[Printable PDF]
[Federal Register: August 6, 2001 (Volume 66, Number 151)]
[Rules and Regulations]
[Page 40886-40890]
From the Federal Register Online via GPO Access [wais.access.gpo.gov] [DOCID:fr06au01-19]
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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
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending 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remove unnecessary or outdated requirements.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 issuing this final
rule as part of the agency's ``Blood Initiative'' in which FDA is
reviewing and revising, when appropriate, its regulations, policies,
guidance, and procedures related to blood, blood components, and Source
Plasma.
DATES: This rule is effective September 5, 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:
I. Background
In the Federal Register of August 19, 1999 (64 FR 45375), FDA
published a proposed rule to amend the biologics regulations by
removing, revising, or updating specific regulations applicable to
blood, blood components, and Source Plasma. The proposed rule was
intended to make the regulations more consistent with current practices
in the blood industry and to remove unnecessary or outdated
requirements. The proposed rule was a companion document to a direct
final rule published in the Federal Register of August 19, 1999 (64 FR
45366). Written comments 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, unless any significant adverse comment was
submitted to FDA during the comment period. 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.
Eight letters of comment were submitted to the docket. After
reviewing the comments, the agency issued in the Federal Register on
January 10, 2001 (66 FR 1834), a confirmation in part of the direct
final rule and technical amendment which confirmed the effective date
of February 11, 2000, for those provisions that did not receive
[[Page 40887]]
significant comment and a technical amendment which reinstated the
former provisions that received significant adverse comments. The
document also made editorial corrections to the regulations.
II. Comments on the Proposed Rule and FDA Responses
FDA received eight letters of comment on the proposed rule. The
comments were submitted by manufacturers, blood establishments, trade
associations, and individuals. Two of the eight comments specifically
supported FDA's goal of removing, revising, or updating the specific
regulations to be more consistent with current practices in the blood
industry. Each of the eight comments submitted recommended changes to
certain provisions of the rule. FDA summarizes and responds to the
received comments in the following section.
A. Compatibility Testing (Proposed Secs. 606.3(j) and 606.151(c))
The proposed rule would amend the sections by removing the
reference to serological tests and making the definition more general
to apply to all tests performed, including computer crossmatching to
establish the matching of a donor's blood or blood components with that
of a recipient.
(Comment 1) One comment on Sec. 606.3(j) suggested that the
proposed term "tests performed" be changed to another term such as
"procedures performed." Another comment noted that the same
terminology occurs in Sec. 606.151(c) and suggested that the phrase be
changed to "Procedures to demonstrate incompatibility between the
donor's cell type and the recipient's serum type."
FDA agrees that the use of the proposed term "tests performed" in
Secs. 606.3(j) and 606.151(c) should be clarified. The use of the term
"tests performed" could be interpreted to not allow for computer
crossmatching. Therefore, FDA is amending these sections in the final
rule. Section 606.3(j) will define compatibility testing to mean
"procedures performed to establish the matching of a donor's blood or
blood components with that of a potential recipient" and
Sec. 606.151(c) will require standard operating procedures for
compatibility testing to include "procedures to demonstrate
incompatibility between the donor's cell type and the recipient's serum
or plasma type."
B. Use of Serum or Plasma for Compatibility Testing (Proposed
Sec. 606.151(b) and (c))
The proposed rule would amend these sections to be more consistent
with current practices with respect to compatibility testing.
(Comment 2) Two comments on Sec. 606.151(b) and (c) stated that the
use of either serum or plasma should be permitted for compatibility
testing/pretransfusion testing, as the use of plasma samples is not
uncommon for some tests.
FDA agrees with the comment and has made the appropriate changes in
the final rule to Sec. 606.151(b) and (c).
C. Entering Blood Containers Prior to Issue (Proposed Sec. 640.2)
The proposed rule would amend the section to be consistent with
current practices with regard to entering containers of blood and blood
components prior to issue.
(Comment 3) One comment on proposed Sec. 640.2 requested
clarification of the proposed language that "blood containers shall
not be entered prior to issue for any purpose except for blood
collection." The comment asked if FDA intends to preclude activities
such as filtering to make a unit leukoreduced, washing to make a unit
IgA deficient, splitting to make a unit appropriate for a transfusion
to a neonate, and pooling of platelets or cryoprecipitate since all
these procedures involved entering the unit for special processing.
FDA does not intend to preclude activities such as those described
in the comment, and is revising the first sentence in Sec. 640.2(b) of
the final rule to read "[T]he blood container shall not be entered
prior to issue for any purpose except for blood collection or if the
method of processing requires the use of a different container."
D. History of Hepatitis (Proposed Secs. 640.3(c)(1) and 640.63(c)(11))
The proposed rule would amend these sections to specify that donors
who have a history of hepatitis before the age of 11 could be eligible
to be donors of Whole Blood or Source Plasma. The proposed change is
consistent with current FDA recommendations in the FDA memorandum dated
April 23, 1992, entitled "Exemptions to Permit Persons With a History
of Viral Hepatitis Before the Age of Eleven to Serve as Donors of Whole
Blood and Plasma: Alternative Procedure."
(Comment 4) One comment on proposed Secs. 640.3(c)(1) and
640.63(c)(11) stated that reference is made to a person with a history
of hepatitis "after the age of eleven" and that the meaning of
"after the age of eleven" is unclear and needs further clarification.
FDA agrees and is changing the phrase to "after the eleventh
birthday" for clarification in both sections.
E. Samples and Segments (Proposed Secs. 640.4(g) and 640.15)
The proposed rule would amend these sections with regard to use of
current terminology for test specimens.
(Comment 5) One comment stated that the proposed change of
terminology from "pilot tubes," "pilot sample tubes," and "pilot
samples," to "samples" and "segments" in Secs. 640.4(g) and 640.15
is confusing. The comment also asked if FDA meant to imply that
"segment identification" must occur and if this excludes the more
critical sample identification that must occur at the time of the
collection of the unit.
FDA is not implying any procedural changes by changing the phrases
"pilot tubes" and "pilot sample tubes" to "samples" and the
phrase "pilot samples" to "segments." FDA is making the changes as
proposed, to reflect current terminology used for test specimens. The
proposed headings and introductory text for Secs. 640.4(g) and 640.15
are revised in the final rule to be consistent with the terminology
change.
F. Rh Factor Terminology (Proposed Sec. 640.5)
The proposed rule would amend the section to be more consistent
with current terminology used in the determination of the Rh factors.
(Comment 6) One comment stated that in Sec. 640.5 the use of the
term "D\u\" is inappropriate as the term "weak D" is currently
accepted and reflects the significant changes in Anti-D reagents over
the past years.
FDA agrees with the comment and is replacing the term "Rho
"variant (D\u\)" with the term "weak D (formerly D\u\)."
G. Specified Timeframes for Component Preparation (Proposed Secs.
640.16(a), 640.24(b), 640.34(a) through (d) and (e)(1), and
640.54(a)(2))
The proposed rule would amend these sections by changing the
specific timeframes prescribed for certain practices and procedures in
component preparation. The proposed changes would allow more
flexibility by permitting different timeframes depending upon the
directions for use of the particular blood collection device (blood
collecting, processing, and storage system) being used.
[[Page 40888]]
(Comment 7) Four comments requested clarification of the phrase
"within the timeframe specified in the directions for use for the
specific device." (See proposed Secs. 640.16(a), 640.24(b), 640.34(a)
through (d) and (e)(1), and 640.54(a)(2).) One comment stated that due
to the solution components, the blood collection bags (or systems) are
approved for use as "drugs" not "devices." The comment requested
clarification as to whether the proposed rule is applicable to blood
collecting, processing, and storage systems approved as "drugs."
Another comment stated that manufacturers would now be required to
include information concerning specified timeframes in their product
labeling. Two comments requested that the current language be retained
for the most part by keeping the present timeframes but that some added
flexibility could be allowed by adding the phrase "or within the
timeframe specified in the directions for use of the specific device."
The concern was that few, if any, manufacturers include this time
period in their labeling and choose instead to refer to the regulations
as well as industry standards. Another comment stated that the proposed
rule as written would remove from 21 CFR part 640 detailed requirements
for manufacturing blood components, and as a result these would be
required as part of the drug or device product labels. The comment also
stated that to add the detailed requirements to the drug or device product
labels would be burdensome on manufacturers of manual blood
collecting, processing, and storage systems, and it would take 2 to 3
years to exhaust existing product inventories and make appropriate
changes.
FDA agrees that the use of the word "device" in the phrase
"within the timeframe specified in the directions for use for the
specific device" is inadequate and confusing in describing the blood
collecting, processing, and storage system (or blood bag). The use of
the word "device" is confusing because: (1) These systems are
approved as "drugs" due to the solution components, and (2) the
instructions for use are currently in the package inserts for the
approved systems. Therefore, FDA is replacing the word "device" used
in the proposed phrase with "blood collecting, processing, and storage
system" so that the revised phrase reads "within the timeframe
specified in the directions for use for the blood collecting,
processing, and storage system used." In response to the request for
flexibility, FDA is retaining where appropriate the specific timeframes
for component preparation, and adding the alternative phrase "within
the timeframe specified in the directions for use for the blood
collecting, processing, and storage system."
H. Reducing Repeat Testing in Plasmapheresis (Proposed Sec. 640.23(a))
The proposed rule would amend the section by reducing the
requirements for repeat testing of blood samples from donors
participating in frequent plateletpheresis collection procedures.
In Sec. 640.23(a) the agency proposed the revision "Results of
tests performed in accordance with Sec. 640.5(b) and (c) for Platelets,
Pheresis products shall be valid for a period not to exceed 3 months."
(Comment 8) One comment stated that this revision may introduce the
potential for error in that other tests, which should have been
performed, will inadvertently be omitted. Another comment stated that
with respect to the revision of Sec. 640.23(a), the rationale why ABO/Rh
testing is valid for only 3 months is not clear since donors do not
change blood type and that the testing is done only to confirm that
samples are from the correct donor.
After reviewing the comments, FDA recognizes that the issues
concerning this section are more complex than can be addressed in this
rule. Therefore, FDA is retaining the wording for this section as it is
currently written. If an establishment wishes to perform testing at
intervals other than those stated in the regulation, they may request a
variance for alternative testing under Sec. 640.120.
I. Timeframes for Freezing Plasma (Proposed Secs. 640.34(b) and 640.54(a)(2))
The proposed rule would amend the sections concerning the
timeframes for freezing plasma.
(Comment 9) Two comments on proposed Sec. 640.34(b) concern the use
of the term "frozen solid." The comments stated that use of the
proposed term "frozen solid" seems to imply that the FDA memorandum
of November 13, 1989, entitled "Eight-Hour Hold" would no longer be
in effect. The memorandum states that plasma should be placed in a
freezer within 8 hours.
FDA agrees with the comment and the term "frozen solid" is
replaced with the phrase "separated and placed in a freezer within 8
hours" in Sec. 640.34(b) and for consistency, in the standards for
cryoprecipitate in Sec. 640.54(a)(2).
J. Availability of a Qualified Licensed Physician (Proposed Sec. 640.62)
The proposed rule would require a qualified licensed physician to
be available on the premises or available to attend the donor within 15
minutes when certain procedures concerning blood and blood products are
performed.
(Comment 10) Five comments were submitted on the proposed revision
in Sec. 640.62 as to the availability of a licensed physician at a
collection facility. One comment said that the new section was
potentially confusing and compliance would be difficult at individual
blood collection centers and at mobile activities. A second comment
requested that "the services of a licensed physician" be changed to
"emergency medical services" since the ability to call 911 is usually
readily available. A third comment stated that the proposed rule did
not give any rationale for the specification of the time constraint nor
did the proposed rule define the phrase "available to attend" as
indicative that the physician was physically present or whether
telephone advice and consultation is authorized. A fourth comment
stated that potential donor safety concerns could be better served
through a requirement for documented standard operating procedures
within the donor center as outlined in Sec. 640.4(a) for the collection
of whole blood. A fifth comment applauded the fact that the agency
relaxed the requirement for the physical presence of a physician for
plasmapheresis, and the collection of Source Plasma.
Due to the variety of comments received on this section, FDA is
retaining the present language in Sec. 640.62 and intends to address
this requirement in a future rulemaking. Comments submitted concerning
this section will be considered at that time.
III. Analysis of Impacts
A. Review Under Executive Order 12866, the Regulatory Flexibility Act,
and the Unfunded Mandates Reform Act of 1995
FDA has examined the impact of the final rule under Executive Order
12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612) (as amended
by subtitle D of the Small Business Regulatory Fairness Act of 1996
(Public Law 104-121)), and the Unfunded Mandates Reform Act of 1995
(Public Law 104-4). Executive Order 12866 directs agencies to assess
all costs and benefits of available regulatory alternatives and, when
regulation is necessary, to select regulatory approaches that maximize
[[Page 40889]]
net benefits (including potential economic, environmental, public
health and safety, and other advantages; distributive impacts; and
equity). The agency believes that this final rule is consistent with
the regulatory philosopy and principles identified in the Executive
order. In addition, this final rule is not a significant regulatory
action as defined by the Executive order and so is not subject to
review under the Executive order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options to minimize any significant impact of a rule on
small business entities. Because the final rule amendments have no
compliance costs and do not result in any new requirements, the agency
certifies that the final rule will not have a significant negative
impact on a substantial number of small entities. Therefore under the
Regulatory Flexibility Act, no further analysis is required. This final
rule also does not trigger the requirement for a written statement
under section 202(a) of the Unfunded Mandates Reform Act because it
does not impose a mandate that results in an expenditure of $100
million or more by State, local, and tribal governments in the
aggregate, or by the private sector in any one year.
B. Environmental Impact
The agency has determined under 21 CFR 25.31(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
IV. Paperwork Reduction Act of 1995
FDA tentatively concludes that this final rule contains no
collections of information. Therefore, clearance by the Office of
Management and Budget under the Paperwork Reduction Act of 1995 is not
required.
V. Federalism
FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the rule
does not contain policies that have substantial direct effects on the
States, on the relationship between National Government and the States,
or on the distribution of power and responsibilities among the various
levels of government. Accordingly, the agency has concluded that the
rule does not contain policies that have federalism implications as
defined in that order and, consequently, a federalism summary impact
statement is not required.
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 under authority delegated by the
Commissioner of Food and Drugs, 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 procedures performed to
establish the 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 or plasma samples less than 3
days old for all pretransfusion testing if the recipient has been
pregnant or transfused within the previous 3 months.
(c) Procedures to demonstrate incompatibility between the donor's
cell type and the recipient's serum or plasma type.
* * * * *
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.
5. Section 640.2 is amended by revising paragraph (b) to read as
follows:
Sec. 640.2 General requirements.
* * * * *
(b) Blood container. The blood container shall not be entered prior
to issue for any purpose except for blood collection or when the method
of processing requires use of a different container. The 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 the 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 after the 11th birthday;
* * * * *
7. Section 640.4 is amended by revising the introductory text of
paragraph (g) and paragraphs (g)(1), (g)(2), (g)(4), and (g)(5) to read
as follows: Sec. 640.4 Collection of the blood.
* * * * *
(g) Samples and segments for laboratory tests. Samples and segments
for laboratory tests shall meet the following standards:
(1) One or more segments shall be provided with each unit of blood
when issued or reissued except as provided in Sec. 640.2(c)(2) and all
segments 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 segments accompanying a unit of blood shall be collected at the
time of filling the original blood container.
* * * * *
(4) All segments 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) Segments for compatibility testing shall contain blood mixed
with the appropriate anticoagulant.
* * * * *
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 specimen of blood taken
from the
[[Page 40890]]
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
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
the test is negative, the results shall be confirmed by further testing
which shall include tests for the "weak D (formerly D\u\)." Blood may
be labeled "Rh Negative" if further testing is negative. Units
testing positive after additional more specific testing shall be
labeled as "Rh Positive." Only Anti-Rh Blood Grouping Reagents
licensed under, or that otherwise meet the requirements of, this
subchapter shall be used, and the technique used shall be that for
which the reagent is specifically designed to be effective.
* * * * *
9. Section 640.15 is revised to read as follows:
Sec. 640.15 Segments for testing.
Segments collected in integral tubing shall meet the following
standards:
(a) One or more segments shall be provided with each unit of Whole
Blood or Red Blood Cells when issued or reissued.
(b) Before they are filled, all segments shall be marked or
identified so as to relate them to the donor of that unit of red cells.
(c) All segments 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.
10. Section 640.16 is amended by revising paragraph (a) to read as
follows:
Sec. 640.16 Processing.
(a) Separation. Within the timeframe specified in the directions
for use for the blood collecting, processing, and storage system used,
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 cells
except when a cryoprotective substance or additive solution is added
for prolonged storage.
* * * * *
11. 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 collection center 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 or within the
timeframe specified in the directions for use for the blood collecting,
processing, and storage system.
* * * * *
12. Section 640.34 is amended by revising paragraphs (a) through
(d) and (e)(1) to read as follows:
Sec. 640.34 Processing.
(a) Plasma. Plasma shall be separated from the red blood cells and
shall be stored at -18 deg.C or colder within 6 hours after transfer
to the final container or within the timeframe specified in the
directions for use for the blood collecting, processing, and storage
system 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, and placed in a freezer
within 8 hours or within the timeframe specified in the directions for
use for the blood collecting, processing, and storage system, and
stored at -18 deg.C or colder.
(c) Liquid Plasma. Liquid Plasma shall be separated from the red
blood cells and shall be stored at a temperature of 1 to 6 deg.C
within 4 hours after filling the final container or within the
timeframe specified in the directions for use for the blood collecting,
processing, and storage system.
(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 completion of the phlebotomy or within the timeframe
specified in the directions for use for the blood collecting,
processing, and storage system. The time and speed of the
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 and 24 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) * * *
(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 within 6 hours after filling the
final container or within the timeframe specified in the directions for
use for the blood collecting, processing, and storage system.
* * * * *
13. Section 640.54 is amended by revising paragraph (a)(2) to read
as follows:
Sec. 640.54 Processing.
(a) * * *
(2) The plasma shall be placed in a freezer within 8 hours after
blood collection or within the timeframe specified in the directions
for use for the blood collecting, processing, and storage system. 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.
* * * * *
14. 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 after the 11th
birthday;
* * * * *
Dated: June 29, 2001.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 01-19461 Filed 8-3-01; 8:45 am]
BILLING CODE 4160-01-S