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Red Blood Cell Immunization Programs

Judy Ellen CiaraldiBS, MT(ASCP)SBB, CQA(ASQ)

CBER, OBRR, DBA

September 16, 2009

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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

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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(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

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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))

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Donors of ImmunogenRed 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 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

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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,

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

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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

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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

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NEW RBC DONORSTest 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

NR

NR

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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

NR

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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

inspected 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 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

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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

programs Possible adverse reactions

– May develop unexpected antibodies that cause delays in obtaining compatible blood for transfusions

Restrictions for female participants

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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

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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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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

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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

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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, 640.72(a)(3))

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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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 review – Observe operations are consistent with SOPs and

regulations– Observe all procedures requested in submission

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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/OtherRecommendationsforManufacturers/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

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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.htm