank notifies eye bank of positive cultures and intent to discard 3 weeks after corneas are transplanted. Eye bank SOP listed Pseudomonas as an organism that should be considered as significant if discovered on recovery/preprocessing culture results in Zones D, E and F and requires a Medical Director consult for potential sepsis. Immediate Correction Eye bank reviews donor record and confirms that eligibility determination was appropriate. Cornea recovery took place prior to tissue recovery, so there is no potential for contamination. Consult with Medical Director with this information who determined donor potentially septic due to culture site that grew Pseudomonas. Follow up with transplanting surgeons found both performed preoperative cultures. One had no growth. The other grew Propionibacterium acnes, a usual ocular flora. Neither patient showed evidence of adverse reaction. Kristin Mathes Lions VisionGift

40 Ocular Tissue Case Study #5 Is this a reportable deviation? Yes. Why or why not? Medical Director determined the positive culture results indicate a sepsis. Kristin Mathes Lions VisionGift

41 Ocular Tissue Case Study #5 Which Core GTP applies? Facilities Environmental Control Equipment Supplies and Reagents Recovery Processing and Process Controls Labeling Controls Storage Receipt, Predistribution Shipment, and Distribution Donor Eligibility Kristin Mathes Lions VisionGift

Thank You! Erica Agy Quality Assurance Compliance Specialist Seattle Cancer Care Alliance eagy@seattlecca.org 206.288.

42 Thank You! Erica Agy Quality Assurance Compliance Specialist Seattle Cancer Care Alliance Ashley Bilbo, BS, CTBS Manager of Quality Systems LifeNet Health Kristin Mathes, MA Chief Quality & Regulatory Officer Lions VisionGift th ANNUAL FDA & The Changing Paradigm for HCT/P Regulation February 13-15, 2017

Recent FDA Inspection Findings and Trends

Recent FDA Inspection Findings and Trends Jan-09 Feb-09 Mar-09 Apr-09 May-09 Jun-09 Jul-09 Aug-09 Sep-09 Oct-09 Nov-09 Dec-09 Jan-10 Feb-10 Mar-10 Apr-10 May-10 Jun-10 Jul-10 Aug-10 Sep-10 Oct-10 Nov-10 Dec-10 Jan-11 Feb-11 Mar-11 Apr-11 May-11