[Printable PDF]
[Federal Register: August 19, 1999 (Volume 64, Number 160)]
[Rules and Regulations]
[Page 45366-45374]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr19au99-18]
[[Page 45366]]
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: Direct 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remove unnecessary or outdated requirements.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 these
amendments directly as a final rule because they are noncontroversial
and there is little likelihood that FDA will receive any significant
comments opposing the rule. Elsewhere in this issue of the Federal
Register, FDA is publishing a proposed rule under FDA's usual
procedures for notice and comment in the event the agency receives any
significant adverse comments. If FDA receives any significant adverse
comment sufficient to terminate the direct final rule, FDA will
consider such comments on the proposed rule in developing the final
rule. FDA is issuing this 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 February 11, 2000. Submit written
comments on or before December 3, 1999. If no timely significant
comments are received, the agency will publish a document in the
Federal Register within 30 days after the comment period on this direct
final rule ends, confirming the effective date of the final rule. If
timely significant adverse comments are received, the agency will
publish a document in the Federal Register withdrawing the direct final
rule before its effective date.
ADDRESSES: Submit written comments on the direct final 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. Blood Initiative
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.
In the Federal Register of June 3, 1994 (59 FR 28821 and 59 FR 28822,
respectively), FDA issued two documents entitled ``Review of General
Biologics and Licensing Regulations'' (Docket No. 94N-0066) and
``Review of Regulations for Blood Establishments and Blood Products''
(Docket No. 94N-0080). The documents announced the agency's intent to
review biologics regulations, 21 CFR parts 600, 601, 606, 607, 640, and
660 and requested written comments from the public. Interested persons
were given until August 17, 1994, to respond to the documents. In
response to requests for additional time, FDA twice extended the
comment period, as announced in the Federal Register of August 17, 1994
(59 FR 42193), and November 14, 1995 (59 FR 56448). In addition, FDA
responded to requests for a public meeting to allow for the
presentation of comments regarding the agency's intent to review the
biologics regulations. On January 26, 1995, FDA held a public meeting
to provide an opportunity for all interested individuals to present
their comments and to assist the agency in determining whether the
regulations should be revised, rescinded, or continued without change.
Since the time of the regulation review, FDA has implemented a number
of changes to its regulations and policies applicable to the general
biologics and licensing regulations, some of which applied to blood
products as well as other biological products. (See, e.g., the final
rules issued on May 14, 1996 (61 FR 24313); August 1, 1996 (61 FR
40153); November 6, 1996 (61 FR 57328); July 24, 1997 (62 FR 39890);
and October 15, 1997 (62 FR 53536).)
Because of the importance of a safe national blood supply, the U.S.
House of Representatives Committee on Government Reform and Oversight,
Subcommittee on Human Resources and Intergovernmental Relations (the
Subcommittee) and other groups such as the General Accounting Office
(GAO), and the Institute of Medicine (IOM) have reviewed the agency's
polices, practices, and regulations. Reports issued following the
respective reviews contained a number of recommendations as to how FDA
might improve the biologics regulations, particularly as they apply to
the continued safety of blood products. The relevant reports are: (1)
``Protecting the Nation's Blood Supply From Infectious Agents: The Need
for New Standards to Meet New Threats,'' by the Subcommittee (August 2,
1996); (2) ``Blood Supply: FDA Oversight and Remaining Issues of
Safety,'' by GAO (February 25, 1997); (3) ``Blood Supply: Transfusion-
Associated Risks,'' by GAO (February 25, 1997); and (4) ``HIV and the
Blood Supply: An Analysis of Crisis Decisionmaking,'' by IOM (July 13,
1995). These reports are on file with the Dockets Management Branch
(address above) under the docket number found in brackets in the
heading of this document.
FDA has reviewed these reports and agrees with the majority of the
recommendations contained within them. However, rather than to only
respond specifically to the recommendations from the Subcommittee, GAO,
IOM, and the public, FDA has convened a number of internal task forces
to review a variety of issues related to the regulation of blood and
blood products, including how to most appropriately update the existing
regulations applicable to blood and blood products. In the future, FDA
intends to issue a number of blood-related regulations that various FDA
task groups are preparing. FDA emphasizes that for many of the changes
discussed in section III of 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 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.
FDA is not describing the specific recommendations it received and
the numerous objectives of the Blood Initiative in this document.
Future rulemaking and other notices will describe and discuss specific
recommendations and regulatory objectives as they apply to each
rulemaking.
II. Legal Authority
FDA is issuing this new rule under the biologics products and
[[Page 45367]]
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 Direct Final Rule
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 and to
remove unnecessary or outdated requirements. FDA is issuing these
amendments as a direct final rule because the agency 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
following changes, 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. In the following paragraphs, FDA
discusses each of the rule changes in the direct final rule.
Part 606 (21 CFR part 606) is amended as follows:
Section 606.3, Definitions, is amended so that the definitions
provided in the section are consistent with current meanings and
usages.
The definition of ``Component'' in Sec. 606.3(c) is amended to
apply to blood obtained from a single donor and no longer includes 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 Sec. 606.3(e) is amended by
removing the restriction that plasmapheresis may be ``immediately
repeated, once'' because current automated plasmapheresis collection
practices often use more than two cycles for collection.
The definition of ``Plateletpheresis'' in Sec. 606.3(f ) is 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 Sec. 606.3(j) is
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
potential 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) are 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) is also 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'' is 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) is 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) is 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.
Section 606.100(d) is 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's regulatory requirements.
Section 606.121(a) is amended by removing the reference that the
``Guideline for the Uniform Labeling of Blood and Blood Components'' is
available from Dockets 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 is 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) is amended by deleting 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 is 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 is amended to allow instructions for
thawing between 30 and 37 deg.C, permitting more flexibility in the
preparation of the component.
Section 606.151(b) is 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 preceding 3 months.
Section 606.151(c) describes compatibility testing and is 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) is 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) is amended by changing ``person(s)
responsible'' to ``the person(s) performing the
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procedure'' to clarify that the person(s) performing the labeling
procedure is responsible for documenting the performance of that
procedure.
Section 606.170(b) is amended by deleting ``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) is amended as follows:
Section 640.2(b) is removed because Whole Blood collection in open
systems is no longer acceptable nor has it been performed for many
years. Section 640.2(d) is revised. In Sec. 640.2 paragraphs (c), (e),
and (f) are redesignated as paragraphs (b), (c), and (d), respectively.
Redesignated Sec. 640.2(b) and (c)(2) are revised by removing
references to the original blood container because, 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) is 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) is 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) are 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) are 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) are 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 FDA has identified as a possible source of viral
hepatitis. These changes are consistent with recommendations 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) have been
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) are 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 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) is 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) is amended by
removing the reference to the specific anticoagulant formulae. Section
640.4(d)(1) through (d)(4) is 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) are amended to remove references to
Sec. 640.4(d)(2) and (h), which are being removed.
Section 640.4(g)(5) has been 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) is removed
because heparin anticoagulant solutions are no longer used for the
routine collection of blood.
Section 640.5(c) is 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 is also 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 have
been 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) are removed because the use of more
modern methods of manufacturing and equipment have eliminated the use
of pilot tubes attached to blood units. In Sec. 640.15 paragraph (d) is
redesignated as paragraph (c).
Section 640.16(a) is 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) is 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'' have been
replaced with the words ``sample(s)'' or ``segment(s)'' to reflect
current terminology for various testing specimens. The following
sections are amended by replacing ``pilot tubes,''
[[Page 45369]]
``pilot samples,'' or ``pilot sample tubes'' with ``segments'' or
``samples'' as appropriate: Secs. 640.2(e)(2), 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) is 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 period not to exceed 3 months, thereby, eliminating the
necessity of repeat testing of blood samples from donors participating
in frequent plateletpheresis collection procedures.
Section 640.24(b) is 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 are 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) are amended to require testing
only in those months in which blood products are 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) are 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) is amended by deleting 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) are amended to include the proper
name of the product ``Plasma, Cryoprecipitate Reduced'' as per
recommendations of the Blood Products Advisory Committee at its
September 18 and 19, 1997 meeting. Section 640.34(g)(2) is amended to
permit 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 is 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) is 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 g per 100 mL of blood, to be consistent
with current accepted practices.
Section 640.63(c)(5) is 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) is 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) is 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) is added to address the collection of Source
Plasma using automated collection devices. The regulation delineates
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) is amended by replacing ``compiled every 3
months'' with ``shall be available'' to eliminate the necessity of
compiling documents at specified time intervals.
IV. Rulemaking Action
In the Federal Register of November 21, 1997 (62 FR 62466), FDA
described its procedures on when and how FDA will employ direct final
rulemaking. FDA has determined that this rule is appropriate for direct
final rulemaking because FDA views this rule as including only
noncontroversial amendments and anticipates no significant adverse
comments. Consistent with FDA's procedures on direct final rulemaking,
FDA is publishing elsewhere in this issue of the Federal Register, a
companion proposed rule to amend the biologics regulations by removing,
revising, and updating existing regulations to be more consistent with
current accepted practices. The companion proposed rule provides a
procedural framework within which the rule may be finalized in the
event the direct final rule is withdrawn because of any significant
adverse comment. The comment period for the direct final rule runs
concurrently with the companion proposed rule. Any comment received
under the companion proposed rule will be considered as comments
regarding the direct final rule.
FDA has provided a comment period on the direct final rule of 75
days after August 19, 1999. If the agency receives any significant
adverse comment, FDA intends to withdraw this direct final rule action
by publication of a document in the Federal Register within 30 days
after the comment period ends. A significant adverse 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
[[Page 45370]]
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 any significant adverse comment is received during the comment
period, FDA will publish, within 30 days after the comment period ends,
a document withdrawing the direct final rule. If FDA withdraws the
direct final rule, any comments received will be applied to the
proposed rule and will be considered in developing a final rule using
the usual Administrative Procedure Act notice-and-comment procedures.
If FDA receives no significant adverse comments during the
specified comment period, FDA intends to publish a confirmation
document within 30 days after the comment period ends confirming the
effective date.
V. Analysis of Impacts
A. Review Under Executive Order 12866 and the Regulatory Flexibility
Act and Unfunded Mandates Reform Act of 1995
FDA has examined the impact of the direct final rule under
Executive Order 12866, 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 direct final rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. This direct final 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 direct final rule amendments have
no compliance costs and do not result in any new requirements, the
agency certifies that the direct final 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 direct 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 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.
VI. The Paperwork Reduction Act of 1995
This direct final rule contains no collection of information.
Therefore, clearance by the Office of Management and Budget under the
Paperwork Reduction Act of 1995 is not required.
VII. Request for Comments
Interested persons may, on or before December 3, 1999, submit to
the Docket Management Branch (address above) written comments regarding
this final rule. 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, 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 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:
[[Page 45371]]
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, 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
[[Page 45372]]
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:
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
[[Page 45373]]
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.
* * * * *
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
[[Page 45374]]
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. 99-21292 Filed 8-18-99; 8:45 am]
BILLING CODE 4160-01-F