1. 1 Hot Topics New Blood and Plasma Issues Barbara Carmichael Investigator, U.S. Food & Drug Administration Florida District - Jacksonville, FL Resident Post June 2, 2011

2. 2 Lecture Outline Clarification of various issuesClarification of various issues Top 10 Biologics ObservationsTop 10 Biologics Observations New Guidance DocumentsNew Guidance Documents –NAT Reentry (May 2010) –Anti-HBc Reentry (May 2010) –HCV Lookback (December 2010) –Leukocyte Reduction, Draft ( January 2011) –CJD/vCJD (May 2010) –Chagas (December 2010) –Operations (November 2010)

3. 3 Storage of Thawed FFP or PF24 up to 24 hrs - Requesting a Variance Storage of thawed FFP or PF24 @ 1-6°C for up to 24 hrs [as recommended by BPAC], instead of 6 hours (21 CFR 606.122 (m)(3)). Until the regulation is revised a variance must be requested. Written request to : Director, Div. Blood Applications, OBRR/CBER/FDA/HFM-370 c/o Document control Center/HFM-99 1401 Rockville Pike, Suite 200N Rockville, MD 20852-1448 Phone no. (301) 827-3543

4. 4 MTS Gel Card - Off Label Use MTS Anti-IgG Card - states it is for direct and indirect antiglobulin test MTS Buffered Gel Card– states it is for detection of antibodies to RBCs –Neither product includes labeling/directions for use as an immediate spin compatibility test –The card is not a reliable detector of ABO incompatibilities (which are predominantly IgM); published studies document reported compatibility test failures –Discrepancy between AABB Manual & device labeling –Cannot be used as sole cross-match until Ortho submits data for BLA supplement approval [and labeling change]; will result in 483 citation

5. 5 Overlay Label? Can we overlay a Codabar label with an ISBT label?Can we overlay a Codabar label with an ISBT label? Can we overlay the whole label when we further process one of our units (e.g., irradiate)?Can we overlay the whole label when we further process one of our units (e.g., irradiate)? Can we overlay the whole label when we further process a unit from an outside supplier?Can we overlay the whole label when we further process a unit from an outside supplier?

6. 6 Overlay Label? FDA Response We believe it is acceptable to overlay an original label provided the current computer software or recordkeeping system has the capability to preserve the information on the original label. If the software or records cannot record the information from the original label, then overlaying the whole label is not permitted.We believe it is acceptable to overlay an original label provided the current computer software or recordkeeping system has the capability to preserve the information on the original label. If the software or records cannot record the information from the original label, then overlaying the whole label is not permitted. Original information includes collection facility, ABO/Rh, special antigen typings, anticoagulants, etc.Original information includes collection facility, ABO/Rh, special antigen typings, anticoagulants, etc.

7. 7 Top 10 Biologics Observations in 2010 As of 05/31/2011

8. 8 Citation #1 Cited 127 times /ID 76 Written SOPs Not Maintained or Followed or Accessible 21 CFR 606.100(b) 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].

9. 9 Citation #2 Cited 49 times /ID 98 Investigations Not Conducted or Completed 21 CFR 606.100(c) Failure to [perform a thorough investigation] [make a record of the conclusions and follow-up] of [an unexplained discrepancy] [a failure of a lot or unit to meet any of its specifications].

10. 10 Citation #3 Cited 29 times /ID 155 Failure to Maintain Records 21 CFR 606.160(b) Failure to maintain [donor] [processing] [storage and distribution] [compatibility testing] [quality control] [general] Records.

11. 11 Citation #4 Cited 29 times /ID 9225 BPD Reporting 21 CFR 606.171 Failure to submit a biological product deviation report [within 45 days from the date you acquired information suggesting that a reportable event occurred].

12. 12 Citation #5 Cited 29 times /ID 154 Records Not Concurrent with Performance 21 CFR 606.160(a)(1) 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.

13. 13 Citation #6 Cited 28 times /ID 160 Records Fail to Provide Complete History 21 CFR 606.160(a)(1) 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.

14. 14 Citation #7 Cited 21 times /ID 31 Personnel/Training 21 CFR 606.20(b) 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.

15. 15 Citation #8 Cited 14 times /ID 4425 Equipment Not Maintained 21 CFR 606.60(a) 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.

16. 16 Citation #9 Cited 13 times /ID 12202 Thorough Investigation of Adverse Reaction 21 CFR 606.170(a) A thorough investigation of each reported adverse report was not made. A thorough investigation of each reported adverse report was not made. [This citation is new to the Top 10 this year; while ‘Records are Illegible’ fell off the Top 10 list this year.]

17. 17 Citation #10 Cited 12 times /ID 67 Supplies & Reagents 21 CFR 606.65(e) Failure to use supplies and reagents in a manner consistent with instructions provided by the manufacturer.

18. 18 New Guidance Documents

19. 19 NAT [HIV-1 & HCV] Reentry May 2010 Guidance (finalizes draft dated July 2005)May 2010 Guidance (finalizes draft dated July 2005) 4 new simplified algorithms for reentry4 new simplified algorithms for reentry Retests - should use the same test as that used for the original reactive sample; if not available use one of same or greater sensitivity (e.g. HIV-1 Group O)Retests - should use the same test as that used for the original reactive sample; if not available use one of same or greater sensitivity (e.g. HIV-1 Group O) SOP Revisions will be considered “minor change” to an approved license so date of SOP implementation should be reported in Annual ReportSOP Revisions will be considered “minor change” to an approved license so date of SOP implementation should be reported in Annual Report

20. 20 HIV-1 Donor Re-entry Algorithm After 8 weeks Test follow-up SAMPLE (no donation) HIV- 1 NAT and anti-HIV- 1 /2 EIA NAT Non-reactive anti-HIV- 1 /2 EIA RR NAT Reactive anti-HIV- 1 /2 EIA RR NAT Reactive anti-HIV- 1 /2 EIA Negative NAT Non-reactive anti-HIV- 1 /2 EIA Negative NAT Reactive anti-HIV- 1 /2 EIA Negative HIV- 1 p24 EIA Negative (if done) NAT Non-reactive or not done anti-HIV- 1 /2 EIA RR HIV- 1 Western Blot or IFA – IND, Negative, or Not done HIV- 1 p24 EIA Negative (if done) NAT Non-reactive anti-HIV- 1 /2 EIA Negative HIV- 1 p24 EIA RR (if done) – Neut. test Positive or IND DEFER DONOR & Continue follow-up DEFER DONOR PERMANENTLY DEFER DONOR PERMANENTLY RE-ENTER DONOR (Donor eligible for future donation) Optional: Test with HIV- 1 WB WB positive: Defer donor permanently WB negative or IND: Re-test donor again after 8 weeks

21. 21 HCV Donor Re-entry Algorithm After 6 months Test follow-up SAMPLE (no donation) HCV NAT and anti-HCV EIA NAT Non-reactive anti-HCV EIA RR NAT Reactive anti-HCV EIA RR NAT Reactive anti-HCV EIA Negative NAT Non-reactive anti-HCV EIA Negative NAT Reactive anti-HCV EIA Negative NAT Non-reactive or Not done anti-HCV EIA RR RIBA IND, Negative, or Not done DEFER DONOR & Continue follow-up DEFER DONOR PERMANENTLY DEFER DONOR PERMANENTLY RE-ENTER DONOR (Donor eligible for future donation) Optional: Test with HCV RIBA RIBA positive or IND: Defer donor permanently RIBA negative: Re-test donor again after 6 months

22. 22 Anti-HBc Reentry [if tested RR on >1 occasion] May 2010 Guidance [finalizes draft from 2008]. –Change due to availability of FDA-licensed HBV NAT & improved specificity of anti-HBc assays –Obtain a new pre-donation blood sample after a minimum of 8 wks following last RR anti-HBc test –Must be Neg. for HBsAg, anti-HBc AND HBV by NAT –If f/u medical testing done during this 8 week period, any reactive/positive results would make the donor NOT eligible for reentry and indefinite deferral is recommended. –If implement this method then report in Annual Report. If want to use an alternate method, licensed establishments must submit a supplement for prior approval

23. 23 “Lookback” for HCV Guidance was updated December 2010 [orig. 2007] Reflects new anti-HCV testing technologiesReflects new anti-HCV testing technologies Changes to make guidance consistent with regs, e.g.:Changes to make guidance consistent with regs, e.g.: –21 CFR 610.48 - One time review of historical HCV testing records, requires completion of actions specified by 2/19/09 –Asked to go back to Jan 1988, but are aware that prior to implementation the requirement for record retention was 5 years –notification by the transfusion service was expanded to include a recipient’s physician of record within the specified time frame [3 days after becoming aware of test results]

24. 24 Pre-Storage Leukoreduction Draft Guidance January 2011 (replacing 2001 draft)Draft Guidance January 2011 (replacing 2001 draft) Recommendations for validation and QC for monitoring the process, including an algorithm for sample size calculationRecommendations for validation and QC for monitoring the process, including an algorithm for sample size calculation Testing of donors for traits that affect the process, such as hemoglobin STesting of donors for traits that affect the process, such as hemoglobin S Use of mixing devices during collectionUse of mixing devices during collection Option for supplemental labeling of components with low WBC countOption for supplemental labeling of components with low WBC count Calculation of RBC recovery by RBC massCalculation of RBC recovery by RBC mass

25. 25 CJD/vCJD Guidance for Industry: Revised Preventative Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products May 2010 (Implement by January 2011)

26. 26 CJD/vCJD (cont.) No changes in CJD deferral policiesNo changes in CJD deferral policies Blood and plasma donors who have received a blood component transfusion in France since 1980 are deferred indefinitely for vCJD riskBlood and plasma donors who have received a blood component transfusion in France since 1980 are deferred indefinitely for vCJD risk Recognized the AABB full-length DHQ materials (v.1.3) as an acceptable mechanism to screen blood donorsRecognized the AABB full-length DHQ materials (v.1.3) as an acceptable mechanism to screen blood donors –DHQ contains transfusion in France question –Guidance advises licensed firms how to report if using AABB DHQ (v.1.3)

27. 27 Chagas Guidance for Industry: Use of Serological Tests to Reduce the Risk of Transmission of Trypanosoma cruzi Infection in Whole Blood and Blood Components Intended for Transfusion December 2010 (Implement by December 2011)

28. 28 Chagas (cont.) Only applies to blood components for transfusion (not to Source Plasma)Only applies to blood components for transfusion (not to Source Plasma) Includes question to ask all donors at each donation if they ever had Chagas diseaseIncludes question to ask all donors at each donation if they ever had Chagas disease Recommends one-time (selective) testing of allogeneic donors and autologous donors whose units will be crossed overRecommends one-time (selective) testing of allogeneic donors and autologous donors whose units will be crossed over –Nonreactive donors do not need to be tested again at subsequent donations –Blood banks should have records for testing history Reactive donors or donors with history of Chagas are indefinitely deferredReactive donors or donors with history of Chagas are indefinitely deferred

29. 29 Chagas (cont.) No donor re-entry at this timeNo donor re-entry at this time Disposition of reactive unitsDisposition of reactive units –Destroy reactive donations –Can be used for research or plasma used for noninjectable reagents –Autologous use only Lookback of units from reactive donorLookback of units from reactive donor Statement in Circular that blood is from donors tested for T. cruzi on at least one donationStatement in Circular that blood is from donors tested for T. cruzi on at least one donation Advises licensed firms on how to report changes to FDAAdvises licensed firms on how to report changes to FDA

30. 30 Operational Procedures Guidance for Industry: Recommendations for Blood Establishments: Training of Back-up Personnel, Assessment of Blood Donor Suitability and Reporting Certain Changes to an Approved Application November 2010 (Implement immediately)

31. 31 Operational Procedures (cont.) Replaces November 2009 draft [H1N1 guidance document] –Removed reference to H1N1 since pandemic is over, but retained those provisions with general applicability Training of Back-up Personnel –Have adequate trained back-up personnel in the event of personnel shortages (e.g., pandemics, natural disasters, bioterrorism) –Use existing training program; recommend train more than 1 back-up person for each critical function –And of course…...Document training

32. 32 Operational Procedures (cont.) Donor Suitability – 24 Hours to Clarify Donor Suitability – 24 Hours to Clarify 640.3(a) and 640.63(a) – determine donor suitability on day of collection; regs don’t define “day of collection” –Firm may clarify a donor’s response to a question or obtain omitted responses within 24 hours of the time of collection –Does not apply to missing/unacceptable vital signs or hgb/hct –Licensed firms must have CBER approved SOPs for this, including contacting donor, determine donor’s identity and if in confidential setting –Should be handled as deviation & included in QA tracking and investigation procedures

33. 33 Operational Procedures (cont.) Reporting certain changes to FDA as Changes Being Effected (CBE) under 601.12(c)(5) –Changes were previously reported as CBE-30 –Using a different registered outside/contract testing lab to perform donor testing However, submit as PAS if using lab not registered for donor screeningHowever, submit as PAS if using lab not registered for donor screening –Implementation of written or audio/visual methods to self-administer your currently approved donor history questionnaire Supersedes July 2003 Guidance for self-administered questionnaire that required a CBE-30Supersedes July 2003 Guidance for self-administered questionnaire that required a CBE-30 Still follow CCPs described in the July 2003 GuidanceStill follow CCPs described in the July 2003 Guidance Computer-Assisted DHQ process is still a CBE-30Computer-Assisted DHQ process is still a CBE-30

34. 34 Where can I find the guidances? CBER website –Click on “Vaccine, Blood & Biologics” link –Scroll down to “Forms and Regulatory Information” –Click on “Blood Guidances” http://www.fda.gov/BiologicsBloodVaccines/Guidance ComplianceRegulatoryInformation/Guidances/Blood/d efault.htm http://www.fda.gov/BiologicsBloodVaccines/Guidance ComplianceRegulatoryInformation/Guidances/Blood/d efault.htm

35. 35 THANK YOU! Enjoy the rest of your day!