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Whole Blood and Blood Components

Diane K. Hall

Consumer Safety Officer CBER, OBRR, DBA

September 16, 2009

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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

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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

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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

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General SOPs

• 606.160(b)(5)(iv): Validate shipping containers• 606.65(e): Supplies shall be used in a manner

consistent with manufacturer’s instructions• If applicable, submit SOP for Sterile

Connecting Device procedure **

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Whole Blood

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Whole Blood21 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

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Red Blood Cells

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RBCs21 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

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RBC Modifications

Red Blood Cells Washed

Red Blood Cells Rejuvenated

Red Blood Cells Frozen

Red Blood Cells Deglycerolized

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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

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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

manufacturer’s 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

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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) ***

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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) ***

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Autologous Donations

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Autologous Donations

• 640.3(b): Donor qualifications• 610.40(d): Infectious disease testing • 606.100(b)(20): Donor deferral

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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

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Autologous DonationsLabels (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

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Autologous DonationsLabels (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)

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Autologous DonationsLabels (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”

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Plasma Components

Fresh Frozen Plasma (FFP)

Plasma Cryoprecipitate Reduced

Plasma Frozen Within 24 Hours After Phlebotomy

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Plasma21 CFR 640.30 – 640.34

• 640.31: Suitability of donors• 640.32: Collection of source material• 640.33: Testing the blood• 640.34: Processing

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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

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Platelet Components

Platelets

Pooled Platelets-5d, Leukocytes Reduced

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Platelets21 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

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Platelets

• 640.22(d) : Phlebotomy shall be performed by:– A single uninterrupted venipuncture– With minimal damage to and manipulation of

donor’s tissue

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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

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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

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Platelets640.24(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 >5.5x1010 platelets per unit (75%

of tested units)

• The volume of original plasma used to resuspend the platelets shall maintain a pH of >6.2

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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

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Platelets: Product QC

640.24(c), 640.25: Acceptance Criteria forPlatelets• pH: >6.2• Platelet yield: 5.5x1010 platelets/unit in >75% of

tested units

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Considerations for Pooled Platelets-5d, Leukocytes Reduced

Approved submissions have typically contained• Manufacturing: Use a process based on the

manufacturer’s package insert that is capable of demonstrating the specified acceptance criteria

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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

manufacturer’s instructions• Acceptance Criteria

– Acceptance criteria: manufacturer’s recommendations for product specifications

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Cryoprecipitate Components

Cryoprecipitated AHF

Pooled Cyroprecipitated AHF

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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

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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

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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

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Cryoprecipitated AHF

610.53(c): for Cryoprecipitated AHF• Storage: <-18C• Dating period: 1 year from the date of Whole

Blood collection

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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

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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 unit’s date of

collection

• Product QC and Acceptance Criteria– Same as Cryoprecipitated AHF

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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/GuidanceComplianceRegulatoryInformation/Guidances/Blood/default.htm

Eight-Hour Hold

http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/OtherRecommendationsforManufacturers/MemorandumtoBlood

Establishments/default.htm

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Questions - Contact us!

• Mailing address:

Director, Division of Blood Applications, OBRR, CBER, FDAHFM-370c/o Document Control Center, HFM-991401 Rockville Pike, Suite 200NRockville, MD 20852-1448

• Telephone: 301-827-3543

• FAX: 301-827-3534