Comment on Draft Guidance:

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Comment on Draft Guidance
Collection of Platelets by Automated Methods
Richard Benjamin, MD PhD Chief Medical Officer
American Red Cross Biomedical Services, National
Headquarters Washington, DC
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Items for discussion

• Apheresis process validation for bacterial
  contamination
• Duration of medication deferral for platelet
  inhibitors
• Number of platelet components collected per year

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Product Performance Qualification (Component
Collection)

• You should use the following collection
  performance qualification criteria
• Test a minimum of 60 consecutive single (30 for
  double and 20 for triple) collections for each
  type of automated blood cell separator for (1)
  actual platelet yield, pH, volume, visible RBCs
  and (2) for residual WBC count and percent
  recovery (Ref. 2), with 0 failures in each
  category. Perform bacterial contamination
  testing on 500 collections with 0 failures. Refer
  to Table 1.

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Issue SummaryTopic II. Public Comments on
Guidance for Industry and FDA Review Staff
Collection of Platelets by Automated Methods
(Draft)

• Item 1 Process Validation for Bacterial Safety
• ..One element of process validation is the
  determination qualification of the product
  integrity, which includes bacterial testing to
  ensure adequacy of an aseptic process for blood
  collection and component processing. FDAs draft
  guidance recommended that that process validation
  for microbial safety should include culture-based
  testing of 500 consecutive collections for
  bacterial contamination, with no more than one
  positive test result. The rationale for this
  sample size is to assure with gt95 confidence
  that the true bacterial contamination rate is
  less than 1. Based on published literature (ref
  1), the bacterial contamination rate for a
  conforming process should not exceed 13,000. At
  this level, the proposed validation test would be
  expected to yield a false result of
  non-conformance in fewer than 3 of
  determinations.

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BacT/ALERT Bacterial Detection System
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Positive Bacterial Cultures using BacT/Alert
Methods of Failure(n 350,840 1/1/05
-010/31/05)

• Total positive 1 1,519
• False positives
• Contamination at inoculation 1 2,580
• BacT/ALERT incubator failure
• Apheresis kit contamination/integrity 0
• Donor bacteremia
• Phlebotomy 15,012
• (Skin plug/site preparation)

Failure is not due to failure of the Apheresis
equipment or process. In most cases root cause
of true positives (ie donor bacteremia vs
incomplete skin preparation) cannot be
determined. Proof that true contamination rate
is lt1 has no medical significance.
Fang CT et al Transfusion 2005, 451485
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Recommendation

• Conclusions
• Positive cultures are common but rarely indicate
  apheresis process failure.
• 100 QC is in place to ensure product sterility
  and confirm process integrity
• 500 cultures will unduly delay licensure of
  products
• Suggested 1 cutoff has no medical significance
• Criteria are not applied to other variables
  (Yield, pH, volume, WBC count, RBC content)
• Bacterial cultures should be performed on 60
  consecutive products to prove process integrity,
  in keeping with other required parameters.

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ASA 5 day deferral

• Not supported by available evidence
• Inconsistent with current AABB Standard
• Current deferral period of 36 hours is supported
  by published reports and expected recovery of
  platelet function

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Platelet Function in Recipients of Platelets from
Donors Ingesting Aspirin.Stuart et al. New Eng J
Med 287 1105-1109, 1972
Prolonged bleeding times were corrected to normal
in recipients of platelets from donors who had
taken ASA 36 hours before donation
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NSAIDS 3 day deferral

• NSAIDs are common 5 to 10 of the adult US
  population, or 15 million to 25 million people,
  use an NSAID on a regular basis.
• Commonly used NSAIDS have short half-lives
• Platelet function normalizes within 24 hours of
  cessation of regular ibuprofen use in healthy
  individuals (Goldenberg et al. Ann Intern Med
  2005 142506-509.
• Commonly used NSAIDS
• Reversible inhibition
• Modest bleeding time abnormalities which usually
  do not exceed the upper limit of normal
• Dose-dependent effect dilution after
  transfusion with recovery of platelet function

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Number of components/year
The yearly change in platelet counts in regular
donors, regardless of their frequency of
donation, is distributed around a mean decrease
of 3,900/uL per year, which is a clinically
insiginificant difference
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Number of components/yr

• Impact on availability loss of 35,786 products
  from high-frequency, high yield donors ( 6 of
  distributable inventory)
• No evidence that donors who gave more than 24
  components per year are at greater risk of
  significant changes in platelet counts than those
  who give fewer than 24 components/yr

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Impact on supply

• If the component number, physician-on-site, NSAID
  deferral, and volume loss limitations were
  implemented.
• Loss of 65,000 Platelet, Apheresis components
  per year
• 40 million additional cost
• No evidence that these changes would increase
  donor or patient safety.

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ARC Recommendations

• Process validation for bacterial safety
• Modify to 60 consecutive negative cultures
  instead of 500
• Deferrals for platelet inhibitors
• ASA 36 hour deferral supported by data
• NSAIDS Eliminate requirement for 3 d deferral
• Number of platelet components per year
• Do not impose additional restrictions
• Appropriate safeguards are already in place to
  prevent collection of a donor with an
  unacceptable platelet count