Red Blood Cell Immunization Programs - PowerPoint

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					Red Blood Cell Immunization
       Judy Ellen Ciaraldi
           CBER, OBRR, DBA

                                  C B
          September 16, 2009
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•   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

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               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

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               Source Plasma Donor
   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))
    –   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

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             Source Plasma Product
•   Contains high titer of RBC antibody
•   Made into injectable and noninjectable
•   Must meet standards for normal Source
    •   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))
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              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
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             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
    –   PAS – Using new SOPs for donor selection and collection
    –   AR – Using previously approved SOPs
    –   Blood establishment registration form updated to include
        Whole Blood collection
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        Whole Blood/Red Blood Cells
•   Must meet standards for Whole Blood
    •   600.15, 610.53, 640.5 – Storage and shipping temps,
    •   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
    •   Label contains applicant name, address, collection facility
        registration number (606.121.(c))
    •   No license number on Whole Blood/Red Blood Cells         C B
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        Whole Blood/Red Blood Cells
   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

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              Immunogen RBC
              Qualifying Process
   Test new RBC donors for all infectious diseases in
   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
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                                                  10   E R
 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

Test recipients at 3, 6, 9, 12
  months for all markers
 Frozen cells qualified for
  routine use – Donor is
       “pedigreed”                    C B
                                 11   E R

       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

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    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
   RBCs drawn into syringe
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         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
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         Submitting RBC Immunization
   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
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            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

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          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
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              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
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           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
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                  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
   Possible adverse reactions
    –   May develop unexpected antibodies that cause delays in
        obtaining compatible blood for transfusions
   Restrictions for female participants                       C B
                                                          20   E R
   Immunization procedures must be on file at
    centers where immunizations are performed
   Medical oversight, responsibilities
   Evaluation of clinical responses and adverse
   Whole Blood and Source Plasma donor
    selection procedures and testing
    –   Criteria for participation in and discontinuation from
        program                                                       C B
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                       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
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                                            22   E R
                       SOPs (cont.)
   Evaluation of immunogen RBCs received from
   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                                C B
                                                              23   E R
             Immunization Records
   Donor name, ID number
   Injection preparation – date, employee name,
    visual inspection
   Injection – date, employee name, route, volume
   Immunogen RBCs – lot number, expiration
   Physician approval
    –   Selection of immunogen RBCs
    –   Injection – date and volume
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                                            24   E R
         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

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

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                                             27   E R
               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
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           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
    –   Observe operations are consistent with SOPs and
    –   Observe all procedures requested in submission
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   Blood memorandum: Revised Recommendations for
    Red Blood Cells Immunization Programs for Source
    Plasma Donors (3/14/95)
   Guidelines for Immunization of Source Plasma
    (Human) Donors with Blood Substances (6/80)

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                                                          30   E R
                  References (cont.)
   Guidance for Industry: Informed Consent
    Recommendations for Source Plasma Donors
    Participating in Plasmapheresis and Immunization
    Programs (8/8/07)

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