1. CBER Red Blood Cell Immunization Programs Judy Ellen Ciaraldi BS, MT(ASCP)SBB, CQA(ASQ) CBER, OBRR, DBA September 16, 2009

2. CBER 2 Outline RBC Immunization Processes Source Plasma (donor and product) RBCs (donor and product) Immunogen RBC qualification and preparation RBC immunization procedures Considerations on how to submit for a RBC immunization program CBER review of RBC immunization programs

3. CBER 3 Source Plasma Donor  Must meet all donor suitability criteria in 640.63, 640.65, and 610.40 – Physical examination within 1 week before first immunization (640.63(b)(2)) unless active donor  Should not have child-bearing capability – Male – Female who is post-menopausal or surgically sterile  Tested for RBC antigen profile – D, C, E, c, e, K, Fya, others as needed

4. CBER 4 Source Plasma Donor (cont.)  If donors elicit no response (no antibodies develop), they can return to normal Source Plasma donor pool if they meet normal donor suitability criteria – Deferred for 12 months after last injection (640.63(c)(13)) unless… – Documented proof that only qualified cells were injected – Request for an alternative procedure under 640.120 to donate in less than 12 months has been approved

5. CBER 5 Source Plasma Product Contains high titer of RBC antibody Made into injectable and noninjectable products Must meet standards for normal Source Plasma 640.64 & 640.69 – Collection and storage 640.70 & 640.76 – Storage and shipping temps; labeling 610.40 – Infectious disease testing Label must state the immunizing antigen or specific antibody present (640.70(a)(7))

6. CBER 6 Donors of Immunogen Red Blood Cells  Must meet all Whole Blood donor suitability criteria (640.3 and 610.40)  Must not have been transfused within previous 12 months (640.3(c)(3))  Should be available for infectious disease testing for the qualification process  May also be a Source Plasma donor – Track RBC and plasma volumes donated or lost – Track donation intervals

7. CBER 7 Whole Blood Collection  Procedures must be consistent with 640.4  Volumes and frequency must not exceed those for routine Whole Blood donations (640.3)  If implementing Whole Blood collection in Source Plasma center, report to FDA as follows: – PAS – Using new SOPs for donor selection and collection – AR – Using previously approved SOPs – Blood establishment registration form updated to include Whole Blood collection

8. CBER 8 Whole Blood/Red Blood Cells Must meet standards for Whole Blood 600.15, 610.53, 640.5 – Storage and shipping temps, processing 610.40 – Infectious disease testing With FDA approval, may ship to lab before testing completed (610.40(g)) Label unit with tests completed and pending (606.121(h)) These blood components need not be licensed if collected as part of approved RBC immunization program Label contains applicant name, address, collection facility registration number (606.121.(c)) No license number on Whole Blood/Red Blood Cells

9. CBER 9 Whole Blood/Red Blood Cells (cont.)  Tested for RBC antigen profile – D, C, E, c, e, K, Fya, others as needed  Storage: – Liquid – 1-6 C (shelf life determined by anticoagulant) – Frozen - -65 C or colder for up to 10 years – Deglycerolized – 1-6 C for approved shelf life based on sterility data

10. CBER 10 Immunogen RBC Qualifying Process  Test new RBC donors for all infectious diseases in 610.40  If negative, freeze RBC for 12 months  After 12 months, retest RBC donor  If negative, inject deglycerolized RBCs into no more than 3 acceptable Source Plasma donors  Test Source Plasma donors for infectious diseases at 3, 6, 9 and 12 months after immunization  If Source Plasma (SP) donors are negative, RBCs are qualified to be used to immunize other SP donors

11. CBER 11 NEW RBC DONORS Test potential donor for all infectious disease markers Collect RBCs and store frozen for 12 months Test donor and intended recipients for all markers Immunize up to 3 Recipients Test recipients at 3, 6, 9, 12 months for all markers Frozen cells qualified for routine use – Donor is “pedigreed” NR

12. CBER 12 QUALIFIED (PEDIGREED) RBC DONORS Test donor for all infectious disease markers Collect RBCs and store frozen for 12 months Retest donor for all infectious disease markers Frozen Red Blood Cells qualified for routine use NR

13. CBER 13 Preparation of Immunogen RBCs  RBCs glycerolized and frozen  RBCs thawed and deglycerolized  Sterility testing done on 1 sample from each lot  Aseptically aliquoted into sterile, pyrogen-free single-dose labeled vials  Shipped to Source Plasma donor; visually inspected  RBCs drawn into syringe

14. CBER 14 RBC Immunization Procedure  De Novo (donors who do not have pre-existing RBC antibodies) immunization only allowed for anti-D – Maximum 50 mL in 4 month period – Donor not responding after 150 mL should be dropped  Re-stimulation (boost) of pre-existing antibody – Maximum of 4 mL up to 5 times/month – Not to exceed 40 mL in 6 month period  Immunization only done with qualified RBCs  May immunize on same day as plasmapheresis, but only after plasmapheresis procedure  Physician (or trained individual) can do injections

15. CBER 15 Submitting RBC Immunization Programs  RBC immunization programs have been approved by CBER – PAS supplement – Pre-approval inspections  RBC immunization programs are “site- specific” approvals  Contractual arrangements are possible – Perform injections – Collect plasma – Supply Whole Blood and/or immunogen RBCs

16. CBER 16 Submission Content  Forms: 356h and 2567  Applicant name and license number  Contact name and information  Facility name, address and registration number  Contractor information  Medical oversight

17. CBER 17 Submission Content (cont.)  Informed consent form (640.61 & 640.72(a)(3))  RBC immunization program SOPs  Immunization records for 5 donors  Sterility data for 10 lots – Support deglycerolized RBC expiration date  Labels  May reference previously approved SOPs, forms, labels – Include approved reference number

18. CBER 18 Contractor Information  Name and license number  Address and registration number  List of activities done under contract  Where records are maintained  Describe quality oversight of contractor  Contract manufacturers must be registered and licensed in many cases – Exception: Sterility testing lab exempt from registration

19. CBER 19 Medical Supervision of RBC Immunization Program  Physician must: (640.66) – Certify the donor’s health to participate – Administer the informed consent – Approve injection schedule – Select the antigen to be injected – Evaluate clinical response (including monitoring reactions)  Physician must be on premises during RBC immunization (640.62)  Keep donor at center after immunization to observe for immediate reactions

20. CBER 20 Informed Consent  Volume, route and schedule of injections  Criteria for discontinuation from program  Participate in only one immunization program at a time  May not be eligible for other donation programs  Possible adverse reactions – May develop unexpected antibodies that cause delays in obtaining compatible blood for transfusions  Restrictions for female participants

21. CBER 21 SOPs  Immunization procedures must be on file at centers where immunizations are performed (640.66)  Medical oversight, responsibilities  Evaluation of clinical responses and adverse reactions  Whole Blood and Source Plasma donor selection procedures and testing – Criteria for participation in and discontinuation from program

22. CBER 22 SOPs (cont.)  Whole Blood collection and preparation of immunogen RBCs – Immunogen RBC qualification – Sterility testing – Aliquoting – Quality control procedures – Freezing and deglycerolizing  Transport/ship immunogen RBCs to Source Plasma donor

23. CBER 23 SOPs (cont.)  Evaluation of immunogen RBCs received from supplier  Immunization procedures – Physician approval – Preparation of injection – Injection volume and schedule, administration route – When titrations will be performed – Handling and storing of vials (1-6 C)  Monitor for unexpected antibodies (e.g., additional antibodies)  Proper documentation procedures

24. CBER 24 Immunization Records  Donor name, ID number  Injection preparation – date, employee name, visual inspection  Injection – date, employee name, route, volume  Immunogen RBCs – lot number, expiration date  Physician approval – Selection of immunogen RBCs – Injection – date and volume

25. CBER 25 Immunization Records (cont.)  Adverse reactions (640.72(d))  Antibody name, test results and titers – Unexpected antibodies (e.g., additional antibodies)  ABO group, Rh type and RBC phenotyping

26. CBER 26 Other Records (606.160 & 640.72)  Whole Blood and Source Plasma donor selection and testing  Informed consent for immunization (640.61, 640.72(a)(3))  Freezing and deglycerolizing, including quality control tests  Ongoing sterility test results  Trace immunogen RBCs to Whole Blood donor

27. CBER 27 Other Records (cont.)  Storage and shipping temperatures  Collection procedures – Volume – RBC loss – Donation reactions  Immunogen RBC qualification procedures  Evidence of review done to identify and correct deficiencies (606.100(c))

28. CBER 28 CBER Review of RBC Immunization Programs  Based on desk review and inspection  Donor selection consistent with applicable regulations and guidance documents  SOPs include all critical procedures – Medical oversight  Informed consent includes recommendations in guidance document  Forms contain all information and show evidence of QA review

29. CBER 29 CBER Review of RBC Immunization Programs (cont.)  All facilities (including contractors) are FDA registered and licensed when required, and have acceptable compliance checks  Labels consistent with 640.70 – Include immunizing antigen  Pre-approval inspection scheduled after desk review – Observe operations are consistent with SOPs and regulations – Observe all procedures requested in submission

30. CBER 30 References  Blood memorandum: Revised Recommendations for Red Blood Cells Immunization Programs for Source Plasma Donors (3/14/95) – http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianc eRegulatoryInformation/OtherRecommendationsforManufacturer s/MemorandumtoBloodEstablishments/default.htm http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianc eRegulatoryInformation/OtherRecommendationsforManufacturer s/MemorandumtoBloodEstablishments/default.htm  Guidelines for Immunization of Source Plasma (Human) Donors with Blood Substances (6/80) – http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianc eRegulatoryInformation/Guidances/Blood/default.htm http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianc eRegulatoryInformation/Guidances/Blood/default.htm

31. CBER 31 References (cont.)  Guidance for Industry: Informed Consent Recommendations for Source Plasma Donors Participating in Plasmapheresis and Immunization Programs (8/8/07) – http://www.fda.gov/BiologicsBloodVaccines/GuidanceComp lianceRegulatoryInformation/Guidances/Blood/ucm073433.h tm http://www.fda.gov/BiologicsBloodVaccines/GuidanceComp lianceRegulatoryInformation/Guidances/Blood/ucm073433.h tm