Hot Topics
New Blood and Plasma Issues
Barbara Carmichael
Investigator, U.S. Food & Drug Administration
Florida District - Jacksonville, FL Resident Post
June 2, 2011
1
Lecture Outline
• Clarification of various issues
• Top 10 Biologics Observations
• New 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)
2
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
3
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
4
Overlay 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 a unit from an outside supplier?
5
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.
• Original information includes collection facility,
ABO/Rh, special antigen typings, anticoagulants, etc.
6
Top 10 Biologics Observations in 2010
As of 05/31/2011
7
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].
8
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].
9
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.
10
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].
11
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.
12
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.
13
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.
14
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.
15
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.
[This citation is new to the Top 10 this year; while
‘Records are Illegible’ fell off the Top 10 list this year.]
16
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.
17
New Guidance Documents
18
NAT [HIV-1 & HCV] Reentry
• May 2010 Guidance (finalizes draft dated July 2005)
• 4 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)
• SOP Revisions will be considered “minor change” to
an approved license so date of SOP implementation
should be reported in Annual Report
19
HIV-1 Donor Re-entry Algorithm
• 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
After 8 weeks
Test follow-up SAMPLE (no donation)
HIV-1 NAT and anti-HIV-1/2 EIA
NAT Reactive
anti-HIV-1/2 EIA RR
NAT Reactive
anti-HIV-1/2 EIA Negative
NAT Non-reactive
anti-HIV-1/2 EIA RR
DEFER DONOR
PERMANENTLY
DEFER DONOR
PERMANENTLY
DEFER DONOR &
Continue follow-up
NAT Non-reactive
anti-HIV-1/2 EIA Negative
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
20
HCV Donor Re-entry Algorithm
• NAT Non-reactive or Not done
• anti-HCV EIA RR
• RIBA IND, Negative, or Not done
• NAT Reactive
• anti-HCV EIA Negative
After 6 months
Test follow-up SAMPLE (no donation)
HCV NAT and anti-HCV EIA
NAT Reactive
anti-HCV EIA RR
NAT Reactive
anti-HCV EIA Negative
NAT Non-reactive
anti-HCV EIA RR
NAT Non-reactive
anti-HCV EIA Negative
DEFER DONOR
PERMANENTLY
DEFER DONOR
PERMANENTLY
DEFER DONOR &
Continue follow-up
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
21
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
22
“Lookback” for HCV
Guidance was updated December 2010 [orig. 2007]
• Reflects new anti-HCV testing technologies
• 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]
23
Pre-Storage Leukoreduction
• Draft Guidance January 2011 (replacing 2001 draft)
• Recommendations 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 S
• Use of mixing devices during collection
• Option for supplemental labeling of components with low
WBC count
• Calculation of RBC recovery by RBC mass
24
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)
25
CJD/vCJD (cont.)
• No 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 risk
• Recognized 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)
26
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)
27
Chagas (cont.)
• 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 disease
• Recommends 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 deferred
28
Chagas (cont.)
• No donor re-entry at this time
• Disposition 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 donor
• Statement 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 FDA
29
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)
30
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
31
Operational Procedures (cont.)
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
32
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
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-30
• Still follow CCPs described in the July 2003 Guidance
• Computer-Assisted DHQ process is still a CBE-30
33
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
34
THANK YOU!
Enjoy the rest of your day!
35