hot topics new blood and plasma issues

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Hot TopicsHot TopicsNew Blood and Plasma New Blood and Plasma

IssuesIssuesBarbara CarmichaelBarbara Carmichael

Investigator, U.S. Food & Drug AdministrationInvestigator, U.S. Food & Drug Administration

Florida District - Jacksonville, FL Resident PostFlorida District - Jacksonville, FL Resident Post

June 2, 2011June 2, 2011

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Lecture OutlineLecture Outline• Clarification of various issuesClarification of various issues• Top 10 Biologics ObservationsTop 10 Biologics Observations• New Guidance DocumentsNew Guidance Documents

– NAT Reentry (May 2010)NAT Reentry (May 2010)– Anti-HBc Reentry (May 2010)Anti-HBc Reentry (May 2010)– HCV Lookback (December 2010) HCV Lookback (December 2010) – Leukocyte Reduction, Draft ( January 2011)Leukocyte Reduction, Draft ( January 2011)– CJD/vCJD (May 2010)CJD/vCJD (May 2010)– Chagas (December 2010)Chagas (December 2010)– Operations (November 2010)Operations (November 2010)

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Storage of Thawed FFP or Storage of Thawed FFP or PF24 up to 24 hrs -PF24 up to 24 hrs - Requesting a VarianceRequesting a Variance

Storage of thawed FFP or PF24Storage of thawed FFP or PF24 @ 1-6°C for @ 1-6°C for up to 24 hrsup to 24 hrs [as recommended by BPAC], [as recommended by BPAC], instead of 6 hoursinstead of 6 hours (21 CFR 606.122 (m)(3)). (21 CFR 606.122 (m)(3)). Until the regulation is revised a variance must be Until the regulation is revised a variance must be requested.requested.

Written request toWritten request to : :Director, Div. Blood Applications, Director, Div. Blood Applications,

OBRR/CBER/FDA/HFM-370OBRR/CBER/FDA/HFM-370c/o Document control Center/HFM-99c/o Document control Center/HFM-99

1401 Rockville Pike, Suite 200N1401 Rockville Pike, Suite 200NRockville, MD 20852-1448Rockville, MD 20852-1448Phone no. (301) 827-3543Phone no. (301) 827-3543

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MTS Gel Card - Off Label MTS Gel Card - Off Label UseUse

MTS Anti-IgG CardMTS Anti-IgG Card - states it is for direct and indirect - states it is for direct and indirect antiglobulin test antiglobulin test

MTS Buffered Gel CardMTS Buffered Gel Card– – states it is for detection of antibodies states it is for detection of antibodies to RBCsto RBCs

– Neither product includes labeling/directions for use as an Neither product includes labeling/directions for use as an immediate spin compatibility test immediate spin compatibility test

– The card is not a reliable detector of ABO incompatibilities The card is not a reliable detector of ABO incompatibilities (which are predominantly IgM); published studies document (which are predominantly IgM); published studies document reported compatibility test failuresreported compatibility test failures

– Discrepancy between AABB Manual & device labelingDiscrepancy between AABB Manual & device labeling– Cannot be used as sole cross-match until Ortho submits data Cannot be used as sole cross-match until Ortho submits data

for BLA supplement approval [and labeling change]; will result for BLA supplement approval [and labeling change]; will result in 483 citationin 483 citation

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Overlay Label?Overlay Label?

• Can we overlay a Codabar label with an ISBT Can we overlay a Codabar label with an ISBT label? label?

• Can we overlay the whole label when we further Can we overlay the whole label when we further

process one of our units (e.g., irradiate)? process one of our units (e.g., irradiate)?

• Can we overlay the whole label when we further Can we overlay the whole label when we further process a unit from an outside supplier?process a unit from an outside supplier?

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Overlay Label?Overlay Label?FDA ResponseFDA Response

• We believe it is acceptable to overlay an We believe it is acceptable to overlay an original label provided the current computer original label provided the current computer software or recordkeeping system has the software or recordkeeping system has the capability to preserve the information on the capability to preserve the information on the original label. If the software or records original label. If the software or records cannot record the information from the cannot record the information from the original label, then overlaying the whole label original label, then overlaying the whole label is not permitted.is not permitted.

• Original information includes collection Original information includes collection facility, ABO/Rh, special antigen typings, facility, ABO/Rh, special antigen typings, anticoagulants, etc.anticoagulants, etc.

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Top 10 Biologics Top 10 Biologics Observations in 2010 Observations in 2010

As of 05/31/2011As of 05/31/2011

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Citation #1 Citation #1 Cited 127 Cited 127 times times /ID 76/ID 76

Written SOPs Not Maintained or Written SOPs Not Maintained or Followed or AccessibleFollowed or Accessible

21 CFR 606.100(b) Written standard operating 21 CFR 606.100(b) Written standard operating procedures including all steps to be followed in procedures including all steps to be followed in the [collection] [processing] [compatibility the [collection] [processing] [compatibility testing] [storage] [distribution] of blood and testing] [storage] [distribution] of blood and blood components for [homologous blood components for [homologous transfusion] [autologous transfusion] [further transfusion] [autologous transfusion] [further manufacturing purposes] are not always manufacturing purposes] are not always [maintained] [followed] [maintained on the [maintained] [followed] [maintained on the premises].premises].

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Citation #2 Citation #2 Cited 49 times Cited 49 times /ID /ID 9898

Investigations Not Conducted or Investigations Not Conducted or CompletedCompleted

21 CFR 606.100(c) Failure to [perform a thorough21 CFR 606.100(c) Failure to [perform a thorough

investigation] [make a record of the conclusions investigation] [make a record of the conclusions andand

follow-up] of [an unexplained discrepancy] [a follow-up] of [an unexplained discrepancy] [a failure of afailure of a

lot or unit to meet any of its specifications].lot or unit to meet any of its specifications].

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Citation #3 Citation #3 Cited 29 times Cited 29 times /ID /ID 155155

Failure to Maintain RecordsFailure to Maintain Records

21 CFR 606.160(b) Failure to maintain 21 CFR 606.160(b) Failure to maintain [donor][donor]

[processing] [storage and distribution][processing] [storage and distribution]

[compatibility testing] [quality control] [compatibility testing] [quality control] [general][general]

Records.Records.

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Citation #4 Citation #4 Cited 29 timesCited 29 times /ID /ID 92259225

BPD ReportingBPD Reporting

21 CFR 606.171 21 CFR 606.171 Failure to submit a biologicalFailure to submit a biological

product deviation report [within 45 days from product deviation report [within 45 days from thethe

date you acquired information suggesting that date you acquired information suggesting that aa

reportable event occurred].reportable event occurred].

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Citation #5 Citation #5 Cited 29 timesCited 29 times /ID 154/ID 154

Records Not Concurrent with PerformanceRecords Not Concurrent with Performance

21 CFR 606.160(a)(1) Records are not concurrently21 CFR 606.160(a)(1) Records are not concurrently

maintained with the performance of each significant maintained with the performance of each significant stepstep

in the [collection] [processing] [compatibility testing]in the [collection] [processing] [compatibility testing]

[storage] [distribution] of each unit of blood and blood[storage] [distribution] of each unit of blood and blood

components so that all steps can be clearly traced. components so that all steps can be clearly traced.

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Records Fail to Provide Complete HistoryRecords Fail to Provide Complete History

21 CFR 606.160(a)(1) Records fail to [identify the21 CFR 606.160(a)(1) Records fail to [identify theperson performing the work] [include dates of theperson performing the work] [include dates of thevarious entries] [show test results] [include various entries] [show test results] [include

interpretationinterpretationof the results] [show the expiration date assigned toof the results] [show the expiration date assigned tospecific products] [be as detailed as necessary] so as tospecific products] [be as detailed as necessary] so as toprovide a complete history of the work performed. provide a complete history of the work performed.

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Personnel/Training Personnel/Training 21 CFR 606.20(b) The personnel responsible for the 21 CFR 606.20(b) The personnel responsible for the

[collection][collection]

[processing] [compatibility testing] [storage] [distribution] [processing] [compatibility testing] [storage] [distribution] ofof

blood or blood components are not adequate in [number]blood or blood components are not adequate in [number]

[educational background] [training and experience, [educational background] [training and experience, includingincluding

professional training as necessary] to assure competentprofessional training as necessary] to assure competent

performance of their assigned functions, and to ensure that performance of their assigned functions, and to ensure that thethe

final product has the safety, purity, potency, identity andfinal product has the safety, purity, potency, identity and

effectiveness it purports or is represented to possess.effectiveness it purports or is represented to possess.

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Equipment Not MaintainedEquipment Not Maintained

21 CFR 606.60(a) Equipment used in the 21 CFR 606.60(a) Equipment used in the [collection][collection]

[processing] [compatibility testing] [storage and[processing] [compatibility testing] [storage and

distribution] of blood and blood components is notdistribution] of blood and blood components is not

[observed] [standardized] [calibrated] on a regularly[observed] [standardized] [calibrated] on a regularly

scheduled basis as prescribed in the SOP Manual. scheduled basis as prescribed in the SOP Manual.

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Thorough Investigation of Adverse Thorough Investigation of Adverse ReactionReaction

21 CFR 606.170(a) 21 CFR 606.170(a) A thorough investigation of each reported A thorough investigation of each reported

adverse report was not made.adverse report was not made.

[This citation is new to the Top 10 this year; while [This citation is new to the Top 10 this year; while ‘Records are Illegible’ fell off the Top 10 list this ‘Records are Illegible’ fell off the Top 10 list this year.]year.]

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Citation #10 Citation #10 Cited 12 Cited 12 times times /ID 67/ID 67

Supplies & ReagentsSupplies & Reagents

21 CFR 606.65(e) Failure to use 21 CFR 606.65(e) Failure to use supplies andsupplies and

reagents in a manner consistent with reagents in a manner consistent with instructionsinstructions

provided by the manufacturer.provided by the manufacturer.

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New Guidance New Guidance DocumentsDocuments

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NAT [HIV-1 & HCV] ReentryNAT [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 Retests - should use the same test as that used for

the original reactive sample; if the original reactive sample; if not available use not available use one of same or greater sensitivityone of same or greater sensitivity (e.g. HIV-1 (e.g. HIV-1 Group O)Group O)

• SOP Revisions will be considered “minor change” to SOP Revisions will be considered “minor change” to an approved license so date of SOP implementation an approved license so date of SOP implementation should be reported in Annual Report should be reported in Annual Report

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HIV-1 Donor Re-entry HIV-1 Donor Re-entry AlgorithmAlgorithm

After 8 weeksTest follow-up SAMPLE (no donation)

HIV-1 NAT and anti-HIV-1/2 EIA

NAT Non-reactiveanti-HIV-1/2 EIA RR

NAT Reactiveanti-HIV-1/2 EIA RR

NAT Reactiveanti-HIV-1/2 EIA Negative

NAT Non-reactiveanti-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 DONORPERMANENTLY


RE-ENTER DONOR(Donor eligible for future

donation)

Optional: Test with HIV-1 WBWB positive: Defer donor permanentlyWB negative or IND: Re-test donor again after 8 weeks

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HCV Donor Re-entry Algorithm

After 6 monthsTest follow-up SAMPLE (no

donation)HCV NAT and anti-HCV EIA

NAT Non-reactiveanti-HCV EIA RR

NAT Reactiveanti-HCV EIA RR

NAT Reactiveanti-HCV EIA Negative

NAT Non-reactiveanti-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



RE-ENTER DONOR(Donor eligible for future donation)

Optional: Test with HCV RIBARIBA positive or IND: Defer donor permanentlyRIBA negative: Re-test donor again after 6 months

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Anti-HBc ReentryAnti-HBc Reentry [if tested RR on [if tested RR on

>1 occasion]>1 occasion] May 2010 Guidance May 2010 Guidance [finalizes draft from 2008].[finalizes draft from 2008].

– Change due to availability of FDA-licensed HBV NAT & Change due to availability of FDA-licensed HBV NAT & improved specificity of anti-HBc assaysimproved specificity of anti-HBc assays

– Obtain a new pre-donation blood sample after a minimum Obtain a new pre-donation blood sample after a minimum of 8 wks following last RR anti-HBc testof 8 wks following last RR anti-HBc test

– Must be Neg. for HBsAg, anti-HBc AND HBV by NATMust be Neg. for HBsAg, anti-HBc AND HBV by NAT– If f/u medical testing done If f/u medical testing done duringduring this 8 week period, any this 8 week period, any

reactive/positive results would make the donor reactive/positive results would make the donor NOT NOT eligible for reentry and indefinite deferral is eligible for reentry and indefinite deferral is recommended. recommended.

– If implement this method then report in Annual Report. If If implement this method then report in Annual Report. If want to use an alternate method, licensed establishments want to use an alternate method, licensed establishments must submit a supplement for prior approvalmust submit a supplement for prior approval

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““Lookback” for HCV Lookback” for HCV Guidance was Guidance was updatedupdated December 2010 [orig. 2007] 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 21 CFR 610.48 - One time review of historical HCV testing records, requires completion of actions specified by 2/19/09 records, requires completion of actions specified by 2/19/09

– Asked to go back to Jan 1988, but are aware that prior to Asked to go back to Jan 1988, but are aware that prior to implementation the requirement for record retention was 5 implementation the requirement for record retention was 5 years years

– notification by the transfusion service was expanded to notification by the transfusion service was expanded to include a recipient’s physician of record within the specified include a recipient’s physician of record within the specified time frame [3 days after becoming aware of test results]time frame [3 days after becoming aware of test results]

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Pre-Storage Leukoreduction Pre-Storage Leukoreduction

• Draft Draft GuidanceGuidance January 2011 (replacing 2001 draft) January 2011 (replacing 2001 draft)• Recommendations for validation and QC for monitoring Recommendations for validation and QC for monitoring

the process, including an algorithm for sample size the process, including an algorithm for sample size calculationcalculation

• Testing of donors for traits that affect the process, such Testing of donors for traits that affect the process, such as hemoglobin Sas hemoglobin S

• Use of mixing devices during collectionUse of mixing devices during collection• Option for supplemental labeling of components with Option for supplemental labeling of components with

low WBC countlow WBC count• Calculation of RBC recovery by RBC massCalculation of RBC recovery by RBC mass

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CJD/vCJDCJD/vCJD

Guidance for Industry:Guidance for Industry:

Revised Preventative Measures to Reduce the Revised Preventative Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-

Jakob Disease (vCJD) by Blood and Blood Jakob Disease (vCJD) by Blood and Blood ProductsProducts

May 2010May 2010

(Implement by January 2011)(Implement by January 2011)

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CJD/vCJD (cont.)CJD/vCJD (cont.)

• No changes in CJD deferral policiesNo changes in CJD deferral policies• Blood and plasma donors who have Blood and plasma donors who have

received a blood component transfusion received a blood component transfusion in France since 1980 are deferred in France since 1980 are deferred indefinitely for vCJD riskindefinitely for vCJD risk

• Recognized the AABB full-length DHQ Recognized the AABB full-length DHQ materials (v.1.3) as an acceptable materials (v.1.3) as an acceptable mechanism to screen blood donorsmechanism to screen blood donors– DHQ contains transfusion in France questionDHQ contains transfusion in France question– Guidance advises licensed firms how to Guidance advises licensed firms how to

report if using AABB DHQ (v.1.3)report if using AABB DHQ (v.1.3)

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ChagasChagas


Use of Serological Tests to Reduce the Risk Use of Serological Tests to Reduce the Risk of Transmission of Trypanosoma cruzi of Transmission of Trypanosoma cruzi

Infection in Whole Blood and Blood Infection in Whole Blood and Blood Components Intended for TransfusionComponents Intended for Transfusion

December 2010December 2010

(Implement by December 2011)(Implement by December 2011)

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Chagas (cont.)Chagas (cont.)• Only applies to blood components for Only applies to blood components for

transfusion (not to Source Plasma)transfusion (not to Source Plasma)• Includes question to ask all donors at each Includes question to ask all donors at each

donation if they ever had Chagas diseasedonation if they ever had Chagas disease• Recommends one-time (selective) testing of Recommends one-time (selective) testing of

allogeneic donors and autologous donors allogeneic donors and autologous donors whose units will be crossed overwhose units will be crossed over– Nonreactive donors do not need to be tested Nonreactive donors do not need to be tested

again at subsequent donationsagain at subsequent donations– Blood banks should have records for testing Blood banks should have records for testing

historyhistory• Reactive donors or donors with history of Reactive donors or donors with history of

Chagas are indefinitely deferredChagas are indefinitely deferred

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Chagas (cont.)Chagas (cont.)• No donor re-entry at this timeNo donor re-entry at this time• Disposition of reactive unitsDisposition of reactive units

– Destroy reactive donationsDestroy reactive donations– Can be used for research or plasma used for Can be used for research or plasma used for

noninjectable reagentsnoninjectable reagents– Autologous use onlyAutologous use only

• Lookback of units from reactive donorLookback of units from reactive donor• Statement in Circular that blood is from donors Statement in Circular that blood is from donors

tested for T. cruzi on at least one donationtested for T. cruzi on at least one donation• Advises licensed firms on how to report Advises licensed firms on how to report

changes to FDAchanges to FDA

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Operational ProceduresOperational Procedures


Recommendations for Blood Establishments: Recommendations for Blood Establishments: Training of Back-up Personnel, Assessment Training of Back-up Personnel, Assessment of Blood Donor Suitability and Reporting of Blood Donor Suitability and Reporting

Certain Changes to an Approved Certain Changes to an Approved ApplicationApplication

November 2010November 2010

(Implement immediately)(Implement immediately)

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Operational Procedures Operational Procedures (cont.)(cont.)

Replaces November 2009 draft Replaces November 2009 draft [H1N1 guidance [H1N1 guidance document]document]– Removed reference to H1N1 since pandemic is over, Removed reference to H1N1 since pandemic is over,

but retained those provisions with general applicability but retained those provisions with general applicability

Training of Back-up PersonnelTraining of Back-up Personnel– Have adequate trained back-up personnel in the event Have adequate trained back-up personnel in the event

of personnel shortages (e.g., pandemics, natural of personnel shortages (e.g., pandemics, natural disasters, bioterrorism)disasters, bioterrorism)

– Use existing training program; recommend train more Use existing training program; recommend train more than 1 back-up person for each critical functionthan 1 back-up person for each critical function

– And of course…...Document training And of course…...Document training

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Operational Procedures (cont.)Operational Procedures (cont.)

Donor Suitability – 24 Hours to ClarifyDonor Suitability – 24 Hours to Clarify

640.3(a) and 640.63(a) – determine donor suitability 640.3(a) and 640.63(a) – determine donor suitability on day of collectionon day of collection; regs don’t define “day of ; regs don’t define “day of

collection”collection”– Firm may clarify a donor’s response to a question or Firm may clarify a donor’s response to a question or

obtain omitted responses within 24 hours of the time of obtain omitted responses within 24 hours of the time of collectioncollection

– Does Does notnot apply to missing/unacceptable vital signs or apply to missing/unacceptable vital signs or hgb/hct hgb/hct

– Licensed firms must have CBER approved SOPs for this, Licensed firms must have CBER approved SOPs for this, including contacting donor, determine donor’s identity including contacting donor, determine donor’s identity and if in confidential settingand if in confidential setting

– Should be handled as deviation & included in QA Should be handled as deviation & included in QA tracking and investigation procedurestracking and investigation procedures

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Operational Procedures Operational Procedures (cont.)(cont.)

Reporting certain changes to FDA as Reporting certain changes to FDA as CChanges hanges BBeing eing EEffected (CBE) under 601.12(c)(5)ffected (CBE) under 601.12(c)(5)– Changes were previously reported as CBE-30Changes were previously reported as CBE-30– Using a different registered outside/contract testing lab Using a different registered outside/contract testing lab

to perform donor testing to perform donor testing • However, submit as PAS However, submit as PAS if using lab not if using lab not

registeredregistered for donor screening for donor screening– Implementation of written or audio/visual methods to Implementation of written or audio/visual methods to

self-administer your currently approved donor history self-administer your currently approved donor history questionnairequestionnaire• Supersedes July 2003 Guidance for self-administered Supersedes July 2003 Guidance for self-administered

questionnaire that required a CBE-30questionnaire 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

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Where can I find the Where can I find the guidances?guidances?

CBER websiteCBER website – Click on “Vaccine, Blood & Biologics” linkClick on “Vaccine, Blood & Biologics” link– Scroll down to “Forms and Regulatory Scroll down to “Forms and Regulatory

Information”Information”– Click on “Blood Guidances”Click on “Blood Guidances”

http://www.fda.gov/BiologicsBloodVaccines/http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/GuidanceComplianceRegulatoryInformation/Guidances/Blood/default.htmGuidances/Blood/default.htm

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THANK YOU!THANK YOU!

Enjoy the rest of your day!Enjoy the rest of your day!

hot topics new blood and plasma issues

Documents

original label

codabar label

citationoverlay label

isbt label

times id

b failure

c failure

original information