1. FABB - 2013 HOT TOPICS Current Issues in Blood Banking Ron Jackson Director, Compliance Branch FDA FLORIDA DISTRICT June 7, 2013

2. New Labeling Regulations

3. Published in Federal Register –“Revisions to Labeling Regulations for Blood and Blood Components, including Source Plasma” –77 FR 7, January 3, 2012 Became effective July 2, 2012 Codified in Title 21 of the Code of Federal Regulations - April 2012 edition Affects the following regs: –21 CFR 606.121 –21 CFR 606.122 –21 CFR 640.70 –21 CFR 640.74

4. Most Notable Changes April 2012 CFR contains both the old and new regs Labeling regs were updated to be consistent with current practices Changed the reg citation for certain requirements. For example: –Recovered plasma label requirements previously in 21 CFR 606.121(e)(5), are now in 21 CFR 606.121(e)(4) –Source Plasma labeling regs. previously in 21 CFR 640.70, were moved to 21 CFR 606.121

5. Most Notable Changes Unique Facility Identifier (UFI) –21 CFR 606.121(c)(2) –Discussed on page 77 FR 11 of the Federal Register –UFI now required to be on labels of blood intended for transfusion –Blood establishments need to track where unit was collected. The UFI can be: The FDA registration number The ISBT facility code Some other designation that will identify specific location where product was collected Incorporated into donation number and use a validated computer or other recordkeeping system to identify where unit was collected –Not applicable to Source Plasma; FDA is aware the approved labels have sufficient information

6. Most Notable Changes Autologous Unit Labeling –21 CFR 606.121(i) –Previously all auto units were labeled with “For Autologous Use Only” –Now acceptable auto units that can be crossed over into allogeneic inventory are labeled as “Autologous Donor” –Unacceptable auto units that cannot be crossed over are labeled as “For Autologous Use Only” –Note: AABB standards will only include “For Autologous Use Only” statement because they discourage crossover –“For Autologous Use Only” can be on all auto units, but these units cannot be crossed over

7. Most Notable Changes Circular of Information –Changed name from “Instruction Circular” to “Circular of Information” –21 CFR 606.122(m)(3) –Removed requirement to administer thawed FFP or PF24 within 6 hours –States circular must have instructions when to begin administering FFP and PF24 after thawing –Current circular states FFP and PF24 must be administered within 24 hours after thawing –Eliminates requirement for 21 CFR 640.120 variance to store thawed FFP and PF24 for up to 24 hours before administering –Note: Circular states 5-day Thawed Plasma is unlicensed; CBER will not approve variances for this product

8. Additional Information in Preamble 77 FR 11 (21 CFR 606.121(b) – –Original labels may be altered to accurately the identify contents of the unit, e.g., after irradiation, washing, etc. –This includes reprinting a new full-face label, but blood establishments must be able to re-create all other original information and it must be done with a validated process 77 FR 12 (21 CFR 606.121(c)(11) – –Source Plasma donors are tested for syphilis every 4 months; it is a donor test (vs. a test on the donation) –Confirmed that it is not required to put negative syphilis results on each Source Plasma unit –But if syphilis test is reactive, the unit associated with the positive test and all subsequent units from that donor must include positive syphilis test result (until test is negative)

9. Most Notable Changes 77 FR 13 (21 CFR 606.121(c)(11) - –It is acceptable for Source Plasma units to have negative infectious disease test results on label before testing has been completed –It is acceptable for these units to be shipped to quarantined storage, including to an independent off-site storage facility –The storage facilities must be under the control of the Source Plasma firm; this includes those owned by or under contract to the Source Plasma firm –If unit is pre-labeled with negative test result but is later found to be positive when testing is completed, the unit must be relabeled; the negative result must be obliterated and replaced with the positive result

10. Summary of Notable Changes Source Plasma labeling regs were removed from 640.70 and are now included in 606.121 Blood establishments must be able to determine from label where each unit was collected “For Autologous Use Only” can be on the labels of all auto units if they will not be crossed over Variances are no longer needed to store thawed FFP and PF24 for up to 24 hours before administering Full-face labels on modified products can be re-created using a validated process Source Plasma units can be pre-labeled with negative infectious disease test results before testing is completed and shipped to storage facilities under firm’s control; positive units must be relabeled Source Plasma units must be labeled with positive syphilis test results (index unit and subsequent units until test is negative)

11. References Federal Register – 77 FR 7, January 3, 2012 Title 21 CFR – April 2012 –21 CFR 606.121 –21 CFR 606.122 –21 CFR 640.70 –21 CFR 640.74 CBER - Blood and Plasma Branch CSOs –301-827-3543

12. New Apheresis Plasma Products

13. Plasma Frozen Within 24 Hours After Phlebotomy (PF24) Plasma Frozen Within 24 Hours After Phlebotomy Held At Room Temperature Up To 24 Hours After Phlebotomy (PF24RT24)

14. Apheresis Devices approved and/or cleared to manufacture new Plasma products Fenwal ALYX Fenwal Amicus TerumoBCT Trima Accel

15. Plasma Frozen Within 24 Hours After Phlebotomy (PF24) Must be stored at 1 – 6C within 8 hours of collection and prepared and frozen within 24 hours after phlebotomy. Indicated for replacement of non-labile clotting factors. This product is not equivalent to Fresh Frozen Plasma.

16. Plasma Frozen Within 24 Hours After Phlebotomy Held At Room Temperature Up To 24 Hours After Phlebotomy (PF24RT24) Can be stored at room temperature for up to 24 hour after collection. Product must be prepared and frozen within 24 hours after phlebotomy. Indicated for replacement of non-labile clotting factors. This product is not equivalent to Fresh Frozen Plasma.

17. Example of Instructions for Use

19. Circular of Information 21 CFR 606.122 Circular of information. A circular of information must be available for distribution if the product is intended for transfusion.

20. Circular of Information The December 2009 version of the AABB COI may be modified by the following FDA accepted statement: http://www.aabb.org/resources/bct/Pages/aabb_coi.aspx

21. This may either be glued or stapled into the current December 2009 edition

22. Please Note Whole Blood –PF24 has been a licensable product for > 20 years –PF24RT24 has NOT been cleared or approved to be manufactured from Whole Blood

23. Platelet Manufacturing Rest Period and Agitation

24. The Science… Centrifugated platelets aggregate irreversibly if subjected to rough agitation The procedures should describe a “Rest Period” for 10 minutes to an hour prior to resuspension.

25. The Regulations… 21 CFR 640.25 [Platelets] General requirements. (a)Storage. Immediately after resuspension, Platelets shall be placed in storage at the selected temperature range. If stored at 20 to 24 deg. C, a continuous gentle agitation of the platelet concentrate shall be maintained …

26. Additional Information Trima Accel

27. Additional Information CaridianBCT Guide to Platelet and Plasma Collections 2001

28. Additional Information Fenwal Amicus

29. Guidance for Industry Implementation of an Acceptable Abbreviated Donor History Questionnaire (aDHQ) and Accompanying Materials for Use in Screening Frequent Donors of Blood and Blood Components

30. Defined Donor Criteria for Frequent Donor Two previous donations using the full-length Donor History Questionnaire (DHQ), one within last 6 months Includes deferral of less than 6 months duration, if within 6 months of “successful donation.” (usable component, not a factor) Deferrals greater than 6 months disqualify approval for use of aDHQ must start over

31. SOP should state actions to be taken if: –a. Incorrect questionnaire administered –b. Questionnaire is incomplete –c. Ensure that donor unit quarantined until eligibility issued are resolved. If unit distributed, BDPR required Investigation required New questions – both full-length DHQ and aDHQ for 1 year from date added.

32. Eligibility for using the aDHQ Administered on day of donation Donor must meet the defined criteria for “Frequent donor” AND blood collection facility has a system in place to determine appropriateness

33. Methods of Administration Written Procedure (SOP) May be Self-Administered with f/u review by trained donor historian May be administered by donor historian Donor may be deferred prior to completion of entire questionnaire, if specified in SOP Encourage donor to ask questions

34. Day of Donation (aDHQ ) Must read Donor Education Materials prior to completing questionnaire Must be given Medication Deferral List and List of BSE countries to be used Alternatively, one or all lists can be prominently displayed at donation site for donors’ use while donors complete aDHQ

35. Common Problems in Biologics Inspections

36. Source: Turbo EIR Database

37. Scope Timeframe 01/2012 to 12/2012 Approx. # of Inspections in Database 1,038 Approx. # of Observations in Database 343

38. Applicable Regulations Blood GMP’s –43% relate to Written SOPs –27% cite records deficiencies –22% pertain to performance failures – 4% identify training and/or personnel issues – 4% specify equipment calibration issues

39. Frequency of Observations 21 CFRCount 606.100(b) - 147 606.160(a)(1) - 70 606.100(c) - 46 606.160(b) - 22 606.20(b) - 15 606.60(b) - 15 606.65(e) - 15 606.171 - 13

40. 606.100(b) – SOPs Cited in 147 inspections Written standard operating procedures including all steps to be followed in the [collection] [processing] [compatibility testing] [storage] [distribution] of blood and blood components for [homologous transfusion] [autologous transfusion] [further manufacturing purposes] are not always [maintained] [followed] [maintained on the premises]. Specifically, ***

41. 606.100(c) Cited in 46 inspections Failure to [perform a thorough investigation] [make a record of the conclusions and follow- up] of [an explained discrepancy] [a failure of a lot or unit to meet any of its specifications]. Specifically, ***

42. 606.160(a)(1) Cited in 29 inspections Records fail to [identify the person performing the work] [include dates of the various entries] [show test results] [include interpretation of the results] [show the expiration date assigned to specific products] [be as detailed as necessary] so as to provide a complete history of the work performed. Specifically, ***

43. 606.160(a)(1) cont’d : Cited in 28 inspections Records are not concurrently maintained with the performance of each significant step in the [collection] [processing] [compatibility testing] [storage] [distribution] of each unit of blood and blood components so that all steps can be clearly traced. Specifically, ***

44. 606.160(a)(1) cont’d: Cited in 13 inspections Records are [illegible] [not indelible] Specifically, ***

45. 606.160(b) Cited in 22 inspections Failure to maintain [donor] [processing] [storage and distribution] [compatibility testing] [quality control] [general] records. Specifically, ***

46. 606.65(e) Cited in 15 inspections Failure to use supplies and reagents in a manner consistent with instructions provided by the manufacturer. Specifically, ***

47. 606.60(b) Cited in 15 inspections Equipment used in the [collection] [processing] [compatibility testing] [storage and distribution] of blood and blood components is not [observed] [standardized] [calibrated] on a regularly scheduled basis as prescribed in the SOP Manual. Specifically, ***

48. 606.20(b) Cited in 15 inspections The personnel responsible for the [collection] [processing] [compatibility testing] [storage] [distribution] of blood or blood components are not adequate in [number] [educational background] [training and experience, including professional training as necessary] to assure competent performance of their assigned functions, and to ensure that the final product has the safety, purity, potency, identity and effectiveness it purports or is represented to possess. Specifically, ***

49. 606.171 Cited in 13 inspections Failure to submit a biological product deviation report [within 45 days from the date you acquired information suggesting that a reportable event occurred] Specifically, ***

50. Top 10 Biologics Observations Used in Turbo EIR Between 01/01/2012 And 12/31/2012

51. FDA Enforcement Statistics Summary Fiscal Year 2012 Seizures8 Injunctions17 Warning Letters4,882 Recall Events4,075 Recalled Products9,469 Debarments 20

52. Seizures by FDA Center Fiscal Year 2012

53. Injunctions by FDA Center Fiscal Year 2012

54. Warning Letters by FDA Center Fiscal Year 2012

55. Total Recalled Products by FDA Center Fiscal Year 2012 Class I, II and III

56. Recalled Products – All Centers Fiscal Years 2007 – 2012

57. FDA Recalls By Center - All Classes Fiscal Year 2012

58. FDA Recalls – Class I By Center Fiscal Year 2012

59. FDA Recalls - Class II By Center Fiscal Year 2012

60. FDA Recalls - Class III By Center Fiscal Year 2012

61. FLA-DO Legal Actions

62. Questions??

63. Contact Information: CBER - Blood and Plasma Branch CSOs: (301) 827-3543 FLA-DO: Biologics Specialist: (904) 281-1924 ext. 116 FLA-DO District Office: (407) 475-4700