[Federal Register Volume 64, Number 160 (Thursday, August 19, 1999)]
[Proposed Rules]
[Pages 45375-45382]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-21293]



  Federal Register / Vol. 64, No. 160 / Thursday, August 19, 1999 / 
Proposed Rules  

[[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.

-----------------------------------------------------------------------

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remove unnecessary or outdated requirements.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

[[Page 45377]]

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

[[Page 45378]]

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