FDA

1
FDAs Current Considerations of Parvovirus B19
Nucleic Acid Testing (NAT)

• Mei-ying W. Yu, PhD
• Division of Hematology
• CBER/FDA

Extraordinary SoGAT Meeting on Parvovirus B19
NIBSC, UK March 2, 2007
2
FDAs Discussion of Parvovirus B19 NAT (I)

• Sep 1999 Blood Products Advisory Committee (BPAC)
• Safety of Pooled Plasma S/D Treated correlated
  with those lots having lt104 geq/mL of B19 DNA in
  manufacturing pool (a phase 4 study).
• For plasma for further manufacturing, B19 NAT
  screening was recommended as an in-process test.
• In-date () blood components were recommended to
  be quarantined and destroyed when possible.
• Dec 1999 FDA NAT Workshop
• The possibility of limiting lt104 geq/mL of B19
  DNA in all manufacturing pools was discussed.

3
FDAs Discussion of Parvovirus B19 NAT (II)

• Dec 1999 NHLBI Parvovirus B19 Workshop
• FDAs in-process B19 NAT standard for plasma for
  further manufacturing was presented.
• Dec 2001 FDA NAT Workshop
• Proposed limit lt104 IU/mL of B19 DNA in all
  manufacturing pools due to the WHO Std
  availability
• Mar 2002 BPAC
• FDAs current thinking on B19 NAT for Blood and
  Plasma
• Jul 2002 Ad Hoc PHS Panel
• Medical benefits to donors and close contacts

4
FDAs Discussion of Parvovirus B19 NAT (III)

• Dec 2002 BPAC
• B19 NAT testing of Whole Blood (WB) donations
  would reduce the risk to transfusion recipients
  if high-titer positive units (106 geq/mL) of WB
  and its components were withheld from use.
• Based upon current limitations, a threshold value
  was however considered not yet sufficiently
  established to warrant screening of WB donors.
• Temporary deferral of high-titer positive donors
  is warranted only for apheresis donations to make
  transfusion components but not WB or Source
  Plasma donations (due to either donation
  frequency or resolution time)
• Potential medical benefits to close contacts of
  B19 infected donors warrant notification of
  high-titer donors.
• But only if donor notification can be completed
  within several weeks of donations.

5
In-Process B19 NAT Testing of Plasma for Further
Manufacturing (I)

• Minipool NAT testing (Pool size 96 512)
• Most Source Plasma fractionators are performing
  high-titer B19 minipool NAT screening by in-house
  methods.
• Sensitivities of NAT assays differ, but most
  tests will exclude original donations exceeding a
  B19 DNA level of 105 to 107 IU/mL.
• Reactive minipools are resolved to single
  reactive donations, which are rejected.
• Blood collection establishments voluntarily
  retrieve and discard in-date components to
  prevent their use in transfusion when a donor of
  plasma is found to have high titer B19.
• Little is known about the minimal infectious dose
  for B19. However, we reported that infusion of 2
  X104 IU of B19 DNA in a FVIII product devoid of
  anti-B19 IgG infected a seronegative individual
  (Wu et al, Transfusion 2005).

6
In-Process B19 NAT Testing of Plasma for Further
Manufacturing (II)

• Manufacturing pool NAT testing
• To ensure that high-titer plasma donations are
  removed as a result of minipool NAT screening,
  the viral load in manufacturing pools destined
  for plasma derivatives is measured directly and
  can be limited to 104 IU/mL of B19 DNA, the
  standard proposed by the FDA.
• Anti-B19 in large pools complexes/neutralizes
  virus
• Some manufacturing procedures clear 4 logs of the
  virus when validated using a model parvovirus.

7
In-Process B19 NAT Testing of Plasma for Further
Manufacturing (III)

• FDA has reviewed and approved some in-house B19
  NAT procedures for minipools and manufacturing
  pools under Biologics Licensing Applications
  (BLAs) or their supplements for plasma
  derivatives.
• B19 NAT testing is validated as an analytical
  procedure with respect to sensitivity,
  specificity, and reproducibility.
• Primers and probes used for B19 NAT testing
  should be chosen so that all B19 genotypes can be
  detected.

8
Issues To Be Considered

• Because of known risks to those individuals who
  are pregnant, chronically anemic, and
  immuno-compromised, B19 NAT testing may be
  changed to donor screening testing if commercial
  tests are available as kits and the resolution
  time to confirmation (i.e., minipool single
  () donation) is short, similar to NAT for
  HCV/HIV/HBV.
• Currently the mean resolution time by industry is
  long (25 to 60 days, PPTA presentation at Dec
  2002 BPAC).
• Unresolved issues
• Up-front donor screening
• Lookback retrieval of in-date products
  notification of recipients