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

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

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

4. 4 FDA Guidance Documents used for 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. 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. 6 FDA Apheresis Review Checklists Leukocyte Reduction Review Checklist: General Quality Control (QC) Sheets Device Manufacturer’s Instructions for Use and Product Specifications

7. 7 FDA Apheresis Review Checklists http://www.fda.gov/BiologicsBloodVaccin es/BloodBloodProducts/Regulationofthe BloodSupply/ReviewChecklist/default.ht m

8. 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. 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. 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. 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. 12 General Submission Content Records and Forms – we recommend the following: – Product processing, collection information – Product quality control records

13. 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. 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. 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. 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. 17 General Submission Content Just remember with labeling: Leukocytes Removed Leukocytes Poor Leukocytes Depleted Leukocytes Reduced

18. 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. 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. 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. 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. 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. 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. 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. 25 Review Considerations for Platelets, Pheresis Monthly quality control (submit 2 months) – Other as specified by device manufacturer

26. 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. 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. 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. 29 Helpful Tip Percent recovery is calculated with an absolute Red Blood Cell volume. Volume x HCT = absolute RBC volume

30. 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. 31 Summary Approvals are specific for: – Apheresis instrument – Product collected – Collection facility for apheresis – Manufacturing facility for filtration