1. HCT/P Compliance Update 6th Annual FDA and the Changing Paradigm for HCT/P Regulation Orlando, FL, February 3-5, 2010 Mary Malarkey, Director, OCBQ, CBER

2. Summary Inspections by the numbers Inspections by the numbers Issues identified Issues identified Regulatory actions and Regulatory actions andcitations HCT/P Deviation Reports HCT/P Deviation Reports Recalls Recalls

3. Inspections

4. FY08 HCT/P Inspections Accomplished FY08 HCT/P Inspections Accomplished *Sum of individual inspections do not equal total due to some inspections that were conducted for products in multiple categories Type of HCT/P establishment # Inspections AccomplishedHours/Inspection Reproductive tissues 15842.4 Cord blood stem cells Peripheral blood stem cells 1931.7 All other HCT/Ps (e.g. musculoskeletal, ocular, recovery, distributors) 21334.4 Total/Average Total/Average383*37.5

5. FY09 HCT/P Inspections Accomplished FY09 HCT/P Inspections Accomplished *Sum of individual inspections do not equal total due to some inspections that were conducted for products in multiple categories Type of HCT/P establishment # Inspections AccomplishedHours/Inspection Reproductive tissues 16742.8 Cord blood stem cells Peripheral blood stem cells 42 4241.9 All other HCT/Ps (e.g. musculoskeletal, ocular, recovery, distributors) 23440.5 Total/Average Total/Average437*41.7

6. OAI/VAI/NAI? OAI – Official Action Indicated – objectionable conditions found that warrant action OAI – Official Action Indicated – objectionable conditions found that warrant action VAI – Voluntary Action Indicated – objectionable conditions found but do not meet the threshold for regulatory action VAI – Voluntary Action Indicated – objectionable conditions found but do not meet the threshold for regulatory action NAI – No Action Indicated – no objectionable conditions found (generally no FDA-483) NAI – No Action Indicated – no objectionable conditions found (generally no FDA-483) http://www.fda.gov/ora/inspect_ref/fmd/fm d86.htm http://www.fda.gov/ora/inspect_ref/fmd/fm d86.htm http://www.fda.gov/ora/inspect_ref/fmd/fm d86.htm http://www.fda.gov/ora/inspect_ref/fmd/fm d86.htm

7. FY08 HCT/P Inspection Classifications Type of HCT/P establishment NAIVAIOAI Reproductive tissues 1064010 Cord blood stem cells Peripheral blood stem cells 15 15 4 0 All other HCT/Ps (e.g. musculoskeletal, ocular, recovery, distributors) 164 46 46 1 Total Total285 90 9011

8. FY09 HCT/P Inspection Classifications Type of HCT/P establishment NAIVAIOAI Reproductive tissues 10948 7 Cord blood stem cells Peripheral blood stem cells 28 28 10 10 4 All other HCT/Ps (e.g. musculoskeletal, ocular, recovery, distributors) 172 54 54 3 Total Total309 112 11214

9. FY09 HCT/P Inspection Results Approx. 30% of HCT/P inspections resulted in issuance of Form FDA- 483s; Approx. 30% of HCT/P inspections resulted in issuance of Form FDA- 483s; Consistent with FY08 and FY07. Consistent with FY08 and FY07.

10. FDA Form 483 “This document lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations, and do not represent a final agency determination regarding your compliance. If you have an objection regarding an observation, or have implemented, or plan to implement, corrective action in response to an observation, you may discuss the objection or action with the FDA representative(s) during the inspection or submit this information to FDA at the address above….” “This document lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations, and do not represent a final agency determination regarding your compliance. If you have an objection regarding an observation, or have implemented, or plan to implement, corrective action in response to an observation, you may discuss the objection or action with the FDA representative(s) during the inspection or submit this information to FDA at the address above….”

11. Inspectional Focus in FY09 Risk-based inspectional approach to prioritizing HCT/P inspections. Examples: Risk-based inspectional approach to prioritizing HCT/P inspections. Examples: –Increase in adverse reaction reports for corneas – Candida – Eye Banks –27 private cord blood banks proactively identified for inspection to gauge the industry

12. GTP Issues Identified Eye banks not validating processing (e.g. preparation of corneas for EK, DSEAK) with respect to prevention of contamination and cross contamination during processing Eye banks not validating processing (e.g. preparation of corneas for EK, DSEAK) with respect to prevention of contamination and cross contamination during processing Cord blood banks not validating processing with respect to prevention of contamination and cross contamination during processing Cord blood banks not validating processing with respect to prevention of contamination and cross contamination during processing

13. Other GTP issues Lack of environmental controls and monitoring - to assure consistency and maintain validated state. Lack of environmental controls and monitoring - to assure consistency and maintain validated state. Lack of or inadequate validation of microbiological test methods (i.e. part of definition of processing) Lack of or inadequate validation of microbiological test methods (i.e. part of definition of processing)

14. DE Issues – Cord Blood 21 CFR 1271.75(a)(1) - Donors were not screened by a review of relevant medical records for clinical evidence of communicable disease agents and diseases. 21 CFR 1271.75(a)(1) - Donors were not screened by a review of relevant medical records for clinical evidence of communicable disease agents and diseases. –Asking questions about the donor's medical history and relevant social behavior, including risk factors for relevant communicable disease agents and diseases, and communicable disease risks associated with xenotransplantation. –A review of medical records, including a physical assessment for clinical evidence of cell associated communicable disease agents and disease.

15. DE Issues – Cord Blood - 2 21 CFR 1271.47(a) - Procedures for all steps performed in the screening, testing, and determining of donor eligibility of HCT/Ps were not established and maintained. 21 CFR 1271.47(a) - Procedures for all steps performed in the screening, testing, and determining of donor eligibility of HCT/Ps were not established and maintained. –No written procedures for screening donors for clinical evidence of communicable diseases. –Testing procedures do not require testing for HTLV-I/II for donors of viable, leukocyte-rich cells or tissue.

16. Regulatory Actions

17. Warning Letters Require a company response Require a company response –You should apply to all sites Other government agencies notified Other government agencies notified Posted on the website Posted on the website Inadequacies in your 483 response will be addressed if submitted within 15 days of inspection* Inadequacies in your 483 response will be addressed if submitted within 15 days of inspection* Usually FDA's last attempt to get company's attention before enforcement action Usually FDA's last attempt to get company's attention before enforcement action Warning Letter close out letters from FDA now issued and posted on website* Warning Letter close out letters from FDA now issued and posted on website*

18. Untitled Letters Communication to the industry on concerns Communication to the industry on concerns May ask for a response May ask for a response Other federal agencies not advised Other federal agencies not advised No warning statement No warning statement

19. Regulatory Actions FY09 Regulatory Actions Issued Regulatory Actions Issued –4 Warning Letter (repro) (FY08 – 1) –3 Untitled Letter (repro) (FY08 – 1) –1 Order to Cease Manufacturing of HCT/Ps (cord blood)

20. Regulatory Actions FY10* Regulatory Action Issued Regulatory Action Issued –5 Untitled Letters 3 repro 3 repro 1 eye bank 1 eye bank 1 cord blood bank 1 cord blood bank * As of 1/15/10

21. FY09- FY10 Regulatory Actions: Deviations Cited - Repro Failure to test specimens from anonymous or directed reproductive donors for evidence of infection due to relevant communicable diseases [21 CFR 1271.85(a)(b) and (c)]. HIV, HCV, HTLV – I/II, CMV, Chlamydia, Neisseria. Failure to test specimens from anonymous or directed reproductive donors for evidence of infection due to relevant communicable diseases [21 CFR 1271.85(a)(b) and (c)]. HIV, HCV, HTLV – I/II, CMV, Chlamydia, Neisseria. Failure to screen an anonymous or directed reproductive donor of cells or tissue by reviewing the donor's relevant medical records for risk factors for, and clinical evidence of, relevant communicable disease agents and diseases [21 CFR 1271.75(a)]. Failure to screen an anonymous or directed reproductive donor of cells or tissue by reviewing the donor's relevant medical records for risk factors for, and clinical evidence of, relevant communicable disease agents and diseases [21 CFR 1271.75(a)].

22. FY09- FY10 Regulatory Actions: Deviations Cited - Repro Failure to collect a donor specimen for testing for relevant communicable diseases within 30 days prior to oocyte recovery or up to seven days after oocyte recovery or up to seven days before or after recovery for semen donors [21 CFR 1271. 80(b)]. Failure to collect a donor specimen for testing for relevant communicable diseases within 30 days prior to oocyte recovery or up to seven days after oocyte recovery or up to seven days before or after recovery for semen donors [21 CFR 1271. 80(b)]. Failure of a responsible person to determine and document the eligibility of an anonymous or directed donor of reproductive cells or tissue [21 CFR 1271.50(a)]. Failure of a responsible person to determine and document the eligibility of an anonymous or directed donor of reproductive cells or tissue [21 CFR 1271.50(a)].

23. Vista Cord, LLC (Vista Cord) Order to Cease Manufacturing of HCT/Ps (cord blood) Immediately cease manufacturing operations and continue to store cord blood in compliance with 21 CFR 1271.260 Immediately cease manufacturing operations and continue to store cord blood in compliance with 21 CFR 1271.260 To Vista Cord and its CEO and owner, Aubrey B. Allen To Vista Cord and its CEO and owner, Aubrey B. Allen FDA determined that the violations uncovered at Vista Cord, because of their serious nature, provided reasonable grounds to believe that there is a danger to health. The Order was effective immediately. FDA determined that the violations uncovered at Vista Cord, because of their serious nature, provided reasonable grounds to believe that there is a danger to health. The Order was effective immediately. Order to Cease Manufacturing of HCT/Ps was issued on September 24, 2009. Order to Cease Manufacturing of HCT/Ps was issued on September 24, 2009. http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/Tis sueSafety/ucm183756.htm http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/Tis sueSafety/ucm183756.htm

24. Vista Cord Public Health Notification Issued on September 25, 2009, to inform the health care community and the public of the Order. Issued on September 25, 2009, to inform the health care community and the public of the Order. “FDA has identified deviations from requirements regarding donor eligibility screening and testing, processing controls, environmental control and monitoring, equipment and facilities, supplies and reagents, process validation, labeling controls, and receipt of products.” “FDA has identified deviations from requirements regarding donor eligibility screening and testing, processing controls, environmental control and monitoring, equipment and facilities, supplies and reagents, process validation, labeling controls, and receipt of products.” “FDA staff are aware that these units are important to the donor families, and were collected, processed and stored at significant expense….We will work to facilitate the transfer of units to other storage facilities identified by the donor families.” “FDA staff are aware that these units are important to the donor families, and were collected, processed and stored at significant expense….We will work to facilitate the transfer of units to other storage facilities identified by the donor families.”

25. HCT/P Deviation Reports and Issues

26. HCT/P Deviation Reporting FY06FY07FY08FY09 Reportable144153222254 Electronic Reports 100(69%)118(77%)164(74%)205(81%) Non- Reportable 76486345 Total Reports 220201285299

27. HCT/P Deviation Reports Products Involved Product FY0 6 FY0 7 FY0 8 FY0 9 Peripheral Blood Stem Cells 719810884 Cornea/Sclera50354251 Skin562743 Pancreatic Islet Cells, auto 011930 Musculoskeletal23152351 Cord Blood Stem Cells 24410 Therapeutic Cells 610129

28. HCT/P Deviations Reported Reportable HCT/P Deviations FY 06 FY 07 FY 08 FY09 Donor Eligibility 32243734 Donor Screening 128177 Donor Testing 33545438 Environmental Control 1200 Supplies and Reagents 3610 Recovery 28814 Processing141768101 Labeling Control 2122 Storage 1000 Receipt, Pre-Dist., Dist. 43323658 Total143152223254 Non-Reportable77486345

29. HCT/P Deviation Reports Non-Reportable Events No products were distributed No products were distributed Not associated with disease transmission or contamination Not associated with disease transmission or contamination Not related to core GTP Not related to core GTP Product released under urgent medical need Product released under urgent medical need Product not subject to HCT/P deviation reporting Product not subject to HCT/P deviation reporting –Reproductive tissue –Unrelated Allogeneic Stem Cells Reporting establishment is not an HCT/P manufacturer Reporting establishment is not an HCT/P manufacturer

30. HCT/P Deviation Reports Non-Reportable Events Positive pre-implant culture is in general not reportable as a deviation Positive pre-implant culture is in general not reportable as a deviation –Unless a complaint results in an investigation that reveals a departure from GTPs or –If the recipient had an adverse reaction then might be reported as an adverse reaction not HCT/P deviation

31. HCT/P Deviation Reporting FY09 HCT/P Deviation Code HCT/P Deviation CodeCellularHCT/PTissueHCT/PTotal Processing and Processing Controls 663510139.8% Receipt, Pre-Distribution, Shipment & Distribution 5355822.8% Donor Testing 4343815.0% Donor Eligibility 2323413.4% Recovery68145.5% Donor Screening 0772.8% Labeling Controls 0220.8% Supplies and Reagents 0000.0% Environmental Control 0000.0% Storage0000.0% Total131123254100%

32. HCT/P Deviation Reporting FY08 HCT/P Deviation Code HCT/P Deviation Code Cellular HCT/P Tissue HCT/P Total Donor Eligibility 43337 16.6 % Donor Screening 215177.6% Donor Testing 421254 24.2 % Environmental Control 0000.0% Supplies and Reagents 1010.4% Recovery8083.6% Processing and Processing Controls 501868 30.5 % Labeling Controls 0220.9% Storage0000.0% Receipt, Pre-Distribution, Shipment & Distribution 33336 16.1 % Total14083223100%

33. Tissue HCT/P Reports - 1 Processing and process controls – 35 Processing and process controls – 35 –HCT/P contaminated, potentially contaminated or cross contaminated – 34 –In-process controls not followed – 1 Microorganisms involved: Microorganisms involved: –Bacillus, Candida, Clostridium, Enterobacter, Group D Enterococcus, Staphylococcus, Serratia

34. Tissue HCT/P Reports - 2 Donor Testing – 34 Donor Testing – 34 –Unacceptable specimen tested storage condition not met – 25 storage condition not met – 25 Specimen collected >7 days before or after recovery - 1 Specimen collected >7 days before or after recovery - 1 –Testing incorrectly performed – 5 –Testing not performed or documented – 2 –Inappropriate test or test lab used - 1

35. Tissue HCT/P Reports - 3 Donor Eligibility – 32 reports Donor Eligibility – 32 reports –Donor accepted when risk factors, clinical evidence or physical evidence identified – 18 –Donor accepted when reactive for relevant communicable disease – 6 –Donor incorrectly evaluated for plasma dilution – 4 –Donor eligibility not performed or documented - 4

36. Cellular HCT/P Reports - 1 Processing and process controls – 66 Processing and process controls – 66 –HCT/P contaminated, potentially contaminated or cross contaminated during processing – 59 Syringe integrity compromised - 13 Syringe integrity compromised - 13 –In process controls not followed – 7 Microorganisms involved: Microorganisms involved: –Bacillus, Candida, Diphtheroids, Enterobacter, Group D Enterococcus, Klebsiella, Micrococcus, Peptostreptococcus, Propionibacterium, Staphylococcus, Streptococcus

37. Cellular HCT/P Reports - 2 Distribution – 53 Distribution – 53 –Contaminated or potentially contaminated HCT/P – 50 –Distribution without sign off by a responsible person – 2 –Distribution without review of required records - 1 Microorganisms involved: Microorganisms involved: –Bacillus, Micrococcus, Propionibacterium, Staphylococcus, Streptococcus

38. Classified Recalls FY 2009 Classified Recalls FY 2009 *In addition, there were 118 “mixed” Class II and III blood recalls HCT/PRecalls CBER Total Recalls * (all products) FY 09 Class I 00 FY 09 Class II 9807 FY 09 Class III 4312

39. Classified Recalls FY 2008* Classified Recalls FY 2008* *- This table does not include 3 “mixed class” recalls HCT/PRecalls CBER Total Recalls (all products) FY 08 Class I 34 FY 08 Class II 11950 FY 08 Class III 7345

40. HCT/P Recalls

41. Vision for CBER INNOVATIVE TECHNOLOGY ADVANCING PUBLIC HEALTH CBER uses sound science and regulatory expertise to:  Protect and improve public and individual health in the US and, where feasible, globally  Facilitate development, approval and access to safe and effective products and promising new technologies  Strengthen CBER as a preeminent regulatory organization for biologics regulatory organization for biologics

42. We’re Here to Help You! http://www.fda.gov Email CBER: Email CBER: –Manufacturers: matt@cber.fda.gov matt@cber.fda.gov –Consumers, health care –octma@cber.fda.gov Phone: Phone: –+1-301-827-1800