[Printable PDF]
[Federal Register: August 19, 1999 (Volume 64, Number 160)]
[Proposed Rules]
[Page 45375-45382]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr19au99-36]
[[Page 45375]]
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; Companion Document to Direct Final Rule
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
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remove unnecessary or outdated requirements.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 taking this action
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.
This proposed rule is a companion document to the direct final rule
published elsewhere in this issue of the Federal Register. FDA is
publishing this companion proposed rule under FDA's usual procedure for
notice and comment to provide a procedural framework to finalize the
rule in the event the agency receives a significant adverse comment and
withdraws the direct final rule.
DATES: Submit written comments on or before December 3, 1999. If FDA
receives any significant adverse comment regarding this rule, FDA will
publish a document withdrawing the direct final rule within 30 days
after the comment period ends. FDA then will proceed to respond to the
comments under this proposed rule using the usual notice and comment
procedures. Any parties interested in commenting on this document
should do so at this time.
If FDA receives no significant adverse comments within the
specified comment period, the agency intends to publish a document
confirming the effective date of the final rule in the Federal Register
within 30 days after the comment period on the direct final rule ends.
The direct final rule will be effective February 11, 2000.
ADDRESSES: Submit written comments on the proposed rule to the Dockets
Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Dano B. Murphy, Center for Biologics
Evaluation and Research (HFM-17), Food and Drug Administration, 1401
Rockville Pike, Rockville, MD 20852-1448, 301-827-6210.
SUPPLEMENTARY INFORMATION:
I. Background
This proposed rule is a companion to the direct final rule
published in the final rules section of this issue of the Federal
Register. This companion proposed rule will provide the procedural
framework to finalize the rule in the event that the direct final rule
receives any adverse comment and is withdrawn. The comment period for
this companion proposed rule runs concurrently with the comment period
for the direct final rule. Any comments received under this companion
rule will also be considered as comments regarding the direct final
rule. FDA is publishing the direct final rule because the rule contains
noncontroversial changes, and FDA anticipates that it will receive no
significant adverse comment.
A significant comment is defined as a comment that explains why the
rule would be inappropriate, including challenges to the rule's
underlying premise or approach, or would be ineffective or unacceptable
without a change. In determining whether a significant adverse comment
is sufficient to terminate a direct final rulemaking, FDA will consider
whether the comment raises an issue serious enough to warrant a
substantive response in a notice-and-comment process. Comments that are
frivolous, insubstantial, or outside the scope of the rule will not be
considered significant or adverse under this procedure. A comment
recommending a rule change in addition to the rule would not be
considered a significant adverse comment, unless the comment states why
the rule would be ineffective without additional change. In addition,
if a significant adverse comment applies to an amendment, paragraph, or
section of this 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 a significant adverse comment.
If no significant adverse comment is received within the specified
comment period, FDA will publish a document within 30 days after the
comment period ends confirming that the direct final rule will be
effective February 11, 2000. Additional information about FDA's direct
rulemaking procedures is set forth in a guidance published in the
Federal Register of November 21, 1997 (62 FR 62466).
For a variety of reasons, FDA has decided to comprehensively review
and, as necessary, revise its regulations, policies, guidance, and
procedures related to the licensing and regulation of blood products.
FDA is issuing this companion proposed rule and the direct final rule,
published elsewhere in this issue of the Federal Register, 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. The
``Blood Initiative'' is discussed in detail in the preamble to the
direct final rule. FDA emphasizes that for many of the changes
discussed below, additional issues related to the regulations now being
amended continue to be under consideration by the agency. Further, more
substantive changes may be proposed at a later date. Accordingly, any
comment recommending an additional change to these regulations will not
be considered to be an ``adverse comment'' unless the comment
demonstrates that the change being made in the direct final rule
represents a major departure from current regulations or accepted
industry standards, or cannot be implemented without additional
amendments to the regulations.
II. Legal Authority
FDA is proposing to issue this new rule under the biological
product and communicable disease provisions of the Public Health
Service Act (the PHS Act) (42 U.S.C. 262-264) and the drug, device, and
general administrative provisions of the Federal Food, Drug, and
Cosmetic Act (the act) (21 U.S.C. 321, 331, 351-353, 355, 360, 360j,
371, and 374). Under these provisions of the PHS Act and the act, FDA
has the authority to issue and enforce regulations designed to ensure
that biological products are safe, pure, potent, and properly labeled
and to prevent the introduction, transmission, and spread of
communicable disease.
III. Highlights of the Proposed Rule
FDA is proposing to amend 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 and to remove unnecessary or outdated requirements. As,
previously discussed, FDA is also issuing these amendments as a direct
final rule because the agency
[[Page 45376]]
has concluded they are noncontroversial and that there is little
likelihood that there will be comments opposing the rule. FDA
emphasizes that for many of the changes discussed in this document,
additional issues related to the regulations now being amended continue
to be under consideration by the agency. Further, more substantive
changes may be proposed at a later date. Accordingly, any comment
recommending additional changes to these regulations will not be
considered to be an ``adverse comment'' unless the comment demonstrates
that the change being made in the direct final rule represents a major
departure from current regulations or accepted industry standards, or
cannot be implemented without additional amendments to the regulation.
Below FDA is identifying each of the changes included in the proposed
rule.
Part 606 (21 CFR part 606) would be amended as follows:
Section 606.3, Definitions, would be amended to update the
definitions provided in the section for consistency with current
practice and usages.
The definition of ``Component'' in proposed Sec. 606.3(c), would be
amended to clarify that blood is obtained from a single donor and would
no longer include the wording ``single-donor unit.'' This change is to
clarify that blood components may be collected by means other than
separation from a unit of whole blood, such as by automated
plasmapheresis.
The definition of ``Plasmapheresis'' in proposed Sec. 606.3(e),
would be amended by removing the restriction that plasmapheresis may be
``immediately repeated, once'' because current automated plasmapheresis
collection practices often use more than two cycles of collection.
The definition of ``Plateletpheresis'' in proposed Sec. 606.3(f)
would be amended to provide for the common practice of collecting
plasma as a by-product of a plateletpheresis procedure in lieu of
returning all of the residual plasma to the donor.
The definition of ``Compatibility testing'' in proposed
Sec. 606.3(j) would be amended by removing the reference to serological
tests and making the definition more general to apply to all tests
performed to establish the matching of a donor's blood or blood
components with that of a recipient. This change will provide for
current practices used in compatibility testing, such as the electronic
crossmatch and the immediate spin crossmatch.
Section 606.100(b) and (d) would be amended to reflect changes in
terminology, requirements for testing, and availability of standard
operating procedures (SOP's) to be consistent with current practices.
Section 606.100(b) would also be amended by removing the references to
homologous and autologous transfusion because subpart F of part 606
applies to all blood products intended for transfusion. In addition,
the phrase ``unless this is impractical'' would be removed because it
is current good manufacturing practice (CGMP) to make the applicable
SOP's available in all areas where procedures are performed. Section
606.100(b)(7) would be amended by removing ``including testing for
hepatitis B surface antigen as prescribed in Sec. 610.40 of this
chapter'' because other tests, in addition to tests for hepatitis B
surface antigen, are now required and specific reference to this test
is unnecessary. Section 606.100(b)(18) would be amended by removing the
bracketed term ``salvaged'' because its use in Sec. 606.100 is
inconsistent with the use of ``salvaged plasma'' in Sec. 640.76 (21 CFR
640.76). Section 606.100(d) would be amended by removing references to
specific organizations because any SOP's meeting FDA requirements would
be acceptable, regardless of their source, and because FDA cannot
assure that SOP's adopted by particular organizations remain in
compliance with FDA regulatory requirements.
Section 606.121(a) would be amended by removing the reference that
the ``Guideline for Uniform Labeling of Blood and Blood Components'' is
available from the Docket Management Branch as this is no longer the
appropriate office from which to request this document and by removing
the reference to the American Blood Commission because the organization
no longer exists.
Section 606.121(d)(2) specifies the color requirements for
printing the container label and would be amended by adding ``or in
solid black'' because some blood centers use on-demand printers for
printing labels that do not have the capability to print in multiple
colors.
Section 606.121(e)(1)(ii) prescribes the specific anticoagulants
that shall be identified on the container label. Section
606.121(e)(1)(ii) would be amended by removing the references to the
names of specific anticoagulants. This change will allow for more
flexibility for the acceptance and use of new anticoagulants or changes
in nomenclature of existing anticoagulants without requiring amendments
to the regulations.
Section 606.122(f) specifies the warning statement required in the
instruction circular and would be amended by removing the reference to
``hepatitis'' and adding ``infectious agents'' to include a reference
to the additional infectious disease marker tests routinely performed
on blood and blood components because the product intended for
transfusion carries the risk of transmitting other infectious agents.
Section 606.122(n)(4) specifies that the instruction circular for
cryoprecipitated AHF shall contain instructions to thaw the product at
a temperature of 37 deg.C and would be changed to allow instructions
for thawing between 30 and 37 deg.C, permitting more flexibility in
the preparation of the component.
Section 606.151(b) would be amended, consistent with current
accepted practices, to permit SOP's to include use of recipient serum
samples less than 3-days old for compatibility testing if the recipient
has been pregnant or transfused within the proceeding 3 months.
Section 606.151(c) describes compatibility testing and would be
amended by changing ``the testing of the donor's cells with the
recipient's serum'' to ``the testing of the donor's cell type with the
recipient's serum type'' and by replacing ``agglutinating, coating, and
hemolytic antibodies, which shall include the antiglobulin method''
with ``incompatibility.'' This change is intended to accommodate the
use of such procedures as an immediate spin crossmatch and an
electronic crossmatch.
Section 606.151(e) would be amended by changing ``by the physician
requesting the procedure'' to ``by a physician'' to take into account
that a patient may have more than one physician in attendance at any
time.
Section 606.160(b)(2)(v) would be amended by changing ``person(s)
responsible'' to ``the person(s) performing the procedure'' to clarify
that the person(s) performing the labeling procedure is responsible for
documenting the performance of that procedure.
Section 606.170(b) would be amended by removing ``telegraph'' and
adding ``facsimile, express mail, or electronically transmitted mail''
to the possible methods by which the Director, Office of Compliance and
Biologics Quality, Center for Biologics Evaluation and Research, shall
be notified of a complication of blood collection or transfusion
resulting in a fatality.
Part 640 (21 CFR part 640) would be amended as follows:
Section 640.2(b) would be removed because Whole Blood collection
in open systems is no longer acceptable or has
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it being performed for many years. Section 640.2(d) is removed. In
Sec. 640.2 paragraphs (c), (e), and (f) would be redesignated as
paragraphs (b), (c), and (d), respectively. Redesignated paragraphs (b)
and (c)(2) would be revised by removing references to the original
blood container because, to be consistent with current accepted
practices such as washing, freezing, deglycerolization, and division of
units using sterile connecting devices, the original blood container
may, in many cases, no longer be the final container.
Section 640.3(b) would be amended by adding a reference to
autologous donations to permit the collection of autologous Whole Blood
at intervals of less than 8 weeks, consistent with the current practice
of shorter time intervals between collections of blood and blood
components from donors participating in autologous collection programs.
Section 640.3(b)(3) would be amended to provide hematocrit and
hemoglobin values to be used when determining whether a potential donor
can donate Whole Blood, by adding to the end of the current paragraph
``or a hematocrit value of 38 percent, and for autologous donations, a
blood hemoglobin level which shall be demonstrated to be no less than
11.0 g of hemoglobin per 100 mL of blood or a hematocrit value of 33
percent.'' The acceptable hemoglobin and hematocrit values for
autologous donors are consistent with current industry practice and the
American Association of Blood Banks technical manual, 12th edition.
Sections 640.3(c)(1) and 640.63(c)(11) would be amended by
inserting ``after the age of eleven'' after the term ``hepatitis''
because establishments may collect Whole Blood from donors who have a
history of hepatitis prior to age eleven to be consistent with
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'' (21 CFR 640.120). Additional issues concerning
donors who have a history of viral hepatitis continued to be reviewed
by the agency and may be addressed in future rulemaking objectives.
Sections 640.3(c)(2) and 640.63(c)(12) would be amended by
changing the deferral period for donors of Whole Blood who have had
close contact with an individual having viral hepatitis from ``six
months'' to ``12 months.'' Similarly, Secs. 640.3(c)(3) and
640.63(c)(13) would be amended by changing the deferral period from
``six months'' to ``12 months'' for donors of Whole Blood who received
human blood, or any derivative of human blood which the Food and Drug
Administration has identified as a possible source of viral hepatitis.
These changes are consistent with recommendation made in the FDA
memoranda dated April 23, 1992, entitled ``Revised Recommendations for
the Prevention of Human Immunodeficiency Virus Transmission by Blood
and Blood Products and Revised Recommendations for Testing Whole Blood,
Blood Components, Source Plasma and Source Leukocytes for Antibody to
Hepatitis C Virus Encoded Antigen (Anti-HCV).'' In addition,
Secs. 640.3(c)(3) and 640.63(c)(13) would be amended by changing the
reference from a ``licensed establishment'' to a ``blood
establishment'' to clarify that the regulation applies to all
establishments engaged in the collection of blood and blood products.
Sections 640.3(e), 640.31(c), and 640.51(c) would be removed
because FDA has concluded that it is no longer necessary to defer
donors participating in red blood cell immunization programs.
Previously, donors participating in red blood cell immunization
programs were deferred for 12 months because fresh red blood cells were
used to immunize donors. Red blood cells now used in immunization
programs are carefully screened and quarantined thereby minimizing the
risk of transmitting known infectious agents. See FDA memorandum dated
March 14, 1995, entitled ``Revised Recommendations for Red Blood Cell
Immunization Programs for Source Plasma Donors'' for additional
information about current red blood cell immunization practices.
Section 640.4(b) would be amended by removing the word ``clinic''
and replacing it with the word ``center'' to reflect current
terminology and by changing the word ``licensed'' to ``blood'' to
clarify that the regulation applies to all blood establishments engaged
in the collection of blood and blood products. Section 640.4(d) would
be amended by removing the reference to the specific anticoagulant
formulae. Section 640.4(d)(1) through (d)(4) would be removed because
FDA has determined it is unnecessary to provide specific formulae for
anticoagulant solutions in the regulations and that manufacturers
should be able to use any anticoagulant approved by FDA for such use.
Sections 640.13(a), 640.22(a), 640.32(a), and 640.52(a) would be
amended to delete references to Sec. 640.4(d)(2) and (h), which would
be being removed. Section 640.4(g)(5) would be changed to include the
use of different anticoagulants in segments for compatibility testing
to be consistent with the use of different approved anticoagulants in
the manufacture of blood and blood products. Section 640.4(h) would be
removed because heparin anticoagulant solutions are no longer used for
the routine collection of blood.
Section 640.5(c) would be amended to be consistent with current Rh
factor testing practices by removing ``and for other Rh-Hr factors,''
because these tests are not routinely performed. The section would also
be changed to specify that blood testing negative using Anti-D Blood
Grouping Reagents may only be labeled ``Rh Negative'' if the
confirmatory testing includes tests for weak expressions of D. These
changes would be made to be consistent with current accepted practices
which designate that tests for weak expressions of D be performed and
the product labeled consistent with the results of those tests.
Sections 640.6(c) and 640.15(c) would be removed because the use
of more modern methods of manufacturing and equipment have eliminated
the use of pilot tubes attached to the blood units. In Sec. 640.15
paragraph (d) is redesignated as paragraph (c).
Section 640.16(a) would be amended by inserting ``or additive
solution'' after ``cryoprotective substance'' to reflect an additional
procedure for prolonging shelf life now in use in which all the plasma
is removed from a unit of blood.
Section 640.16(b) would be amended by removing all but the first
sentence. The removed text describes blood collection procedures to be
followed when using open vented systems. Use of open vented systems is
no longer consistent with CGMP and has not been used for many years.
All references to ``pilot tubes'' and ``pilot samples'' would be
replaced with the words ``sample(s)'' or ``segment(s)'' to reflect
current terminology for various testing specimens. The following
sections would be amended by replacing ``pilot tubes,'' ``pilot
samples,'' or ``pilot sample tubes'' with ``segments'' or ``samples''
as appropriate in Secs. 640.2(e)(1), 640.4(g) introductory text, and
paragraphs (g)(1), (g)(2), (g)(4), and (g)(5), 640.5, 640.15(a) through
(c), and 640.69(d) introductory text, and paragraphs (d)(1) through
(d)(4).
Section 640.23(a) would be amended to include the preparation of
Platelets prepared by automated collection procedures and to allow the
group and typing tests performed on Platelets prepared by apheresis to
be valid for a
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period not to exceed 3 months, thereby, eliminating the necessity of
repeat testing of blood samples from donors participating in frequent
plasmapheresis collection procedures.
Section 640.24(b) would be amended by changing the time period for
separation of the platelet concentrate from ``4 hours'' to ``within the
time period specified in the directions for use for the specific
device.'' Similar changes would be made to the timeframe for the
storage of plasma that is set forth in Sec. 640.34(a) through (d) and
(e)(1) and the freezing of plasma set forth in Sec. 640.54(a)(2). These
changes, consistent with current accepted practices, permit more
flexibility by permitting different timeframes depending on the
particular blood collection device being used.
Sections 640.25(b) and 640.56(a) would be amended to require
testing only in those months in which blood products would be prepared
for use. This eliminates the need for performing quality control
procedures during those months when product is not being manufactured.
Sections 640.25(c), 640.56(c), and 640.71(a) would be amended to
update references to cite the ``Clinical Laboratories Improvement
Amendments of 1988 (CLIA)'' consistent with nomenclature in the
regulations implementing CLIA in 42 CFR part 493.
Section 640.34(d) would be amended by removing the reference to
storing platelet rich plasma at temperatures between 1 and 6 deg.C
because storage at such temperatures adversely affects platelet
function.
Section 640.34(e)(2) and (e)(3) would be amended to include the
proper name of the product ``Plasma, Cryoprecipitate Reduced'' as per
recommendations of the Blood Products Advisory Committee at the meeting
of September 18 and 19, 1997. Section 640.34(g)(2) would be amended to
permit for proof of continuous monitoring of the temperature to be
within acceptable ranges for the product as an alternative to requiring
the storing of the product in a manner to show evidence of thawing. FDA
believes that, with current technology, monitoring systems of freezers
used for storage are adequately sensitive and reliable to detect any
significant rise in storage temperature.
Section 640.62 requiring that a qualified licensed physician be on
the premises when donor suitability is being determined would be
amended to require a qualified licensed physician to be physically
available on the premises, or be available to attend to the donor
within 15 minutes, when a pheresis procedure is being performed, for
consultation and management of donor adverse reactions, except that the
qualified licensed physician shall be physically available on the
premises when red blood cell immunizations are being performed. FDA has
determined that a qualified licensed physician must always be readily
available, if needed, and shall be on the premises for red blood cell
immunizations.
Section 640.63(c)(3) would be amended by adding at the end of the
sentence ``or a hematocrit level of 38 percent,'' which is equivalent
to a hemoglobin level of 12.5 grams per 100 milliliters of blood, to be
consistent with current accepted practices.
Section 640.63(c)(5) would be amended by adding ``or total
plasma'' after ``A total serum'' to be consistent with current accepted
practice of using a capillary tube coated with anticoagulant for
fingerstick sample collection.
Section 640.65(b)(4) would be amended by changing ``in any 48-hour
period'' to ``2-day'' to permit more flexibility in scheduling donor
appointments and by adding the word ``manual'' to the phrases ``during
a plasmapheresis procedure'' to clarify that the regulation applies to
a manual plasmapheresis collection procedure, but does not apply to
automated apheresis.
Section 640.65(b)(5) would be amended by adding ``during a manual
plasmapheresis procedure'' after the phrases ``removed from the donor''
to clarify that the regulation applies to a manual plasmapheresis
collection procedure, but does not apply to automated apheresis.
Section 640.65(b)(8) would be added to address the collection of
Source Plasma using automated collection devices. The regulation
describes the frequency of collection consistent with Sec. 640.65(b)(4)
and (b)(5) and the volume of plasma to be collected during such
procedures consistent with the plasma collection volumes approved for
each device and with recommendations included in the FDA memorandum to
all plasma establishments dated November 4, 1992, entitled ``Volume
Limits for Automated Collection of Source Plasma.''
Section 640.72(a)(1) would be amended by replacing ``compiled
every 3 months'' with ``shall be available'' to eliminate the necessity
of compiling documents for review at specified periods of time.
IV. Analysis of Impacts
A. Review Under Executive Order 12866 and the Regulatory Flexibility
Act and the Unfunded Mandates Reform Act of 1995
FDA has examined the impact of the companion proposed rule under
Executive Order 12866 and the Regulatory Flexibility Act (5 U. S. C.
601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 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 net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impact; and equity). The agency believes that
this proposed rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. This proposed rule is not
a significant regulatory action as defined by the Executive Order and
therefore 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 proposed rule amendments have no
compliance costs and do not result in any new requirements, the agency
certifies that the proposed rule will not have a significant negative
economic impact on a substantial number of small entities. Therefore,
under the Regulatory Flexibility Act, no further analysis is required.
This proposed 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 1 year.
B. Environmental Impact
The agency has determined under 21 CFR 25.31(j) 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.
V. Paperwork Reduction Act of 1995
FDA tentatively concludes that this proposed 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.
[[Page 45379]]
VI. Request for Comments
Interested persons may, on or before December 3, 1999, submit to
the Docket Management Branch (address above) written comments regarding
this proposal. Two copies of any comments are to be submitted, except
that individuals may submit one copy. Comments are to be identified
with the docket number found in brackets in the heading of this
document. Received comments may be seen in the office above between 9
a.m. and 4 p.m., Monday through Friday.
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, it is proposed that 21 CFR parts 606 and 640 be
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 paragraphs (c), (e), (f),
and (j) to read as follows:
Sec. 606.3 Definitions.
* * * * *
(c) Component means that part of a single-donor's blood separated
by physical or mechanical means.
* * * * *
(e) Plasmapheresis means the procedure in which blood is removed
from the donor, the plasma is separated from the formed elements and at
least the red blood cells are returned to the donor.
(f) Plateletpheresis means the procedure in which blood is removed
from a donor, a platelet concentrate is separated, and the remaining
formed elements are returned to the donor along with a portion of the
residual plasma.
* * * * *
(j) Compatibility testing means the tests performed to establish
the matching of a donor's blood or blood components with that of a
potential recipient.
3. Section 606.100 is amended by revising the introductory text of
paragraphs (b) and (d), and by revising paragraphs (b)(7) and (b)(18)
to read as follows:
Sec. 606.100 Standard operating procedures.
* * * * *
(b) Written standard operating procedures shall be maintained and
shall include all steps to be followed in the collection, processing,
compatibility testing, storage, and distribution of blood and blood
components for transfusion and further manufacturing purposes. Such
procedures shall be available to the personnel for use in the areas
where the procedures are performed. The written standard operating
procedures shall include, but are not limited to, descriptions of the
following, when applicable:
* * * * *
(7) All tests and repeat tests performed on blood and blood
components during manufacturing.
* * * * *
(18) Procedures for preparing recovered plasma, if performed,
including details of separation, pooling, labeling, storage, and
distribution.
* * * * *
(d) In addition to the requirements of this subpart and in
conformity with this section, any facility may utilize current standard
operating procedures such as the manuals of the organizations, as long
as such specific procedures are consistent with, and at least as
stringent as, the requirements contained in this part.
* * * * *
4. Section 606.121 is amended by revising paragraphs (a), (d)(2),
and (e)(1)(ii) to read as follows:
Sec. 606.121 Container label.
(a) The container label requirements are designed to facilitate the
use of a uniform container label for blood and blood components (except
Source Plasma) by all blood establishments.
* * * * *
(d) * * *
(2) The proper name of the product, any appropriate modifier(s),
the donor classification statement, and the statement ``properly
identify intended recipient'' shall be printed in solid red or in solid
black.
* * * * *
(e) * * *
(1) * * *
(ii) The name of the applicable anticoagulant immediately preceding
and of no less prominence than the proper name approved for use by the
Director, Center for Biologics Evaluation and Research.
* * * * *
5. Section 606.122 is amended by revising paragraphs (f) and (n)(4)
to read as follows:
Sec. 606.122 Instruction circular.
* * * * *
(f) The statements: ``Warning. The risk of transmitting infectious
agents is present. Careful donor selection and available laboratory
tests do not eliminate the hazard.''
* * * * *
(n) * * *
(4) Instructions to thaw the product for no more than 15 minutes
at a temperature between 30 and 37 deg.C.
* * * * *
6. Section 606.151 is amended by revising paragraphs (b), (c), and
(e) to read as follows:
Sec. 606.151 Compatibility testing.
* * * * *
(b) The use of fresh recipient serum samples less than 3-days old
for all pretransfusion testing if the recipient has been pregnant or
transfused within the previous 3 months.
(c) The testing of the donor's cell type with the recipient's serum
type by a method that will demonstrate incompatibility.
* * * * *
(e) Procedures to expedite transfusion in life-threatening
emergencies. Records of all such incidents shall be maintained,
including complete documentation justifying the emergency action, which
shall be signed by a physician.
7. Section 606.160 is amended by revising paragraph (b)(2)(v) to
read as follows:
Sec. 606.160 Records.
* * * * *
(b) * * *
(2) * * *
(v) Labeling, including initials of the person(s) performing the
procedure.
* * * * *
8. Section 606.170 is amended by revising paragraph (b) to read as
follows:
Sec. 606.170 Adverse reaction file.
* * * * *
(b) When a complication of blood collection or transfusion is
confirmed to be fatal, the Director, Office of Compliance and Biologics
Quality, Center for Biologics Evaluation and Research, shall be
notified by telephone,
[[Page 45380]]
facsimile, express mail, or electronically transmitted mail as soon as
possible; a written report of the investigation shall be submitted to
the Director, Office of Compliance and Biologics Quality, Center for
Biologics Evaluation and Research, within 7 days after the fatality by
the collecting facility in the event of a donor reaction, or by the
facility that performed the compatibility tests in the event of a
transfusion reaction.
(Information collection requirements approved by the Office of
Management and Budget under control number 0910-0116)
PART 640--ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS
9. 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.
10. Section 640.2 is amended by removing paragraphs (b) and (d), by
redesignating paragraphs (c), (e), and (f) as paragraphs (b), (c), and
(d), respectively, and by revising newly redesignated paragraphs (b)
and (c)(2) 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. 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 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.
(c) * * *
(2) A segment is properly attached and has not been removed, except
that blood lacking a properly attached segment may be reissued in an
emergency provided it is accompanied by instructions for sampling and
for use within 6 hours after entering the container for sampling;
* * * * *
11. Section 640.3 is amended by revising the introductory text of
paragraph (b), by revising paragraphs (b)(3), (c)(1), (c)(2), and
(c)(3) and by removing and reserving paragraph (e) to read as follows:
Sec. 640.3 Suitability of donor.
* * * * *
(b) Qualifications of donor; general. Except as provided in
paragraph (f) of this section and for autologous donations, a person
may not serve as a source of Whole Blood more than once in 8 weeks. In
addition, donors shall be in good health, as indicated in part by:
* * * * *
(3) For allogeneic donors, a blood hemoglobin level which shall be
demonstrated to be no less than 12.5 grams (g) of hemoglobin per 100
milliliters (mL) of blood; or a hematocrit value of 38 percent, and for
autologous donors, a blood hemoglobin level which shall be demonstrated
to be no less than 11.0 g of hemoglobin per 100 mL of blood or a
hematocrit value of 33 percent.
* * * * *
(c) * * *
(1) A history of viral hepatitis after the age of eleven;
(2) A history of close contact within 12 months of donation with an
individual having viral hepatitis;
(3) A history of having received within 12 months of donation,
human blood or any derivative of human blood which the Food and Drug
Administration has advised the blood establishment is a possible source
of viral hepatitis.
* * * * *
12. Section 640.4 is amended by removing paragraphs (d)(1) through
(d)(4) and (h), by redesignating paragraph (i) as paragraph (h), and
revising paragraphs (b) and (d), 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.
* * * * *
(b) The donor center. The pertinent requirements of Secs. 600.10
and 600.11 of this chapter shall apply at both the blood establishment
and at any other place where the bleeding is performed.
* * * * *
(d) The anticoagulant solution. The anticoagulant solution shall
be sterile and pyrogen-free. Anticoagulant solutions shall be
compounded and used according to a formula approved by the Director,
Center for Biologics Evaluation and Research.
* * * * *
(g) Samples for laboratory tests. Samples 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(e)(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 tamper proof
manner that will conspicuously indicate removal and reattachment.
(5) Segments for compatibility testing shall contain blood mixed
with the appropriate anticoagulant.
* * * * *
13. 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 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
this test is negative, the results shall be confirmed by further
testing which shall include tests for the Rho variant
(Du). 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, the regulations of this subchapter shall be used, and
the technique used shall be that for which the reagent is specifically
designed to be effective.
* * * * *
Sec. 640.6 [Amended]
14. Section 640.6 Modifications of Whole Blood is amended by
removing paragraph (c).
15. Section 640.13 is amended by revising paragraph (a) to read as
follows:
Sec. 640.13 Collection of the blood.
(a) The source blood shall be collected as prescribed in
Sec. 640.4.
* * * * *
16. Section 640.15 is revised to read as follows:
[[Page 45381]]
Sec. 640.15 Samples for testing.
Samples collected in integral tubing shall meet the following
standards:
(a) One or more segments 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 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.
17. Section 640.16 is amended by revising paragraphs (a) and (b) to
read as follows:
Sec. 640.16 Processing.
(a) Separation. Within the timeframe specified in the directions
for the use of the specific devices, 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.
(b) Sterile system. All surfaces that come in contact with the red
cells shall be sterile and pyrogen-free.
* * * * *
18. Section 640.22 is amended by revising paragraph (a) to read as
follows:
Sec. 640.22 Collection of source material.
(a) Whole blood used as the source of Platelets shall be collected
as prescribed in Sec. 640.4.
* * * * *
19. 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 or Platelets, Pheresis shall be tested as prescribed in
Secs. 610.40 and 610.45 of this chapter and Sec. 640.5(a), (b), and
(c). 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.
* * * * *
20. 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 the timeframe specified
in the directions for use for the specific device used for the
collection of the unit of whole blood or plasma.
* * * * *
Sec. 640.31 [Amended]
21. Section 640.31 Suitability of donors is amended by removing
paragraph (c).
22. Section 640.32 is amended by revising the first sentence of
paragraph (a) to read as follows:
Sec. 640.32 Collection of source material.
(a) Whole blood shall be collected, transported, and stored as
prescribed in Sec. 640.4. * * *
* * * * *
23. Section 640.34 is amended by revising paragraphs (a) through
(d), (e)(1) through (e)(3), and (g)(2) 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 the timeframe specified
in the directions for use for the specific device 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 the
timeframe specified in the directions for use for the specific device,
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 the timeframe specified in the directions for use for the
specific device 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
the timeframe specified in the directions for use for the specific
device after completion of the 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 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 the timeframe specified in
the directions for use for the specific device after filling the final
container.
(2) Cryoprecipitated AHF shall be removed as prescribed in subpart
F of part 640. The remaining plasma shall be labeled ``Plasma,
Cryoprecipitate Reduced.''
(3) Plasma remaining after both Platelets and Cryoprecipitated AHF
have been removed may be labeled ``Plasma, Cryoprecipitate Reduced.''
* * * * *
(g) * * *
(2) With the exception of Platelet Rich Plasma and Liquid Plasma
the final product shall be inspected for evidence of thawing or
breakage at the time of issuance, however, the containers need not be
stored in a manner that shows evidence of thawing if records of
continuous monitoring of the storage temperature establish that the
temperature remained at -18 deg.C or colder. If continuous monitoring
of the product is not available, the final product shall be stored in a
manner that will show evidence of thawing and shall not be issued if
there is any evidence of thawing.
* * * * *
Sec. 640.51 [Amended]
24. Section 640.51 Suitability of donors is amended by removing
paragraph (c).
25. Section 640.52 is amended by revising paragraph (a) to read as
follows:
Sec. 640.52 Collection of source material.
(a) Whole blood used as a source of Cryoprecipitated AHF shall be
collected as prescribed in Sec. 640.4. Whole blood from which both
Platelets and Cryoprecipitated AHF is derived shall be maintained as
required under Sec. 640.24 until the platelets are removed.
* * * * *
[[Page 45382]]
26. 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 after blood collection within
the timeframe specified in the directions for use for the specific
device. 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.
* * * * *
27. Section 640.56 is amended by revising the introductory text of
paragraph (c) to read as follows:
Sec. 640.56 Quality control test for potency.
* * * * *
(c) The quality control test for potency may be performed by a
clinical laboratory which meets the standards of the Clinical
Laboratories Improvement Act of 1988 (CLIA) (42 U.S.C. 263a) and is
qualified to perform potency tests for antihemophilic factor. Such
arrangements must be approved by the Director, Center for Biologics
Evaluation and Research, Food and Drug Administration. Such testing
shall not be considered as divided manufacturing, as described in
Sec. 610.63 of this chapter, provided the following conditions are met:
* * * * *
28. Section 640.62 is revised to read as follows:
Sec. 640.62 Medical supervision.
A qualified licensed physician shall be available to attend to the
donor within 15 minutes 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, except that during the
administration of immunization red blood cells a qualified licensed
physician shall be on the premises.
29. Section 640.63 is amended by revising paragraphs (c)(3),
(c)(5), (c)(11), (c)(12), and (c)(13) to read as follows:
Sec. 640.63 Suitability of donor.
* * * * *
(c) * * *
(3) A blood hemoglobin level of no less than 12.5 grams of
hemoglobin per 100 milliliters of blood or a hematocrit level of 38
percent;
* * * * *
(5) A total serum or total plasma protein of no less than 6.0 grams
per 100 milliliters of blood;
* * * * *
(11) A history of viral hepatitis after the age of eleven;
(12) Freedom from a history of close contact within 12 months of
donation with an individual having viral hepatitis;
(13) Freedom from a history of having received, within 12 months,
human blood or any derivative of human blood which the Food and Drug
Administration has advised the blood establishment is a possible source
of viral hepatitis, except for specific immunization performed in
accordance with Sec. 640.66.
* * * * *
30. Section 640.65 is amended by revising paragraphs (b)(4) and
(b)(5) and by adding paragraph (b)(8) to read as follows:
Sec. 640.65 Plasmapheresis.
* * * * *
(b) * * *
(4) The amount of whole blood, not including anticoagulant, removed
from a donor during a manual plasmapheresis procedure or in any 2-day
period shall not exceed 1,000 milliliters unless the donor's weight is
175 pounds or greater, in which case the amount of whole blood, not
including anticoagulant, removed from the donor during a manual
plasmapheresis procedure or in any 2-day period shall not exceed 1,200
milliliters.
(5) The amount of whole blood, not including anticoagulant, removed
from a donor during a manual plasmapheresis procedure within a 7-day
period shall not exceed 2,000 milliliters unless the donor's weight is
175 pounds or greater, in which case the amount of whole blood, not
including anticoagulant, removed from a donor during a manual
plasmapheresis procedure within a 7-day period shall not exceed 2,400
milliliters.
* * * * *
(8) The volume of plasma collected during an automated
plasmapheresis collection procedure shall be consistent with the
volumes specifically approved by the Director, Center for Biologics
Evaluation and Research, and collection shall not occur less than 2
days apart or more frequently than twice in a 7-day period.
31. Section 640.69 is amended by revising paragraph (d) to read as
follows:
Sec. 640.69 General requirements.
* * * * *
(d) Samples. If samples are provided, they shall meet the following
standards:
(1) Prior to filling, all samples shall be marked or identified so
as to relate them directly to the donor of that unit of plasma.
(2) All samples shall be filled at the time the final product is
prepared by the person who prepares the final product.
(3) All samples shall be representative of the contents of the
final product or be collected from the donor at the time of filling the
collection container.
(4) All samples shall be collected in a manner that does not
contaminate the contents of the final container.
32. Section 640.71 is amended by revising the introductory text of
paragraph (a) to read as follows:
Sec. 640.71 Manufacturing responsibility.
(a) All steps in the manufacturing of Source Plasma, including
donor examination, blood collection, plasmapheresis, laboratory
testing, labeling, storage, and issuing shall be performed by personnel
of the establishment licensed to manufacture Source Plasma, except that
the following tests may be performed by personnel of an establishment
licensed for blood and blood derivatives under section 351(a) of the
Public Health Service Act, or by a clinical laboratory that meets the
standards of the Clinical Laboratories Improvement Act of 1988 (CLIA)
(42 U.S.C. 263a): Provided, The establishment or clinical laboratory is
qualified to perform the assigned test(s).
* * * * *
33. Section 640.72 is amended by revising paragraph (a)(1) to read
as follows:
Sec. 640.72 Records.
(a) * * *
(1) Documentation shall be available to ensure that the shipping
temperature requirements of Sec. 600.15 of this title and of
Sec. 640.74(b)(2) are being met for Source Plasma intended for
manufacture into injectable products.
* * * * *
Dated: April 20, 1999.
Jane E. Henney,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 99-21293 Filed 8-18-99; 8:45 am]
BILLING CODE 4160-01-F