Leukocyte-Reduced Blood Components

1. Leukocyte-Reduced Blood Components Lore Fields MT(ASCP)SBB Consumer Safety Officer, DBA, OBRR, CBER September 16, 2009

2. Outline • Resources for FDA Review Criteria • FDA Review Checklists • General Content of Leukocyte Reduction Submissions • Review Considerations for Specific Products

3. Resources for FDA Review • Recommendations in FDA guidance documents • Device Operator’s Manuals • Package Inserts for Reagents and Supplies • Published scientific literature

4. FDA Guidance Documents usedfor Reviews • Recommendations and Licensure Requirements for Leukocyte-Reduced Blood Products, 5/29/1996 • Guidance for Industry: Use of Sterile Connecting Devices in Blood Bank Practices, 11/22/2000 • Guidance for Industry and FDA Review Staff: Collection of Platelets by Automated Methods, 12/7/07

5. Operator’s Manuals and Package Inserts for Reviews • Operator’s Manuals and Package Inserts • Apheresis instruments • Leukocyte Reduction Filters • Sterile connecting devices • Residual WBC counters • Collection bags • How we use operator’s manuals and package inserts • Collection procedures • Processing procedures • Product specifications

6. FDA Apheresis Review Checklists • Leukocyte Reduction Review Checklist: General • Quality Control (QC) Sheets • Device Manufacturer’s Instructions for Use and Product Specifications

7. FDA Apheresis Review Checklists http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/RegulationoftheBloodSupply/ReviewChecklist/default.htm

8. Device Manufacturer’s Instructions for Use and Product Specifications Checklists Devices that do not allow the calculation of 85% recovery will have specific instructions on a quality control plan to follow.

9. General Content of Submissions • Form FDA 356h • Detailed Description of Request • SOPs • Records and Forms • Product Quality Control Logs • Labeling • May reference previously approved SOPs, forms and labeling (include STN)

10. General Submission Content • The detailed description of the request typically includes: • Products requested for licensure, including anticoagulants • Collection, processing and testing device(s) (instrument, filter) • List of facilities requesting product licensure (address, registration number) • Cell counting method and where the testing will be performed

11. General Submission Content • SOPs typically submitted include: • Collection procedures, including arm prep • Donor history forms, including informed consent • Product manufacturing procedures, including QC, labeling, splitting, leukocyte reduction, storage, shipping, equipment calibration, etc. • Failure investigation • Quarantine and disposition of unsuitable products

12. General Submission Content • Records and Forms – we recommend the following: • Product processing, collection information • Product quality control records

13. General Submission Content • Completed records and forms • Relevant validation protocols and data (Validation summary only, including failure investigations) • 2 consecutive months quality control data • Red Blood Cells • Platelets, Pheresis • Each type of device and each methodology

14. General Submission Content • Product Quality Control Records • Product description (eg, product name, leukocyte reduced) • Type of collection (eg, single, double) • Collection and testing dates • Product specifications • Product testing results, including WBC counts, platelet yields, absolute RBC volume, pH, RBC recovery, product volume, etc. • Interpretation of each result

15. General Submission Content • Product Quality Control Records (cont.) • Collection device (manufacturer, model number) • Product identification number • Collection center • Technologist identified • Monthly interpretation • Acceptable criteria • Evidence of QA oversight

16. General Submission Content • Labeling • Form FDA 2567 • Circular of Information • Base label and product overlay labels for each product • 21 CFR 606.121(c)(13) – machine readable information • Unique facility identifier • Lot number relating unit to donor • Product code • ABO/Rh of donor • ISBT 128 or Codabar • “Apheresis” in product name or attributes (if applicable)

17. General Submission Content Just remember with labeling: Leukocytes Removed Leukocytes Poor Leukocytes Depleted Leukocytes Reduced

18. Review Considerations for Whole Blood and Red Blood Cells • Validation • No recommendations in LR guidance • establish documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics • Monthly QC • 1% of collections for each product type, selected at random; if less than 400 per month, then 4 of each product type • 95% meet product standards

19. Review Considerations for Whole Blood and Red Blood Cells Whole Blood, Leukocytes Reduced and Red Blood Cells, Leukocytes Reduced should be prepared by a method known to: • leave a residual leukocyte count of less than 5.0 x 10e6 per container and • retain a minimum of 85% of the original component

20. Review Considerations for Platelets • Validation • No recommendations in LR guidance • establish documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics

21. Review Considerations for Platelets • Monthly QC • 1% of collections for each product type, selected at random; if less than 400 per month, then 4 of each product type • 95% meet product standards

22. Review Considerations for Platelets Platelets, Leukocytes Reduced prepared from Whole Blood should be prepared by a method known to: • leave a residual leukocyte count of less than 8.3 x 10e5 per container and • retain a minimum of 85% of the original component

23. Review Considerations for Platelets, Pheresis Validation Summary 95%/95% is a statistical approach to demonstrate a 95% confidence that a product or process conforms to a prespecified standard 95% of the time

24. Review Considerations for Platelets, Pheresis • Validation (continued) • Perform when the automated blood cell separator device or filtration method is first put into use at an establishment and/or as recommended by the automated blood cell separator device manufacturer. • Conduct testing on the collection (parent container) and on the individual components from double and triple collections. • Other as specified by device manufacturer

25. Review Considerations for Platelets, Pheresis • Monthly quality control (submit 2 months) • Other as specified by device manufacturer

26. Review Considerations for Red Blood Cells (Apheresis) • Validation • No recommendations in LR guidance • establish documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics • Monthly QC • 1% of collections for each product type, selected at random; if less than 400 per month, then 4 of each product type • 95% meet product standards or repeat QC

27. Review Considerations for Red Blood Cells (Apheresis) Red Blood Cells, Leukocytes Reduced should be prepared by a method known to: • leave a residual leukocyte count of less than 5.0 x 10e6 per container and • retain a minimum of 85% of the original component

28. Review Considerations for Red Blood Cells (Apheresis) • Devices that are not able to provide a pre-filtration sample. • Devices have been cleared by FDA with an alternative method of determining product quality. • Results of alternative methods must still be recorded and evaluated to ensure that 95% of the products are acceptable. • Methods include: • Computer Software (part of collection device) • Minimum absolute Red Blood Cell Volume

29. Helpful Tip Percent recovery is calculated with an absolute Red Blood Cell volume. Volume x HCT = absolute RBC volume

30. Summary • CBER reviews based on: • Regulations and Guidance Documents • Operator’s Manuals and Package Inserts • Submission typically should include information for substantive review • Consult CBER review checklists • Consult operator’s manuals and package inserts

31. Summary • Approvals are specific for: • Apheresis instrument • Product collected • Collection facility for apheresis • Manufacturing facility for filtration