[Federal Register Volume 66, Number 7 (Wednesday, January 10, 2001)]
[Rules and Regulations]
[Pages 1834-1837]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-533]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 606 and 640

[Docket No. 98N-0673]


Revisions to the Requirements Applicable to Blood, Blood 
Components, and Source Plasma; Confirmation in Part and Technical 
Amendment

AGENCY: Food and Drug Administration, HHS.

ACTION: Direct final rule; confirmation in part and technical 
amendment.

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SUMMARY: The Food and Drug Administration (FDA) is confirming in part 
the direct final rule issued in the Federal Register of August 19, 
1999. The direct final rule amends the biologics regulations by 
removing, revising, or updating specific regulations applicable to 
blood, blood components, and Source Plasma to be more consistent with 
current practices in the blood industry and to remove unnecessary or 
outdated requirements. FDA is confirming the provisions for which no 
significant adverse comments were received. The agency received 
significant adverse comments on certain provisions and is amending 
Title 21 Code of Federal Regulations to reinstate the former 
provisions.

DATES: The effective date for the amendments to the sections published 
in the Federal Register of August 19, 1999 (64 FR 45366), and listed in 
table 1 of this document, is confirmed as February 11, 2000. The 
amendments listed in table 2 of this document are effective January 10, 
2001.

FOR FURTHER INFORMATION CONTACT: Joseph L. Okrasinski, Center for 
Biologics Evaluation and Research (HFM-17), Food and Drug 
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448, 301-827-6210.

SUPPLEMENTARY INFORMATION: Written comments concerning the direct final 
rule were to be submitted on or before December 3, 1999. FDA stated 
that the effective date of the direct final rule would be February 11, 
2000. If no timely significant comments were submitted to FDA during 
the comment period, FDA intended to publish a document in the Federal 
Register within 30 days after the comment period ended, confirming the 
effective date of the final rule. If timely significant comments were 
received, the agency intended to publish a document in the Federal 
Register withdrawing the direct final rule before its effective date. 
Because of complex issues related to this rulemaking and because of 
competing priorities, FDA did not issue a document either confirming or 
withdrawing the direct final rule before its effective date. Therefore 
the Code of Federal Regulations was revised as of April 1, 2000, to 
codify the regulations in the direct final rule.
    The agency received significant comments to the docket. If a 
significant adverse comment applies to an amendment, paragraph, or 
section of the rule and that provision can be severed from the 
remainder of the rule, FDA may adopt as final those provisions of the 
rule that are not subjects of significant adverse comments.
    Thus, FDA is confirming in part the direct final rule (sections 
listed in table 1 of this document) effective February 11, 2000.
    The agency is making technical amendments to 21 CFR 640.25(c), 
640.56(c), and 640.71(a) by replacing ``Clinical Laboratories 
Improvement Act of 1967 (CLIA)'' with ``Clinical Laboratories 
Improvement Amendments of 1988 (CLIA).'' This action is necessary for 
consistency when referring to CLIA in the regulations.

                                Table 1.--Amendments Effective February 11, 2000
----------------------------------------------------------------------------------------------------------------
                 21 CFR Section                                               Action
----------------------------------------------------------------------------------------------------------------
606.3(c), (e), and (f).........................                                                         Revised
606.100(b) and (d).............................                                       Revised introductory text
606.100(b)(7) and (b)(18)......................                                                         Revised
606.121(a), (d)(2), and (e)(1)(ii).............                                                         Revised
606.122(f) and (n)(4)..........................                                                         Revised
606.151(e).....................................                                                         Revised
606.160(b)(2)(v)...............................                                                         Revised
606.170(b).....................................                                                         Revised
640.2(b) and (d)...............................                                                         Removed
640.2(c), (e), and (f).........................                               Redesignated as (b), (c), and (d)
640.2(c)(2)....................................                                                         Revised
640.3(b).......................................                                       Revised introductory text
640.3(b)(3), (c)(2), and (c)(3)................                                                         Revised
640.3(e).......................................                                            Removed and reserved
640.4(d)(1) through (d)(4), and (h)............                                                         Removed
640.4(i).......................................                                   Redesignated as paragraph (h)
640.4(b) and (d)...............................                                                         Revised
640.6(c).......................................                                                         Removed
640.13(a)......................................                                                         Revised
640.16(b)......................................                                                         Revised
640.22(a)......................................                                                         Revised
640.25(c)......................................                                             Nomenclature change
640.31(c)......................................                                                         Removed

[[Page 1835]]

 
640.32(a)......................................                                                         Revised
640.34(e)(2), (e)(3), and (g)(2)...............                                                         Revised
640.51(c)......................................                                                         Removed
640.52(a)......................................                                                         Revised
640.56(c)......................................                                             Nomenclature change
640.63(c)(3), (c)(5), (c)(12), and (c)(13).....                                                         Revised
640.65(b)(4) and (b)(5)........................                                                         Revised
640.65(b)(8)...................................                                                           Added
640.69(d)......................................                                                         Revised
640.71(a)......................................                                             Nomenclature change
640.72(a)(1)...................................                                                         Revised
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    FDA received significant adverse comments on certain provisions of 
the rule, listed in table 2 of this document. Accordingly in this 
rulemaking, because these provisions became effective on February 11, 
2000, the agency is amending these sections identified in table 2 of 
this document to reinstate the former provisions.

                                 Table 2.--Amendments Effective January 10, 2001
----------------------------------------------------------------------------------------------------------------
                 21 CFR Section                                               Action
----------------------------------------------------------------------------------------------------------------
606.3(j).......................................                                                         Revised
606.151(b) and (c).............................                                                         Revised
640.2(b).......................................                                                         Revised
640.3(c)(1)....................................                                                         Revised
640.4(g).......................................                                       Revised introductory text
640.4(g)(1), (g)(2), (g)(4), and (g)(5)........                                                         Revised
640.5..........................................                                       Revised introductory text
640.5(c).......................................                                                         Revised
640.15.........................................                                                         Revised
640.16(a)......................................                                                         Revised
640.23(a)......................................                                                         Revised
640.24(b)......................................                                                         Revised
640.25(c) introductory text....................                                                         Amended
640.34(a) through (e)(1).......................                                                         Revised
640.54(a)(2)...................................                                                         Revised
640.56(c) introductory text....................                                                         Revised
640.62.........................................                                                         Revised
640.63(c)(11)..................................                                                         Revised
640.71(a)......................................                                                         Amended
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    Comments received by the agency regarding the reinstated portions 
of the rule will be applied to the corresponding portion of the 
companion proposed rule (64 FR 45375, August 19, 1999), and will be 
considered in developing a final rule using the usual Administrative 
Procedure Act notice and comment procedures.

List of Subjects

21 CFR Part 606

    Blood, Labeling, Laboratories, Reporting and recordkeeping 
requirements.

21 CFR Part 640

    Blood, Labeling, Reporting and recordkeeping requirements.


    Therefore under the Federal Food, Drug, and Cosmetic Act, the 
Public Health Service Act, and authority delegated by the Commissioner 
of Food and Drugs, the direct final rule published on August 19, 1999 
(64 FR 45366), is confirmed in part and 21 CFR parts 606 and 640 are 
amended as follows:

PART 606--CURRENT GOOD MANUFACTURING PRACTICE FOR BLOOD AND BLOOD 
COMPONENTS

    1. The authority citation for 21 CFR part 606 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360j, 371, 
374; 42 U.S.C. 216, 262, 263a, 264.


    2. Section 606.3 is amended by revising paragraph (j) to read as 
follows:


Sec. 606.3  Definitions.

* * * * *
    (j) Compatibility testing means the in vitro serological tests 
performed on donor and recipient blood samples to establish the 
serological matching of a donor's blood or blood components with that 
of a potential recipient.

    3. Section 606.151 is amended by revising paragraphs (b) and (c) to 
read as follows:


Sec. 606.151  Compatibility testing.

* * * * *
    (b) The use of fresh recipient serum samples less than 48 hours old 
for all pretransfusion testing.
    (c) The testing of the donor's cells with the recipient's serum 
(major crossmatch) by a method that will demonstrate agglutinating, 
coating, and hemolytic antibodies, which shall include the antiglobulin 
method.
* * * * *

PART 640--ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS

    4. The authority citation for 21 CFR part 640 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 
U.S.C. 216, 262, 263, 263a, 264.


[[Page 1836]]



    5. Section 640.2 is amended by revising paragraph (b) to read as 
follows:


Sec. 640.2  General requirements.

* * * * *
    (b) Final container. The original blood container shall be the 
final container and shall not be entered prior to issue for any purpose 
except for blood collection. Such container shall be uncolored and 
transparent to permit visual inspection of the contents and any closure 
shall be such as will maintain an hermetic seal and prevent 
contamination of the contents. The container material shall not 
interact with the contents under customary conditions of storage and 
use, in such a manner as to have an adverse effect upon the safety, 
purity, or potency of the blood.
* * * * *

    6. Section 640.3 is amended by revising paragraph (c)(1) to read as 
follows:


Sec. 640.3  Suitability of donor.

* * * * *
    (c) * * *
    (1) A history of viral hepatitis;
* * * * *

    7. Section 640.4 is amended by revising the introductory text of 
paragraph (g) and by revising paragraphs (g)(1), (g)(2), (g)(4) and 
(g)(5) to read as follows:


Sec. 640.4  Collection of the blood.

* * * * *
    (g) Pilot samples for laboratory tests. Pilot samples for 
laboratory tests shall meet the following standards:
    (1) One or more pilot samples shall be provided with each unit of 
blood when issued or reissued except as provided in Sec. 640.2(c)(2) 
and all pilot samples shall be from the donor who is the source of the 
unit of blood.
    (2) All samples for laboratory tests performed by the manufacturer 
and all pilot samples accompanying a unit of blood shall be collected 
at the time of filling the final container by the person who collects 
the unit of blood.
* * * * *
    (4) All containers for pilot samples accompanying a unit of blood 
shall be attached to the whole blood container before blood collection 
in a tamperproof manner that will conspicuously indicate removal and 
reattachment.
    (5) When CPDA-1 is used, pilot samples for compatibility testing 
shall contain blood mixed with CPDA-1.
* * * * *

    8. Section 640.5 is amended by revising the introductory text and 
paragraph (c) to read as follows:


Sec. 640.5  Testing the blood.

    All laboratory tests shall be made on a pilot sample specimen of 
blood taken from the donor at the time of collecting the unit of blood, 
and these tests shall include the following:
* * * * *
    (c) Determination of the Rh factors. Each container of Whole Blood 
shall be classified as to Rh type on the basis of tests done on the 
pilot sample. The label shall indicate the extent of typing and the 
results of all tests performed. If the test, using Anti-D Blood 
Grouping Reagent, is positive, the container may be labeled ``Rh 
Positive''. If this test is negative, the results shall be confirmed by 
further testing which may include tests for the Rh<INF>o</INF> variant 
(D<SUP>u</SUP>) and for other Rh-Hr factors. Blood may be labeled ``Rh 
Negative'' if negative to tests for the Rh<INF>o</INF> (D) and 
Rh<INF>o</INF> variant (D<SUP>u</SUP>) factors. If the test using Anti-
D Blood Grouping Reagent is negative, but not tested for the 
Rh<INF>o</INF> variant (D<SUP>u</SUP>), the label must indicate that 
this test was not done. Only Anti-Rh Blood Grouping Reagents licensed 
under, or that otherwise meet the requirements of, the regulations of 
this subchapter shall be used, and the technique used shall be that for 
which the serum is specifically designed to be effective.
* * * * *

    9. Section 640.15 is revised to read as follows:


Sec. 640.15  Pilot samples.

    Pilot samples collected in integral tubing or in separate pilot 
tubes shall meet the following standards:
    (a) One or more pilot samples of either the original blood or of 
the Red Blood Cells being processed shall be provided with each unit of 
Red Blood Cells when issued or reissued.
    (b) Before they are filled, all pilot sample tubes shall be marked 
or identified so as to relate them to the donor of that unit of red 
cells.
    (c) Before the final container is filled or at the time the final 
product is prepared, the pilot sample tubes to accompany a unit of 
cells shall be attached securely to the final container in a tamper 
proof manner that will conspicuously indicate removal and reattachment.
    (d) All pilot sample tubes accompanying a unit of Red Blood Cells 
shall be filled at the time the blood is collected or at the time the 
final product is prepared, in each instance by the person who performs 
the collection or preparation.

    10. Section 640.16 is amended by revising paragraph (a) to read as 
follows:


Sec. 640.16  Processing.

    (a) Separation. Within 21 days from date of blood collection 
(within 35 days from date of blood collection when CPDA-1 solution is 
used as the anticoagulant), Red Blood Cells may be prepared either by 
centrifugation done in a manner that will not tend to increase the 
temperature of the blood or by normal undisturbed sedimentation. A 
portion of the plasma sufficient to insure optimal cell preservation 
shall be left with the red blood cells except when a cryoprotective 
substance is added for prolonged storage.
* * * * *

    11. Section 640.23 is amended by revising paragraph (a) to read as 
follows:


Sec. 640.23  Testing the blood.

    (a) Blood from which plasma is separated for the preparation of 
Platelets shall be tested as prescribed in Secs. 610.40 and 610.45 of 
this chapter and Sec. 640.5 (a), (b), and (c).
* * * * *

    12. Section 640.24 is amended by revising paragraph (b) to read as 
follows:


Sec. 640.24  Processing.

* * * * *
    (b) Immediately after collection, the whole blood or plasma shall 
be held in storage between 20 and 24  deg.C, unless it must be 
transported from the donor clinic to the processing laboratory. During 
such transport, all reasonable methods shall be used to maintain the 
temperature as close as possible to a range between 20 and 24  deg.C 
until it arrives at the processing laboratory where it shall be held 
between 20 and 24  deg.C until the platelets are separated. The 
platelet concentrate shall be separated within 4 hours after the 
collection of the unit of whole blood or plasma.
* * * * *


Sec. 640.25  [Amended]

    13. Section 640.25 General requirements is amended in the 
introductory text of paragraph (c) by removing ``Clinical Laboratories 
Improvement Act of 1967'' and by adding in its place ``Clinical 
Laboratories Improvement Amendments of 1988.''

    14. Section 640.34 is amended by revising paragraphs (a) through 
(e)(1) to read as follows:


Sec. 640.34  Processing.

    (a) Plasma. Plasma shall be separated from the red blood cells 
within 26 days after phlebotomy (within 40 days after phlebotomy when 
CPDA-1 solution is used as the anticoagulant), and shall be

[[Page 1837]]

stored at -18  deg.C or colder within 6 hours after transfer to the 
final container, unless the product is to be stored as Liquid Plasma.
    (b) Fresh Frozen Plasma. Fresh Frozen Plasma shall be prepared from 
blood collected by a single uninterrupted venipuncture with minimal 
damage to and minimal manipulation of the donor's tissue. The plasma 
shall be separated from the red blood cells, frozen solid within 6 
hours after phlebotomy and stored at -18  deg.C or colder.
    (c) Liquid Plasma. Liquid Plasma shall be separated from the red 
blood cells within 26 days after phlebotomy (within 40 days after 
phlebotomy when CPDA-1 solution is used as the anticoagulant), and 
shall be stored at a temperature of 1 to 6  deg.C within 4 hours after 
filling the final container.
    (d) Platelet Rich Plasma. Platelet Rich Plasma shall be prepared 
from blood collected by a single uninterrupted venipuncture with 
minimal damage to and manipulation of the donor's tissue. The plasma 
shall be separated from the red blood cells by centrifugation within 4 
hours after phlebotomy. The time and speed of centrifugation shall have 
been shown to produce a product with at least 250,000 platelets per 
microliter. The plasma shall be stored at a temperature between 20 to 
24  deg.C or between 1 and 6  deg.C, immediately after filling the 
final container. A gentle and continuous agitation of the product shall 
be maintained throughout the storage period, if stored at a temperature 
of 20 to 24  deg.C.
    (e) Modifications of Plasma. It is possible to separate Platelets 
and/or Cryoprecipitated AHF from Plasma. When these components are to 
be separated, the plasma shall be collected as described in Sec. 640.32 
for Plasma.
    (1) Platelets shall be separated as prescribed in subpart C of part 
640, prior to freezing the plasma. The remaining plasma may be labeled 
as Fresh Frozen Plasma, if frozen solid within 6 hours after 
phlebotomy.
* * * * *

    15. Section 640.54 is amended by revising paragraph (a)(2) to read 
as follows:


Sec. 640.54  Processing.

    (a) * * *
    (2) The plasma shall be frozen solid within 6 hours after blood 
collection. A combination of dry ice and organic solvent may be used 
for freezing: Provided, That the procedure has been shown not to cause 
the solvent to penetrate the container or leach plasticizer from the 
container into the plasma.
* * * * *


Sec. 640.56  [Amended]

    16. Section 640.56 Quality control test for potency is amended in 
the introductory text of paragraph (c) by removing ``Clinical 
Laboratories Improvement Act of 1988'' and by adding in its place 
``Clinicial Laboratories Improvement Amendments of 1988''.

    17. Section 640.62 is revised to read as follows:


Sec. 640.62  Medical supervision.

    A qualified licensed physician shall be on the premises when donor 
suitability is being determined, immunizations are being made, whole 
blood is being collected, and red blood cells are being returned to the 
donor.

    18. Section 640.63 is amended by revising paragraph (c)(11) to read 
as follows:


Sec. 640.63  Suitability of donor.

* * * * *
    (c) * * *
    (11) Freedom from a history of viral hepatitis;
* * * * *


Sec. 640.71  [Amended]

    19. Section 640.71 Manufacturing responsibility is amended in the 
introductory text of paragraph (a) by removing ``Clinical Laboratories 
Improvement Act of 1988'' and by adding in its place ``Clinicial 
Laboratories Improvement Amendments of 1988''.

    Dated: December 29, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 01-533 Filed 1-9-01; 8:45 am]
BILLING CODE 4160-01-F