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Exceptions and Alternative Procedures Approved Under 21 CFR 640.120

Title 21 Code of Federal Regulations 640.120(a) - The Director, Center for Biologics Evaluation and Research, may approve an exception or alternative procedures to any requirement in subchapter F (Biologics) of Chapter I (Parts 600 - 680) of title 21 of the Code of Federal Regulations regarding blood, blood components or blood products.

Both licensed and unlicensed blood establishments must submit requests for an exception or alternative procedure to the requirements in Parts 600-680. Licensed establishments should submit the request in accordance with 21 CFR 601.12 and may reference our guidance document entitled: Guidance for Industry: Changes to an Approved Application: Biological Products: Human Blood and Blood Components Intended for Transfusion or for Further Manufacture (July 2001).

Requests for such exceptions or alternative procedures should ordinarily be made in writing, however, in limited circumstances, such requests may be made orally and permission may be given orally by the Director. Oral requests and approvals must be promptly followed by written requests and written approvals.

It should be noted that requests for exceptions or alternate procedures includes specific circumstances and may require submission of supporting data unique to the circumstance. Publication of these approvals for a specific exception or alternative procedure does not necessarily mean that they can be generally applied to other manufacturers.

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FEDERAL REGISTER Cumulative List of Exceptions and Alternative Procedures Approved by the Director of the Center for Biologics Evaluation and Research - 9/28/2004 - (PDF), (Text)

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21 CFR 640.120 APPROVALS

As of October 28, 2004, the following exceptions or alternative procedures have been approved under 21 CFR 640.120:

  1. 21 CFR 600.15(a):

      2. Allow use of autologous units that were transported in a shipping container without ice and exposed to temperature of 10.0°C to 10.5°C for 10 minutes.

  2. 21 CFR 606.60(b):

      3. Calibrate digital thermometer according to the schedule recommended by manufacturer, instead of monthly as required by regulation.

  3. 21 CFR 606.65(e):

    1. Deviate from manufacturer’s instructions to use the Gen-Probe Procleix HIV-1/HCV Assay and Roche COBAS Ampliscreen HIV-1 and HCV nucleic acid tests on Whole Blood, Red Blood Cells, Platelets, Source Leukocytes, Therapeutic Exchange Plasma and Recovered Plasma intended for further manufacturing.

    2. Deviate from manufacturer’s instruction to use samples containing up to 200 mg/dL hemoglobin or 800 mg/dL triglycerides in the following assays: Abbott HIV AB HIV-1/HIV-2 (rDNA) EIA (LN3A77), Ortho Hepatitis B Core Antibody ELISA, Ortho Hepatitis B Surface Antigen ELISA System 2, and Roche Alanine Aminotransferase.

    3. Deviate from manufacturer’s instruction to use an alternate testing algorithm for confirming repeatedly reactive HIV-1 p24 antigen test results. Specifically, a licensed HIV-1 single unit Nucleic Acid Test will be performed in place of the HIV-1 p24 antigen neutralization test and the results used for donor notification and counseling and recipient tracing.

    4. Deviate from manufacturer’s instructions to test donor specimens that were initially reactive using Ortho HBsAg System 3, in duplicate using Genetic Systems HBsAg EIA 3.0 (shaker method). If either or both of the donor samples test reactive using Genetic Systems HBsAg EIA 3.0 (shaker method), the donor specimen will be tested using Genetic Systems HBsAg Confirmatory 3.0 (shaker method).

  4. 21 CFR 606.121:

    1. Use of full face green labels for autologous use only units.

    2. Use of black print for all statements on container labels (omit use of statements in red print). [Regulation revised - variance request no longer needed]

    3. Use of "Autologous" on label in lieu of "Paid" or "Volunteer."

    4. Omit special labeling from Red Blood Cells with positive antibody screens that are suspended in additive solution, if the supernatant of the additive solution was tested using approved methods and found to be negative for unexpected antibodies.

    5. Place ABO/Rh label and “Donor Untested” on group and type label position.

    6. Print the anticoagulant name after the proper product name instead of preceding it. (Done for ISBT 128 labels.)

  5. 21 CFR 606.122 (m):

      6. Extend the storage time of thawed Fresh Frozen Plasma at 1-6°C to 24 hours, instead of 6 hours.

  6. 21 CFR 606.151:

    1. Omit performing a minor side crossmatch on red blood cells prepared in additive solutions that have not been screened for unexpected antibodies.

    2. Use of a computer (electronic) crossmatch instead of a major side crossmatch. [Regulation revised - variance request no longer needed]

    3. Use of a type and screen procedure as an alternative method for the antiglobulin crossmatch. [Regulation revised - variance request no longer needed]

    4. Allow use of a recipient sample up to 72 hours old for pre-transfusion testing. [Regulation revised - variance request no longer needed]

  7. 21 CFR 606.160:

      8. Allow distribution of Fresh Frozen Plasma for which there were no temperature records available for 3 days, provided there is no evidence to suggest that the safety, purity, potency of the blood components were affected and the documentation of the investigation of the incident and correction actions taken to prevent a similar incident from occurring, is available for review at the next FDA inspection.

  8. 21 CFR 610.40:

    1. Ship Source Leukocytes to the manufacturer before infectious disease testing has been completed, provided the product is labeled that testing is not complete and stored in quarantine until the manufacturer has received the test results. [Regulation revised - variance request no longer needed]

    2. Ship autologous blood unit to another establishment without testing unit for communicable disease agents. Testing performed on sample drawn on subsequent donation.

    3. Ship autologous blood unit to another establishment for processing and labeling and return to collecting facility without testing unit for communicable disease agents, provided neither facility has a crossover policy.

    4. Allow shipment under quarantine of untested Source Plasma labeled as tested negative, to warehouse operated by another manufacturer for storage until testing is completed.

    5. Reinstate one donor with non-discriminated NDR results on the Procleix HIV-1/HCV assay provided the donor tests negative for HIV RNA and HCV RNA using the Procleix Discriminatory assays and anti-HIV 1\2 using Genetic Systems EIA.

    6. Allow shipment under quarantine of Source Plasma before completion of PCR testing, and labeled as pending NAT, to another licensed manufacturer who will cull and destroy NAT reactive units under a contractual arrangement with the Source Plasma manufacturer.

    7. Allow shipment under quarantine of Source Plasma that are labeled as negative/non-reactive for infectious diseases before completion of the infectious disease tests, to a contract off-site storage facility not operating under an U.S. license. Source Plasma manufacturer will cull and destroy reactive units according to their standard procedures.

    8. Ship autologous blood unit to another establishment without testing unit for communicable disease agents under the following conditions: (1) neither facility has a crossover policy; (2) both establishments belong to the same university hospital system; (3) both establishments have the same medical director; and (4) both establishments share the same computer system.

    9. Allow shipment under quarantine of Source Plasma that is labeled as negative/non-reactive for infectious diseases before completion of the infectious disease tests, to a contract off-site storage facility for temporary storage during a forecasted hurricane, provided the cases are labeled ”Untested” and “Biohazard.” The Source Plasma will be returned to the center after the emergency for culling and distribution according to standard operating procedures.

    10. Ship autologous blood unit to another establishment without testing unit for communicable disease agents under the following conditions: (1) the medical director and surgeon were informed that the units were not tested; and (2) the units were appropriated labeled as required by the Code of Federal Regulations.

    11. Discontinue supplemental testing for HCV using the RIBA HCV 3.0 assay for each donation with a repeatedly reactive anti-HCV EIA screen and a positive HCV NAT result. Donors must be notified of their deferral and the reason for the deferral must include the results of the HCV NAT. The supplemental testing for HCV using the RIBA HCV 3.0 assay must still be performed on each donation with a repeatedly reactive anti-HCV EIA screen and a negative HCV NAT result.

  9. 21 CFR 610.53:

    1. Extend CPD and CP2D liquid plasma expiration date to 42 days when stored at 1-6°C.

    2. Allow use of 53 vials of deglycerolized immunogen Red Blood Cells that were exposed to temperatures from 6 - 8°C for up to 3 hours.

  10. 21 CFR 640.3:

    1. Allow whole blood collection from autologous donors who don't meet donor suitability requirements.

    2. Allow Whole Blood collection from donors with a history of hepatitis before age 11. [Regulation revised - variance request no longer needed]

    3. Allow 4 week intervals between Fresh Frozen Plasma donations when it is collected as a by-product of a plateletpheresis procedure.

    4. Allow individuals with hereditary hemochromatosis to donate blood and blood components more frequently than every eight weeks without examination or certification of health by physician at time of donation and to be exempt from placing special labeling about the donor’s disease on the blood components.

    5. Allow post-donation requalification after day of donation of donors who used an outdated vCJD donor questionnaire.

    6. To allow individuals with hereditary hemachromatosis with hematocrits of 34% or greater or hemoglobins of 11.5 g/dL or greater, to donate 500 mL of Whole Blood, provided that only Red Blood Cells are prepared from the Whole Blood donation. In addition, the Red Blood Cells must contain special labeling to show that its contents are equal to or greater than the contents of a standard 450 mL collection bag. These Red Blood Cells may be used for allogeneic transfusions.

  11. 21 CFR 640.4(h) & 640.11(a):

      12. Allow use of Whole Blood and Red Blood Cells that have been exposed to temperatures up to 11.5°C for 4.5 hours or 17°C for 2 hours and 15 minutes, provided that the safety, purity and potency were not affected.

  12. 21 CFR 640.5:

    • Allow syphilis testing to be performed on 27 donors on a substitute sample drawn after day of donation.

    • Allow specimens used for NAT assay to be collected up to 24 hours prior to the collection of heparinized Whole Blood units.

    • Allow distribution of 1,398 units collected from repeat donors using the historical check as the second ABO group instead of performing a second ABO group on a sample taken from the donor during donation, provided the results of the serological ABO test and historical check agree.

  13. 21 CFR 640.11(a):

    1. Allow use of Red Blood Cells and Red Blood Cells Leukocyte-Reduced that were stored at 1°C to -3°C for up to 4 hours, provided each unit was examined for hemolysis before distribution.

    2. Allow use of Red Blood Cells that were exposed to temperatures between 6°C to 10.5°C for up to 4.75 hours, provided each unit was examined for hemolysis before distribution.

    3. Allow distribution of Red Blood Cells that were exposed to storage temperatures warmer than 6°C, but no warmer than 10°C for less than 4 hours, provided the units were examined and there was no evidence of hemolysis or contamination.

    4. Allow distribution of Red Blood Cells that were exposed to storage temperatures warmer than 6°C, but no warmer than 7.85°C on 2 occasions for a total of 2.75 hours, provided the units were examined and there was no evidence of hemolysis or contamination.

    5. Allow distribution of Red Blood Cells that were exposed to storage temperatures warmer than 6°C, but no warmer than 11.9°C for a total of 40 minutes, provided the units were examined and there was no evidence of hemolysis.

  14. 21 CFR 640.23(b):

      15. Allow ABO and Rh testing on plateletpheresis donors to be performed every 90 days.

  15. 21 CFR 640.32(b):

      16. Relabel Fresh Frozen Plasma collected by apheresis as Recovered Plasma prior to expiration of the original product. (Done to manage Fresh Frozen Plasma inventory collected during periods of increased risk for West Nile Virus.)

  16. 21 CFR 640.34:

    1. Allow use of A and AB Fresh Frozen Plasma that was warmed to -4°C over an 18 hour time period, provided that safety, purity and potency were not affected and the consignee is notified of the temperature deviation. Relabeling or shortening of the expiration date is not required.

    2. Allow plasma manufactured from Whole Blood to be frozen within 24 hours after phlebotomy. Blood component must be labeled as “PLASMA Frozen within 24 Hours after Phlebotomy.”

    3. Allow use of 45 units of Fresh Frozen Plasma that were exposed to temperatures between -6°C and -18°C for a total of 4.5 hours, provided the blood components remained frozen during the whole time period.

    4. Allow distribution of 1,201 units of Fresh Frozen Plasma and 395 units of Plasma Cryoprecipitate Reduced that were exposed to temperatures between -16.4°C and -18°C for a total of 1.5 hours, provided the blood components remained frozen during the whole time period.

  17. 21 CFR 640.34 & 640.54(a):

    1. Allow distribution of 1,235 units of Fresh Frozen Plasma and 963 units of Plasma Cryoprecipitate Reduced and prepare Cryoprecipitated AHF from 1,531 units Cryoprecipitate rich plasma that were exposed to temperatures between -11.8°C and -18°C for a total of 5.5 hours, provided the blood components remained frozen during the whole time period.

    2. b. Allow distribution of Fresh Frozen Plasma, Plasma frozen within 24 hours, Plasma Cryoprecipitate Reduced, Cryoprecipitated AHF and Cryoprecipitate rich plasma that were exposed to storage temperatures between –10.1°C and –18°C during 2 excursions over 2 days for a total of 3 hours 18 minutes, provided the safety, purity, or potency of the components was not affected.

  18. 21 CFR 640.61, 640.62, & 640.63:

    1. Permit trained staff to explain the hazards of plasmapheresis and obtain informed consent.

    2. Allow physician substitutes to perform some of the duties of a physician (i.e., physical examinations of Source Plasma donors) and to approve physician substitute training programs.

  19. 21 CFR 640.63:

    1. Draw one donor with a rare red blood cell antibody who was Anti-HCV positive.

    2. Draw a donor with IgM Anti-HAV with a disease state program approval.

    3. Allow plasmapheresis of an asymptomatic donor with a history of Lyme Disease, provided product is labeled that it was collected from donor with history of Lyme Disease.

    4. Allow a donor with a slightly abnormal Serum Protein Electrophoresis to donate for an Infant Botulism Program.

    5. Allow individuals with childhood history of hepatitis at age 10 or younger to donate. [Regulation revised - variance request no longer needed]

    6. Allow Source Plasma to be collected from a specific anti-e donor whose weight fluctuates between 108-112 lbs to donate, provided the weight does not drop below 108 at time of donation and donor meets all other eligibility requirements.

  20. 21 CFR 640.65:

    1. Allow an infrequent plasmapheresis program in Source Plasma facilities. Donors may donate without a physical examination or Serum Protein Electrophoresis.

    2. Allow collection of Source Plasma from anti-HCV reactive donors with elevated SPE results (no more than 25% over normal limits established by testing lab), provided the donor’s personal physician has given written approval.

  21. 21 CFR 640.66:

      22. Allow a physician substitute to schedule Tetanus Toxoid injections and review responses of donors immunized with licensed vaccines. The center physician must still do weekly evaluation of records.

  22. 21 CFR 640.76:

    1. Allow Source Plasma exposed to more than one episode of storage temperature fluctuations warmer than -20°C and colder than -5°C for less than 72 total hours to not be relabeled as “Source Plasma, Salvaged,” provided the plasma was not allowed to thaw and the consignee is notified of the temperature deviations.

    2. Allow a revised procedure for labeling shipments of Source Plasma, Salvaged. Instead of labeling each unit, the facility may mark "Source Plasma, Salvaged" on the shipping cartons and packing slips.

    3. Allow 600 L. of Source Plasma stored at temperatures ranging from -20°C to +19°C for 3 1/2 hours to be relabeled as “Source Plasma, Salvaged.”

    4. Allow 53 units of Source Plasma intended for further manufacture into injectable products, that were stored at 14°C to be relabeled for further manufacture into noninjectable products, provided that label states that it was stored at 14°C.

  23. 21 CFR 660.22 & 660.28:

    1. Use FTA-ABS methodology as an alternative procedure to quantitative RPR testing on samples with a qualitative reactive RPR test for syphilis.

    2. Use an alternate procedure to perform FDA required tests for lot release action on bulk product prior to filling final containers for red blood cell antigen phenotyping reagents and Anti-Human Globulin reagents.

  24. 21 CFR 660.28:

      25. Allow the use of existing labels for blood grouping reagents, pending reprinting of corrected labels.

 

Updated November 5, 2004
 
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