Comment on Draft Guidance:

1. Comment on Draft Guidance: Collection of Platelets by Automated Methods Richard Benjamin, MD PhD Chief Medical Officer American Red Cross Biomedical Services, National Headquarters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

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

3. 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.

4. 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. FDA’s draft guidance recommended that that process validation for microbial safety should include culture-based testing of 500 consecutive collections for bacterial contamination,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 >95% 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 1:3,000. At this level, the proposed validation test would be expected to yield a false result of non-conformance in fewer than 3% of determinations.

5. BacT/ALERT Bacterial Detection System

6. 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 – ~1:5,012 (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 <1% has no medical significance. Fang CT et al Transfusion 2005, 45:1485

7. 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.

8. 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

9. 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

10. 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; 142:506-509. • 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

11. 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

12. 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

13. 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.

14. 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