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[Federal Register: January 10, 2001 (Volume 66, Number 7)]
[Rules and Regulations]
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[DOCID:fr10ja01-8]
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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outdated requirements.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
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21 CFR Section Action
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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
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21 CFR Section Action
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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 Rho variant
(Du) and for other Rh-Hr factors. Blood may be labeled ``Rh
Negative'' if negative to tests for the Rho (D) and
Rho variant (Du) factors. If the test using Anti-
D Blood Grouping Reagent is negative, but not tested for the
Rho variant (Du), 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