1. CBER Whole Blood and Blood Components Diane K. Hall Consumer Safety Officer CBER, OBRR, DBA September 16, 2009

2. CBER 2 Presentation Outline Submission contents General Standard Operating Procedures (SOPs) Whole Blood and blood components – Whole Blood and Red Blood Cells (RBCs) – RBC Modifications – Autologous Donations – Plasma – Platelets – Cryoprecipitated AHF

3. CBER 3 General Submission Contents 21 CFR 601.12 * Cover Letter Form FDA 356h Form FDA 2567 with Labels Chemistry, Manufacturing and Control Section (CMC) – Appropriate SOPs – Validations and failure investigations – Quality Control (QC) – Records – Contractors names, addresses, registration numbers/CLIA approved

4. CBER 4 General SOPs 21 CFR 606.100: Maintain SOPs for all steps followed in collection, processing, storage and distribution of blood and blood components 640.4(h): Whole Blood storage temperatures during transport from collection site to processing site: – Cooling continuously towards 1-10C, or – Held in an environment maintained at a temperature range specified for that component in the directions for use for the blood collecting, processing, and storage system

5. CBER 5 General SOPs 606.160(b)(5)(iv): Validate shipping containers 606.65(e): Supplies shall be used in a manner consistent with manufacturers instructions If applicable, submit SOP for Sterile Connecting Device procedure **

6. CBER Whole Blood

7. CBER 7 Whole Blood 21 CFR 640.1 - 640.6 640.2: General requirements – Manufacturing responsibility – Blood container – Reissue of blood 640.3: Suitability of donor 640.4: Collection of the blood 640.5: Testing the blood

8. CBER Red Blood Cells

9. CBER 9 RBCs 21 CFR 640.10 - 640.17 640.11: General requirements – Storage – Inspection 640.12: Suitability of donor 640.13: Collection of the blood 640.14: Testing the blood 640.15: Segments for testing 640.16: Processing

10. CBER RBC Modifications Red Blood Cells Washed Red Blood Cells Rejuvenated Red Blood Cells Frozen Red Blood Cells Deglycerolized

11. CBER 11 Considerations for RBC Modifications: Storage and Dating Period Approved submissions have typically contained Red Blood Cells Washed – Storage: 1-6C – Dating period: 24 hours from start of washing process Red Blood Cells Rejuvenated – Storage: 1-6C – Dating period: 24 hours from start of washing process Red Blood Cells Frozen Rejuvenated – Storage: <-65C – Dating period: 10 years for RBCs collected and stored in CPD or CPDA-1 or 3 years for RBCs stored in CPD/ AS-1

12. CBER 12 RBC Modifications: Storage and Dating period 640.17, 610.53(c) Red Blood Cells Frozen (FRBC) – Storage: <-65C – Dating period: 10 years, or as specified in the manufacturers instructions Red Blood Cells Deglycerolized – Storage: 1-6C – Dating period: 24 hours after removal from <65C storage or as specified in the directions for use for the blood collection, processing, and storage system approved by FDA

13. CBER 13 RBC Modifications: Product QC Considerations for Red Blood Cells Washed Approved submissions typically have contained – Two months of product QC – 4 units/month – RBC Percent Recovery *** – Residual Total Protein *** – Sterility testing (10 units) ***

14. CBER 14 RBC Modifications: Product QC Red Blood Cells Deglycerolized and Red Blood Cells Rejuvenated – RBC Percent Recovery *** – Determination of free hemoglobin *** – Monitor glycerol removal *** – Sterility testing (10 units) ***

15. CBER Autologous Donations

16. CBER 16 Autologous Donations 640.3(b): Donor qualifications 610.40(d): Infectious disease testing 606.100(b)(20): Donor deferral

17. CBER 17 Autologous Donations Labels 21 CFR 606.121(i) and (j) Information identifying the patient, e.g. – Name, – Blood Group, – Hospital, – Identification Number Date of donation If applicable, FOR AUTOLOGOUS USE ONLY May use a tie tag attached to the container

18. CBER 18 Autologous Donations Labels (cont.) 606.121(i)(4) If donor fails to meet any Whole Blood donor suitability requirements, FOR AUTOLOGOUS USE ONLY label replaces the Blood Group label 610.40(h)(2)(ii)(B): Components that have reactive infectious disease screening tests must be labeled with the BIOHAZARD legend

19. CBER 19 Autologous Donations Labels (cont.) 610.40(d) If there is no cross over allowed and the units are not shipped anywhere else, then no infectious disease testing is required and the unit can be labeled, DONOR UNTESTED If facilities cross over autologous units or ship to facilities that allow cross over, then all units must be tested for infectious diseases and labeled according to 606.121(i)

20. CBER 20 Autologous Donations Labels (cont.) 610.40(d) If products are shipped to another facility that does not allow cross over, you must assure that the first donation in each 30-day period is tested. – Tested units: Label according to 606.121. – Untested units: Label as DONOR TESTED WITHIN THE LAST 30 DAYS

21. CBER Plasma Components Fresh Frozen Plasma (FFP) Plasma Cryoprecipitate Reduced Plasma Frozen Within 24 Hours After Phlebotomy

22. CBER 22 Plasma 21 CFR 640.30 – 640.34 640.31: Suitability of donors 640.32: Collection of source material 640.33: Testing the blood 640.34: Processing

23. CBER 23 Plasma Components 640.34(b), 640.54(a)(2): Separate plasma from RBCs and place in freezer within 8 hours of phlebotomy or within the timeframe specified in the directions for use for the blood collecting, processing and storage system. 610.53(c) – Storage: <-18C – Dating period: 1 year from the collection date of Whole Blood

24. CBER Platelet Components Platelets Pooled Platelets-5d, Leukocytes Reduced

25. CBER 25 Platelets 21 CFR 640.20-640.27 640.21: Suitability of donors 640.22: Collection of source material 640.23: Testing the blood 640.24: Processing 640.25: General requirements – Storage – Quality control testing – Manufacturing responsibility

26. CBER 26 Platelets 640.22(d) : Phlebotomy shall be performed by: – A single uninterrupted venipuncture – With minimal damage to and manipulation of donors tissue

27. CBER 27 Platelets 640.24: Processing Whole Blood temperatures during transport from collection site to processing site shall be maintained as close as possible to a range between 20-24C Separate within 4 hours or within the timeframe specified in the direction for use for the blood collecting, processing, and storage system

28. CBER 28 Platelets 640.25: Storage 20-24C with continuous gentle agitation, or 1-6C with no agitation 610.53(c): Dating period 72 hours from the time of collection, or 5 days, with approved containers

29. CBER 29 Platelets 640.24(c) and (d) The time and speed of the centrifuge should demonstrate that the manufactured product: – Is an unclumped product – Is without visible hemolysis – Yields a count of >5.5x10 10 platelets per unit (75% of tested units) The volume of original plasma used to resuspend the platelets shall maintain a pH of >6.2

30. CBER 30 Considerations for Platelets: Product QC Approved submissions have typically contained two consecutive months of product QC 21 CFR 640.25 – 4 units/month – pH – Platelet count – Plasma volume

31. CBER 31 Platelets: Product QC 640.24(c), 640.25: Acceptance Criteria for Platelets pH: >6.2 Platelet yield: 5.5x10 10 platelets/unit in >75% of tested units

32. CBER 32 Considerations for Pooled Platelets-5d, Leukocytes Reduced Approved submissions have typically contained Manufacturing: Use a process based on the manufacturers package insert that is capable of demonstrating the specified acceptance criteria

33. CBER 33 Considerations for Pooled Platelets-5d, Leukocytes Reduced Approved submissions have typically contained Product QC – Two consecutive months of product QC – Statistically sound plan – Ensure products meet specifications stated in the manufacturers instructions Acceptance Criteria – Acceptance criteria: manufacturers recommendations for product specifications

34. CBER Cryoprecipitate Components Cryoprecipitated AHF Pooled Cyroprecipitated AHF

35. CBER 35 Cryoprecipitated AHF: 21 CFR 640.50 – 640.56 640.51: Suitability of donors 640.52: Collection of source material 640.53: Testing the blood 640.54: Processing 640.56: Quality control test for potency

36. CBER 36 Cryoprecipitated AHF 640.54(a): Processing Plasma (cryo rich) Separate plasma by centrifugation Place plasma in freezer within 8 hours after collection or within the timeframe specified in the directions for use for the blood collecting, processing, and storage system Store plasma at <-18C until further processed

37. CBER 37 Cryoprecipitated AHF 640.54(b): Processing Final Product Separate the Cryoprecipitated AHF from the plasma by a procedure that has been shown to produce an average of >80 IU of AHF/final container Do not add diluent prior to freezing final product

38. CBER 38 Cryoprecipitated AHF 610.53(c): for Cryoprecipitated AHF Storage: <-18C Dating period: 1 year from the date of Whole Blood collection

39. CBER 39 Considerations for Cryoprecipitated AHF Approved submissions typically have contained two consecutive months of product QC 21 CFR 606.122(n), 640.56 – 4 units/month – Fibrinogen – AHF potency – Acceptance Criteria Fibrinogen: >150 mg Mean AHF potency: >80 IU of AHF/final container

40. CBER 40 Considerations for Pooled Cryoprecipitated AHF Approved submissions have typically contained Manufacturing – Use of Sterile Connecting Device ** – Storage: <-18C – Dating period: 1 year from the oldest units date of collection Product QC and Acceptance Criteria – Same as Cryoprecipitated AHF

41. CBER 41 References *Guidance for Industry: Changes to an Approved Application: Biological Products: Human Blood and Blood Components Intended for Transfusion or for Further Manufacture **Guidance for Industry: Use of Sterile Connecting Devices in Blood Bank Practices ***Guidance for Industry For the Submission of Chemistry, Manufacturing and Controls and Establishment Description Information for Human Blood and Blood Components Intended for Transfusion or for Further Manufacture and For the Completion of the Form FDA 356h Application to Market a New Drug, Biologic or an Antibiotic Drug for Human Use http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInfor mation/Guidances/Blood/default.htm Eight-Hour Hold http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInfor mation/OtherRecommendationsforManufacturers/MemorandumtoBlood Establishments/default.htm

42. CBER 42 Questions - Contact us! Mailing address: Director, Division of Blood Applications, OBRR, CBER, FDA HFM-370 c/o Document Control Center, HFM-99 1401 Rockville Pike, Suite 200N Rockville, MD 20852-1448 Telephone: 301-827-3543 FAX: 301-827-3534