[Federal Register Volume 66, Number 112 (Monday, June 11, 2001)]
[Rules and Regulations]
[Pages 31146-31165]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-14408]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 606, 607, 610, 640, 660, and 809

[Docket No. 98N-0581]


Requirements for Testing Human Blood Donors for Evidence of 
Infection Due to Communicable Disease Agents

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is revising the general 
biological product standards applicable to human blood and blood 
components by updating the hepatitis B virus (HBV) and human 
immunodeficiency virus (HIV) testing requirements, by adding testing 
requirements for hepatitis C virus (HCV), human T-lymphotropic virus 
(HTLV), and by adding requirements for supplemental (i.e., additional, 
more specific) testing approved for such use by FDA when a donation is 
found to be reactive for any of the required screening tests for 
evidence of infection due to communicable disease agents. The agency 
also is requiring manufacturers of certain test kits to use reference 
panels, when available, to verify the acceptable sensitivity and 
specificity of each lot. This final rule is intended to help protect 
the safety and ensure the quality of the Nation's blood supply, to 
enhance the safety of medical devices containing blood or blood 
components, to provide FDA with clear enforcement authority, and to 
promote consistency in the industry. Elsewhere in this issue of the 
Federal Register, FDA is publishing a rule requiring blood and plasma 
establishments to notify donors, including autologous donors, whenever 
the donor is deferred or determined not to be suitable for current or 
future donations of blood and blood components.

DATES: This rule is effective December 10, 2001.

FOR FURTHER INFORMATION CONTACT: Paula S. McKeever, Center for 
Biologics Evaluation and Research (HFM-17), Food and Drug 
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448, 301-827-6210.

SUPPLEMENTARY INFORMATION:

I. Background

    Requirements for testing blood donors for hepatitis B surface 
antigen (HBsAg) and antibody to human immunodeficiency virus (anti-HIV) 
are currently codified in part 610 (21 CFR part 610), and requirements 
for performing a serological test for syphilis are codified in part 640 
(21 CFR part 640). The agency has issued various guidance documents to 
registered blood and plasma establishments providing recommendations 
for testing for antibody to hepatitis B core antigen (anti-HBc), 
antibody to human T-lymphotropic virus types I and II (anti-HTLV I/II), 
antibody to hepatitis C virus (anti-HCV), and HIV-1 p 24 antigen. The 
purposes of the guidance documents are to assist blood and plasma 
establishments in protecting the safety of the blood supply and to 
establish policies with the intent of promoting consistency in the 
industry. These guidance documents represent the agency's current 
thinking on the appropriate testing of human blood donors for evidence 
of infection due to various communicable disease agents. Through 
inspection, we (FDA) determined that blood and plasma establishments 
generally have been following these recommendations. However, there 
have been instances where there have been variations in testing and in 
the determination of suitability of the blood based on the testing 
results. Accordingly, we proposed a regulation requiring testing 
consistent with our current recommendations and industry practice.
    In the Federal Register of August 19, 1999 (64 FR 45340), we 
published a proposed rule to revise the testing requirements codified 
in part 610. The proposed rule would require:
    <bullet> Each donation of human blood or blood component, including 
autologous donations, to be tested for evidence of infection due to 
HIV, types 1 and 2; HBV; HCV; and HTLV, types I and II;
    <bullet> Each donation that tests reactive for any of the required 
screening tests for evidence of infection due to communicable disease 
agents, to be further tested using a supplemental (additional, more 
specific) test that has been approved for such use by FDA;
    <bullet> The required testing to be performed by a laboratory 
certified under the Clinical Laboratory Improvement Amendments of 1988 
(CLIA) or meeting equivalent requirements as described by Health Care 
Financing Administration (HCFA), and registered with FDA in accordance 
with part 607 (21 CFR part 607);
    <bullet> Deferral from future donations of donors who test 
reactive;
    <bullet> Criteria for release or shipment of human blood or blood 
components prior to completion of testing under limited circumstances;

[[Page 31147]]

    <bullet> Restrictions on shipment or use of human blood or blood 
components that test reactive when screened for evidence of infection; 
and
    <bullet> Manufacturers of approved test kits used for testing 
donations of human blood and blood components for evidence of infection 
due to communicable disease agents, or for use in the diagnosis, or 
monitoring of HIV, to verify an acceptable sensitivity and specificity 
of each lot of test kit using a reference panel obtained from FDA, or 
an FDA designated source, when available.
    We provided 90 days for comments on the proposed rule.
    In the same Federal Register issue (64 FR 45355), we proposed new 
Sec. 630.6 to require blood and plasma establishments to notify donors 
of deferral based on evidence of infection due to communicable disease 
agents or failure to satisfy donor suitability criteria. We intended to 
finalize the donor notification rule and issue it simultaneously with 
this document.
    On November 9, 1999, we announced a public workshop held on 
November 22, 1999, and extended to December 22, 1999, the comment 
period on both proposed rules, entitled ``Requirements for Testing 
Human Blood Donors for Evidence of Infection Due to Communicable 
Disease Agents,'' and ``General Requirements for Blood, Blood 
Components, and Blood Derivatives; Notification of Deferred Donors.'' 
The purpose of the public meeting was to provide a public forum for 
gathering information and views regarding the proposed rules.

II. Highlights and Summary of the Final Rule

A. Plain Language

    We have written the final rule using plain language consistent with 
the presidential memorandum on plain language in government writing, 
dated June 1, 1998. We have adopted the plain language approach to make 
the rule more accessible and understandable to the public. As a result, 
we have used pronouns in describing who must comply, e.g., ``you'' 
refers, in the appropriate context, to an establishment that collects 
blood or blood components or to an establishment that is a consignee of 
a collecting establishment. We also have used ``must'' instead of 
``shall,'' and are using charts to clarify provisions.

B. Test Requirements (Sec. 610.40)

    In Sec. 610.40(a) of the final rule, we require the use of 
screening tests for evidence of infection due to communicable disease 
agents, i.e., HIV, types 1 and 2; HBV; HCV; and HTLV, types I and II, 
for each donation of human blood and blood component. In 
Sec. 610.40(b), we are requiring testing using one or more tests to 
reduce adequately and appropriately the risk of disease transmission. 
We are allowing for future advancements in testing methodologies by not 
specifying the test marker(s) for each disease agent. Further testing 
is required of all donations, including autologous (some exceptions 
apply) that are reactive when screened for evidence of infection due to 
any of the communicable disease agents, using supplemental (additional, 
more specific) tests approved for such use by FDA in Sec. 610.40(e). 
(See section IV of this document.) We have eliminated the use of the 
term ``repeatedly reactive'' and replaced it with ``reactive.'' The 
terminology was revised to allow for future technology in testing, 
where the process of repeating an initial reactive result in duplicate 
would no longer be appropriate. However, for the test technologies 
recommended in current guidance, ``reactive'' means ``repeatedly 
reactive,'' because the manufacturers' instructions for current tests 
require duplicate retesting after an initial reactive result.
    Specified exceptions to the testing requirements in Sec. 610.40(c) 
are described as they apply to a dedicated donor (a donor whose 
collections are used by an identified recipient, see section V.B of 
this document), a donor of Source Plasma, a donor of blood or blood 
components intended as a component of, or used to prepare, a medical 
device (see section II.D of this document), and samples used or 
distributed for clinical laboratory testing or research purposes and 
not intended for administration to humans or in the manufacture of a 
product.
    In Sec. 610.40(d) of the final rule, we have created a separate 
paragraph for autologous donations. Testing of autologous donations is 
not required under this section unless an autologous donation of blood 
or blood components potentially could be used for allogeneic 
transfusion or shipped to another establishment. If shipped to an 
establishment that does not permit the use of autologous donations for 
allogeneic use, only the first donation in each 30 day period must be 
tested as discussed in section V of this document.
    In Sec. 610.40(f), testing required under Sec. 610.40(a), (b), and 
(e) must be performed by a laboratory registered under part 607 and 
either certified to perform testing on human specimens under the 
Clinical Laboratory Improvement Amendments of 1988 (42 U.S.C. 263a) 
under 42 CFR part 493 or has met equivalent requirements as determined 
by HCFA under those provisions. Therefore, Sec. 607.65(g) is removed, 
formerly exempting from registration clinical laboratories that are 
approved for Medicare reimbursement and are engaged in the testing of 
blood products in support of other registered blood establishments.
    Release or shipment prior to completion of testing in 
Sec. 610.40(g) may occur in appropriately documented emergency medical 
situations, or when approved in writing by FDA, provided that the 
shipping establishment notifies the consignee that test results are not 
yet available, that the tests for communicable disease agents are 
completed as soon as possible, and that the results are provided 
promptly to the consignee.
    Under Sec. 610.40(h), an establishment must not ship or use blood 
or blood components that have a reactive screening test for a 
communicable disease agent(s) or reactive serological test for 
syphilis, or that were collected from a donor with a previous record of 
a reactive screening test for a communicable disease agent(s) or 
reactive serological test for syphilis. Exceptions to this requirement 
are:
    <bullet> For blood and blood components from autologous donors when 
labeled as required in Sec. 610.40(d);
    <bullet> When approval in writing is obtained from FDA and the 
blood or blood component is labeled as required under 
Sec. 610.40(h)(2)(ii);
    <bullet> Samples for use or distribution, if intended for clinical 
laboratory testing or research and not intended for administration in 
humans or for further manufacturing use;
    <bullet> When a collection from a donor with a record of a reactive 
screening test result tests negative and the donor is shown, or 
previously was shown, to be suitable by an acceptable requalification 
method; and
    <bullet> When a collection from a donor, who tests reactive for 
anti-HBc and otherwise is determined to be suitable, may be used for 
further manufacturing into plasma derivatives without prior FDA 
approval or the ``BIOHAZARD'' legend.

C. Donor Deferral (Sec. 610.41)

    Under Sec. 610.41(a), any donor of blood and blood components, 
including an autologous donor, who tests reactive for a communicable 
disease agent(s) described under Sec. 610.40(a) or reactive with a 
serological test for syphilis must be deferred from future donations. 
Exceptions apply as follows:

[[Page 31148]]

    <bullet> A donor who tests reactive for anti-HTLV I/II or anti-HBc 
only once is permitted to donate again without being deferred from 
further donation unless there is further testing using an approved 
supplemental (additional, more specific) test;
    <bullet> A deferred donor who tests reactive for HIV, types 1 and 
2, HBV, HCV, HTLV types I and II, or syphilis may donate blood or blood 
components to be shipped or used under the provisions described in 
Sec. 610.40(h)(2)(ii);
    <bullet> A deferred donor who showed evidence of infection due to 
HBsAg when previously tested may donate blood or blood components to be 
used in the preparation of Hepatitis B Immune Globulin (Human) provided 
the donor's current donation tests nonreactive for HBsAg and the donor 
otherwise is determined to be suitable;
    <bullet> A deferred donor who tests reactive for anti-HBc or for 
evidence of infection due to HTLV, types I and II, may serve as a donor 
of Source Plasma collected for further manufacturing use;
    <bullet> A deferred donor who tests reactive by a screening test 
for syphilis may serve as a donor of human blood and blood components, 
if the donation is further tested by an adequate and appropriate test 
demonstrating that the reactive screening test is a biological false 
positive; and
    <bullet> A deferred donor who tests reactive for a communicable 
disease agent(s) described under Sec. 610.40(a) or reactive with a 
serological test for syphilis may serve as an autologous donor.
    Under new Sec. 630.6 in the donor notification rule found elsewhere 
in this issue of the Federal Register, all deferred donors, including 
those deferred donors who may serve as donors under specified 
conditions described in Sec. 610.41, must be notified of their 
deferral.
    Under Sec. 610.41(b) the regulations permit the reentry of a 
deferred donor into the donor pool when the donor is requalified by a 
process or method (algorithm) approved by FDA for such purpose.

D. Medical Devices (Secs. 610.42 and 610.44)

    In the proposed rule, we discussed the need for labeling of medical 
devices manufactured from reactive blood or blood components. In the 
final rule, we have changed the text of Sec. 610.42 to require labeling 
for all medical devices that contain blood or a blood component as a 
medical device component, and not just in vitro diagnostic products. 
Under Sec. 610.42(a), when a medical device contains human blood or a 
human blood component as a component of the final device and the human 
blood or blood component was found to be reactive by a screening test 
for a communicable disease agent(s) or reactive by a serological test 
for syphilis then the device labeling requires a warning statement 
indicating that the product was manufactured from a donation found to 
be reactive by a screening test for evidence of infection due to the 
identified communicable disease agent(s). Other labeling requirements 
in subchapter H (Medical Devices) of chapter I would also apply. We 
also are allowing for an exemption approved by FDA to the statement of 
warning in circumstances where the reactivity of the human blood or 
blood component in the device presents no significant health risk 
through the use of the device.
    In proposed Sec. 610.44, manufacturers of test kits would be 
required to use, when available, a reference panel obtained from FDA or 
from a FDA designated source to verify the sensitivity and specificity 
of kits approved for use in testing donations of blood and blood 
components for communicable disease agents listed in Sec. 610.40(a) and 
for an HIV test approved for use in the diagnosis and monitoring of 
HIV.
    In the final rule, we are amending the requirements to clarify that 
when available and appropriate, a manufacturer must use panels that 
have been provided or identified by FDA to verify acceptable 
sensitivity and specificity of kits used to test donations of human 
blood and blood components, including licensed supplemental 
(additional, more specific) tests. The agency is making this change 
after reviewing 21 CFR 660.46. That regulation recognizes that official 
lot release may not be required after a manufacturer consistently 
produces a product that meets specifications. Consistent with this 
policy, the agency has recognized that less strict reference standard 
testing requirements may be appropriate in some situations. 
Accordingly, FDA has revised 1Sec. 610.44 to require use of reference 
panels only when such use is appropriate and panels are available. 
Moreover, FDA may determine that reference panel testing of each lot is 
not appropriate, based on a manufacturer's consistent prior production 
of products of acceptable sensitivity and specificity. In that 
situation, intermittent testing of lots may be appropriate.
    FDA also is clarifying that Sec. 610.44(a)(2) requires 
manufacturers of an HIV test kit approved for use in diagnosis, 
prognosis, or monitoring to use an FDA provided or designated reference 
panel, when available and appropriate to assure acceptable sensitivity 
and specificity of each lot of test kit. When available and 
appropriate, FDA expects the manufacturer to perform testing using the 
panel to assure that each lot meets acceptable sensitivity and 
specificity.
    The agency also is making a conforming amendment to Sec. 809.20(b) 
(21 CFR 809.20(b)), to make clear that Sec. 610.44 applies to all HIV 
test kits that are biological products, and are approved for diagnosis, 
prognosis, or monitoring, including any such kits reviewed under the 
medical device authorities.
    In the proposed rule, we stated that as technology and scientific 
knowledge advance, and the demands placed on the blood industry change, 
there will continue to be instances when a regulation will become 
outdated or where unanticipated circumstances may warrant a departure 
from a regulation. To allow for flexibility in such cases, we discussed 
the availability of approval for exemption upon written request from a 
manufacturer to FDA. We also noted that, under Sec. 640.120, applicants 
may submit requests for exceptions or alternatives to regulations 
regarding blood, blood components, or blood products. Consistent with 
this policy, we created a similar provision in the final rule that is 
applicable to the labeling of medical devices in Sec. 610.42, and 
distribution of lots found not to be acceptable for sensitivity and 
specificity in Sec. 610.44. We would approve an exception or 
alternative under these sections only if we concluded that the safety, 
purity, potency, and effectiveness of the final product were adequately 
assured. Manufacturers may submit, in writing to FDA, a request for an 
exception or alternative to Secs. 610.42(a) and 610.44(b). In limited 
circumstances, a request and approval may be made orally followed by a 
written request and written approval.

E. Technical Amendments

    We also made technical changes to existing regulations, consistent 
with this rulemaking. We removed Secs. 606.121(g), 607.65(g), 610.45, 
640.2(d), and 660.42. We revised Secs. 640.5(f) and 640.67 for 
consistency with Sec. 610.40, and in Secs. 606.121(h)(2) and (h)(3), 
640.14, 640.23(a), 640.33(a), and 640.53(a) we deleted ``Sec. 610.45.'' 
We have amended Secs. 606.121(e)(5)(ii) and 640.70(a)(2) to conform 
with the labeling requirement in Sec. 610.40(h)(2)(ii)(E), and amended 
Sec. 809.20(b) to conform with Sec. 610.44.

[[Page 31149]]

III. Testing for Syphilis

    In the proposed rule, we solicited comments, with supporting data, 
from the public in regard to the value of such a test as a marker of 
high risk behavior, as a surrogate test for other communicable 
diseases, and as a screen for syphilis in blood and blood components to 
prevent transfusion-related transmission. We recognized that many 
scientists, including some members of the blood banking community, 
continue to advocate the elimination of the serological test for 
syphilis as a testing requirement. Comments were received and are 
discussed in comment 28 of this document. We have concluded that there 
are insufficient data to justify eliminating the requirement for a 
serological test for syphilis. Therefore, Secs. 640.5(a) and 640.65(b) 
remain in effect at this time. The agency remains interested in 
receiving scientific data to clarify the value of performing serologic 
tests for syphilis on donations of blood and plasma.

IV. Relevant Guidance

    Over time, we have issued guidance representing the agency's 
current thinking on the adequate and appropriate testing of blood and 
blood component donations for evidence of infection due to various 
communicable disease agents. Because we are not specifying the test or 
tests to be used in this regulation, we are listing in the following 
table the test or tests we currently believe reduce adequately and 
appropriately the risk for transmission of communicable disease agents.

                        Table 1.--Screening Tests
------------------------------------------------------------------------
                                       Components    Components
                         Whole Blood   of, or Used  of, or Used
                          and Blood    to Prepare,  to Prepare,
                         Components      Medical      Medical     Source
         Tests            Including      Devices    Devices Not   Plasma
                          Recovered    Containing    Containing
                           Plasma        Viable        Viable
                                       Leukocytes    Leukocytes
------------------------------------------------------------------------
Serological Test for    X             X             X            X
 Syphilis (STS)
Antibodies to HIV,      X             X             X            X
 types 1 and 2 (anti-
 HIV)
HIV-1 Antigen (HIV-1    X             X             X            X
 Ag)
Hepatitis B Surface     X             X             X            X
 Antigen (HBsAg)
Antibody to Hepatitis   X              X\1\          X\1\
 B Core Antigen (anti-
 HBc)
Antibody to Hepatitis   X             X             X            X
 C Virus Encoded
 Antigen (anti-HCV)
Antibodies to HTLV,     X             X
 types I and II (anti-
 HTLV I/II)
------------------------------------------------------------------------
\1\ Anti-HBc testing not recommended for donations intended solely for
  further manufacturing into in vitro medical devices.


                                                        Table 2.--Additional More Specific Tests
--------------------------------------------------------------------------------------------------------------------------------------------------------
                  Tests                         STS          anti-HIV         HIV-1Ag          HBsAg         anti-HBc        anti-HCV     anti-HTLV I/II
--------------------------------------------------------------------------------------------------------------------------------------------------------
Approved Supplemental Tests                     X               X            X\1\            X\1\                               X
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ A neutralization assay is performed as part of the screening test procedure for a reactive sample.

    As technology advances, we intend to regularly issue guidance 
describing those tests that we believe would adequately and 
appropriately reduce the risk of transmission of communicable disease 
agents. Unless we determine that prior public participation is not 
feasible or appropriate, we intend to issue such guidance in draft, 
giving the opportunity for public comment and for manufacturers to 
prepare to use any appropriate new testing technologies. When prior 
public participation is not feasible or appropriate, for example, when 
immediate action is necessary to protect the public health, we may 
immediately implement the guidance.
    We have prepared a list of guidance documents that currently are 
applicable to these regulations. They are listed in order by date of 
issuance.
    <bullet> Recommendations for the Management of Donors and Units 
that are Initially Reactive for Hepatitis B Surface Antigen (HBsAg); 
December 2, 1987
    <bullet> HTLV-I Antibody Testing; November 29, 1988
    <bullet> FDA Recommendations Concerning Testing for Antibody to 
Hepatitis B Core Antigen (Anti-HBc); September 10, 1991
    <bullet> Clarification of FDA Recommendations for Donor Deferral 
and Product Distribution Based on the Results of Syphilis Testing; 
December 12, 1991
    <bullet> Revised Recommendations for Testing Whole Blood, Blood 
Components, Source Plasma and Source Leukocytes for Antibody to 
Hepatitis C Encoded Antigen (Anti-HCV); April 23, 1992
    <bullet> Revised Recommendations for the Prevention of Human 
Immunodeficiency Virus (HIV) Transmission by Blood and Blood Products; 
April 23, 1992
    <bullet> Revised Recommendations for Testing Whole Blood, Blood 
Components, Source Plasma and Source Leukocytes for Antibody to 
Hepatitis C Virus Encoded Antigen (Anti-HCV) [Supplements previous 
guidance April 23, 1992]; August 5, 1993
    <bullet> Donor Suitability Related to Laboratory Testing for Viral 
Hepatitis and a History of Viral Hepatitis; December 22, 1993
    <bullet> Recommendations for Donor Screening with a Licensed Test 
for HIV-1 Antigen; August 8, 1995
    <bullet> Additional Recommendations for Donor Screening with a 
Licensed Test Kit for HIV-1 Antigen [Supplements previous guidance 
August 8, 1995]; March 14, 1996
    <bullet> Additional Recommendations for Testing Whole Blood, Blood 
Components, Source Plasma, and Source Leukocytes for Antibody to 
Hepatitis C Virus Encoded Antigen (Anti-HCV) [Supplements previous HCV 
guidance--April 23, 1992 and August 5, 1993]; May 16, 1996
    <bullet> Guidance for Industry: Donor Screening for Antibodies to 
HTLV-II; August 15, 1997
    <bullet> Guidance for Industry: Errors and Accidents Regarding 
Saline Dilution of

[[Page 31150]]

Samples Used for Viral Marker Testing; June 11, 1998
    The guidance documents referenced in this document or otherwise 
applicable to the testing of donors of blood and blood components may 
be obtained from the Office of Communication, Training, and 
Manufacturers Assistance (HFM-40), Center for Biologics Evaluation and 
Research (CBER), Food and Drug Administration, 1401 Rockville Pike, 
suite 200N, Rockville, MD 20852-1448. Send one self-addressed adhesive 
label to assist that office in processing your requests. The guidance 
documents may also be obtained by mail by calling the CBER Voice 
Information System at 1-800-835-4709 or 301-827-1800, or by FAX by 
calling the FAX Information System at 1-888-CBER-FAX or 301-827-3844. 
Persons with access to the Internet may connect to CBER at http://www.fda.gov/cber/publications.htm.

V. Comments on the Proposed Rule

    We received 24 letters of comment on the proposed rule, most of 
which raised multiple issues. The comments were submitted by blood 
centers, hospitals, transfusion services, trade associations, and 
professional associations. A number of comments expressly supported our 
revision of communicable disease testing requirements to incorporate 
the agency's guidance and industry practice into one comprehensive 
regulatory framework to help ensure the safety of the blood supply. A 
summary of the comments and the agency's responses follow.

A. Testing of Autologous Donations

    In the proposed rule, each donation of autologous blood and blood 
component would be tested for evidence of infection due to the 
following communicable disease agents: HIV, types 1 and 2; HBV; HCV; 
and HTLV, types I and II. The testing would be performed using 
screening tests approved for such use by FDA. One or more such tests 
would be performed as necessary to reduce adequately and appropriately 
the risk of transmission of communicable disease. Restrictions on 
shipment or use would not apply to autologous blood and blood 
components provided the autologous blood and blood components are 
labeled appropriately. We requested comments on alternatives (including 
the rationale) to testing each autologous donation, such as procedural 
or labeling improvements. A majority of comments submitted to us 
responded to this issue.
    (Comment 1) Six comments support testing autologous donations in 
the same manner as allogeneic donations. The comments argue that a 
significant error rate in the use of autologous blood for allogeneic 
use or use in preparing a product, makes the current risks to 
recipients of blood and blood components unacceptable. They further 
argue that testing will reduce these risks, as well as the risk to 
healthcare workers from inadvertent exposure. Several of these comments 
recommend that autologous donations testing reactive for a communicable 
disease agent(s) should not be exempt from the restrictions on shipment 
and use in the proposed rule. They argue that positive donations of 
autologous blood should be discarded to protect the health of 
healthcare workers and to prevent inadvertent use of such autologous 
blood for allogeneic transfusions.
    Eleven comments oppose testing of autologous donations for evidence 
of infection due to communicable disease agents. These comments argue 
that testing would not significantly reduce the risk of inadvertent 
allogeneic transfusions with autologous blood and blood components 
because testing alone does not address the process errors that cause 
inadvertent allogeneic transfusions. Errors in labeling and handling 
autologous blood will occur regardless of whether donations are tested. 
Several comments argue that we presented no data to suggest testing 
will reduce inadvertent allogeneic transfusion. One comment points out 
that inadvertent allogeneic transfusion errors occur despite the fact 
that an estimated 60 to 70 percent of autologous donations currently 
are tested. The comments that argue against testing instead support 
regulation that focuses on improving quality assurance systems. These 
comments recommend optimizing labeling, separating processing paths and 
segregating storage for autologous donations, as well as requiring 
multiple identifications of recipients to address directly all 
(autologous and allogeneic) transfusion errors. Finally, comments 
opposed to testing autologous donations argue that the significant 
costs of testing are unwarranted given the lack of clinical utility. 
They argue that in many cases, particularly in small, rural hospitals 
where patients will have few alternatives, the costs of testing will be 
prohibitive and will result in reduced availability of autologous 
services. Several comments also suggest that reduced availability of 
autologous donations will result in an increase in allogeneic use with 
its attenuated risks outweighing any minor increase in safety from 
testing autologous donations.
    A number of comments recommend an intermediate position between 
testing all autologous donations and testing none. Three comments 
support testing only one in a series of autologous donations, noting 
that many autologous donors donate multiple donations in a short 
timeframe, therefore, testing each donation would result in significant 
costs without any appreciable increase in safety to the blood supply. 
One comment calls for testing autologous donations once in 30 days if 
the autologous donation is to be shipped from the collection 
establishment before transfusion. If the donation is collected and 
transfused in the same facility, the comment recommends no testing be 
required. The same comment supports labeling all autologous donations 
with a unique label stating ``FOR AUTOLOGOUS USE ONLY'' and all 
reactive or untested donations with a ``BIOHAZARD'' legend. Further, 
the comment calls for prohibiting establishments from using autologous 
donations as allogeneic donations. The comment argues that requiring 
testing every 30 days for shipped autologous donations, labeling 
changes, and preventing the use of autologous blood and blood 
components for allogeneic transfusion are better, more cost-efficient 
methods of protecting patients and health care personnel.
    Based on the comments submitted and our own evaluation, the agency 
has concluded that its proposal to test all autologous donations in the 
same manner as allogeneic donations should be amended. While 
communicable disease testing plays a major role in improving the safety 
of the allogeneic blood supply, we are not convinced that the testing 
of all autologous donations is necessary to improve the safety of the 
general blood supply. It is the inadvertent improper use of autologous 
donations, rather than the product itself, which poses risk to the 
public health. Many of the incidents involving autologous donations 
that compromise transfusion safety are caused by process or clerical 
error. As one comment points out, these errors occur regardless of 
whether the autologous donation is tested and its communicable disease 
status is known. We are persuaded that such errors involving autologous 
donations can be better addressed by changes in labeling and processing 
of autologous donations. We believe that clearly marking autologous 
donations as ``DONOR UNTESTED,'' as well as with the autologous label 
(Sec. 606.121(i) (21 CFR 606.121(i))), will alert healthcare workers 
that they could be handling potentially infectious products and

[[Page 31151]]

should take appropriate precautions. We believe that not requiring 
testing of autologous donations will help assure continued autologous 
services at certain small, rural blood establishments, which do not use 
autologous donations for allogeneic use. We believe that these labeling 
changes will sufficiently increase the safety of autologous 
transfusions without compromising the availability of these services.
    However, we have concluded that under certain circumstances there 
is a potential risk to blood safety from autologous donations, and 
under those circumstances labeling changes alone are insufficient to 
protect the public health. First, blood establishments that permit 
autologous donations to be used for allogeneic transfusions run a 
potentially greater risk of erroneous transfusion of an autologous 
donation to an unintended recipient. We are requiring that 
establishments that maintain a program permitting allogeneic use of 
autologous donations test each autologous donation collected regardless 
of whether the particular blood or blood component is ``crossed-over'' 
for allogeneic use. Positive and reactive donations must be labeled 
with a ``BIOHAZARD'' legend as well as with the label ``FOR AUTOLOGOUS 
USE ONLY'' as required under Sec. 606.121(i). Autologous donations that 
test negative for evidence of infection due to communicable disease 
agents must be labeled ``FOR AUTOLOGOUS USE ONLY'' as further specified 
under Sec. 606.121(i). The agency believes that blood establishments 
that use autologous donations for allogeneic uses should be subject to 
these additional safety measures to prevent erroneous allogeneic uses. 
The agency believes that for such establishments the additional margin 
of safety achieved by testing all donations in the establishment's 
inventory and labeling reactive donations with a ``BIOHAZARD'' legend 
is necessary to protect the public health.
    The second area in autologous transfusion services that presents 
additional safety concerns is the shipment of autologous products from 
the collection facility to another establishment. Errors, including 
clerical errors in inventory management and breakage of autologous 
donations, may occur when the product is handled by a variety of 
individuals and facilities throughout collection, transport, storage, 
and transfusion. We are requiring that blood establishments that ship 
autologous products to other establishments that do not use autologous 
donations for allogeneic use must test the first autologous donation 
collected at the beginning of each 30-day period for evidence of 
infection due to communicable disease agents. We believe a minimum 
requirement of testing the autologous donor's blood at least once in 30 
days is sufficient because autologous donations are usually given in a 
series over a short timeframe. Because these donations are not intended 
to be transfused into any other recipient than the donor, testing once 
in 30 days for evidence of infection due to communicable disease agents 
will give an added measure of safety to those handling the blood 
without the costs of testing each autologous donation. Thus, if an 
autologous donor donated three times over a 30-day period and the 
establishment ships the autologous donations to another establishment 
that does not allow use of autologous donations for allogeneic 
transfusion, the rule requires, at a minimum, that the establishment 
test the first collection only. If the donor donated a fourth time on 
the 31st day or later, the establishment must test the fourth 
collection.
    (Comment 2) One comment raises several additional arguments against 
testing autologous donations including: Testing may give a false sense 
of increased protection resulting in decreased attention and more 
errors; testing may result in denial of services to patients or loss of 
autologous donor programs; and testing of autologous donations 
constitutes the practice of medicine since autologous donors are 
patients under a doctor's care.
    We do not believe that testing of autologous donations will result 
in decreased attention and more errors. Communicable disease testing of 
allogeneic blood and blood components has been an important and 
effective tool to ensure the safety of the blood supply. Testing of 
autologous donations, which are shipped to or collected in an 
establishment that maintains a program that uses autologous blood and 
blood components for allogeneic transfusion will provide an additional 
margin of safety against a potentially greater risk of error. We do not 
believe that communicable disease testing of autologous donations will 
result in a denial of such services to patients or in the loss of such 
programs. We are not requiring testing of autologous blood and blood 
components except when an establishment has a program allowing the use 
of autologous donations for allogeneic transfusion, or ships the 
autologous donations from the collecting facility. We believe this 
approach allows services and programs for autologous collections to 
continue while protecting potential allogeneic recipients and 
healthcare workers who may be exposed to biohazardous blood or blood 
components.
    The comment views the testing of autologous donations as practice 
of medicine. However, we do not consider testing of autologous 
donations to be practice of medicine, but to be a safeguard in 
protecting the public health when autologous donations are made 
available for allogeneic use or when others may be exposed to 
potentially hazardous donations during shipment of autologous donations 
by the collecting establishment. This policy responds to a 
recommendation in the February 1997 report issued by the General 
Accounting Office entitled ``Blood Supply: FDA Oversight and Remaining 
Issues of Safety.''
    (Comment 3) Two comments argue that testing and labeling autologous 
blood and blood components can seriously jeopardize the confidentiality 
of the donor's communicable disease status.
    We do not believe the required testing and labeling of autologous 
donations will seriously compromise the donor's confidentiality. The 
final rule does not require most autologous donors to be tested, and 
labeling on untested autologous donations will not raise 
confidentiality issues. In addition, the label will not identify in any 
manner the donor's particular communicable disease status. The 
``BIOHAZARD'' legend on donations from autologous donors who test 
positive or reactive will serve as a necessary alert for blood 
healthcare workers and help prevent transfusion errors. We recommend 
that autologous donors be informed beforehand if their donations will 
be tested for evidence of infection due to communicable disease agents. 
Thus, autologous donors may choose not to donate in a setting where 
testing is required.
    (Comment 4) Seven comments raise the issue of what to do with 
autologous blood or blood components that test reactive by one or more 
of the communicable disease agents identified in Sec. 610.40(a). 
Several of these comments point out that blood establishments are under 
ethical and legal constraints that would prevent them from discarding 
test positive autologous donations. Several comments suggest that under 
a recent Supreme Court decision it may be a violation of the American 
with Disabilities Act (``ADA'') to deny HIV-infected patients the right 
to use their own blood. Two comments strongly support discarding 
autologous donations testing reactive. These comments argue that the 
risks from

[[Page 31152]]

keeping these positive donations in blood inventories are too great. 
The comments argue these donations should be treated similarly to blood 
from a positive allogeneic donor and discarded.
    We are not prohibiting blood establishments from transfusing 
positive donors with their own blood. These donations, however, if made 
available for autologous use must be labeled ``FOR AUTOLOGOUS USE 
ONLY'' and also with a ``BIOHAZARD'' legend.
    (Comment 5) Several comments call for prohibiting the use of 
autologous donations for allogeneic transfusion for all blood 
collection establishments. The comments argue that the benefit of 
testing would be negated if test positive autologous donations remain 
in the system subject to the processing errors that can occur when use 
of autologous donations for allogeneic transfusions is permitted.
    The agency has determined that this final rulemaking is not the 
appropriate venue to institute a requirement prohibiting use of 
autologous donations for allogeneic use. However, we believe that this 
issue should be considered further in the more general context of 
medical errors. In the interim, we believe that requiring blood 
establishments that continue the practice of using autologous donations 
for allogeneic transfusions to test and appropriately label all their 
autologous donations will help control errors involving autologous 
donations testing reactive for a communicable disease agent(s).
    (Comment 6) Four comments point out that the proposed rule does not 
address perioperative autologous blood collections. Two comments 
suggest that requiring testing of perioperative collections would 
effectively eliminate them because testing would not be completed in 
time for donations to be used. One comment suggests the final rule 
should contain an exception for intraoperatively salvaged blood.
    We are not proposing testing of perioperative blood collections. 
These blood or blood components are collected and used within the same 
facility where the operation is being performed, and are not intended 
for allogeneic use. They also do not become part of the transfusion 
center's or blood collection establishment's inventories. Therefore, we 
do not consider perioperative blood or blood component donations 
subject to testing for evidence of infections under the purview of the 
final rule.
    (Comment 7) Four comments suggest that we deal with the issue of 
the inappropriate use of recovered plasma for further manufacture from 
untested or communicable disease marker reactive autologous blood by 
banning the use of untested or reactive recovered plasma or by 
requiring testing of autologous blood to be used for salvage.
    Under 21 CFR 606.100(b)(18), blood establishments are required to 
establish and maintain standard operating procedures (SOP's) for 
recovered plasma. If a blood establishment intends to use recovered 
plasma from an untested donation for further manufacturing use, the 
donation would then be considered an allogeneic donation subject to the 
testing requirements for allogeneic donations under the final rule. The 
use of untested or reactive autologous blood for further manufacturing 
is prohibited unless exempted under Sec. 610.40(h)(2).

B. Exception for Dedicated Apheresis Donations

    We requested comments on whether to exempt from testing for 
evidence of infection due to communicable disease agents each donation 
from a dedicated apheresis donor (defined in section I.B of this 
document) and instead test such donors only once in each 30-day period.
    (Comment 8) Eight comments responded to this request. One comment 
opposes a once in each 30-day period testing exception for dedicated 
apheresis donors, arguing that recipients of these donations are 
entitled to the same protection as other recipients of blood 
components. The remaining seven comments support allowing testing of 
dedicated apheresis donors only once every 30 days. These comments cite 
the fact that dedicated apheresis donations are often used for patients 
in dire situations who are unable to wait for each donation to be 
tested. They argue that dedicated apheresis donations tested only once 
in each 30-day period would not present a safety concern because new 
tests have substantially increased the reliability of the first 
donation's test results; because subsequent donations during the 30-day 
period would create little additional risk to the recipient, since the 
first donation would expose the recipient to any undetected infection; 
and because new risk of exposure could be caught by taking the donor's 
medical history (including health and social history screening) on the 
day of each subsequent collection. (See 21 CFR 640.3(a).)
    Based on the comments submitted and the agency's own evaluation, we 
have concluded that donations from dedicated apheresis donors must be 
tested for evidence of infection due to communicable disease agents at 
the first donation and at a minimum of once at the beginning of each 
successive 30-day period. This exception from universal testing will 
provide the recipient of dedicated apheresis donations with adequate 
protection against disease transfer since the test results would be 
unlikely to change within the 30-day period. We also believe this 
exception will limit donor exposure when the patient needs frequent 
transfusions and will help avoid delaying treatment of patients in need 
of emergency transfusions.
    (Comment 9) One comment suggests that the communicable disease 
agent testing should be allowed near the time of the first collection 
to facilitate expedited release of dedicated apheresis donations to 
patients in need.
    We have reviewed the comment and will consider permitting 
communicable disease agent testing prior to collection of the first 
dedicated donation in the context of creating specific standards for 
dedicated donations in future rulemaking.
    (Comment 10) Two comments call for use of an abbreviated donor 
screening questionnaire for dedicated apheresis donors.
    Since we are limiting testing for evidence of infection due to 
communicable disease agents to the first donation in each 30-day 
period, we believe that the screening process plays an even more 
important role in evaluating the safety of the blood or blood component 
being collected from the dedicated donor. The possible implications of 
an abbreviated screening are not in the scope of this rulemaking, and 
are under study for future rulemaking.
    (Comment 11) Two comments suggest extending this exception from 
universal testing to other dedicated blood components (e.g. dedicated 
granulocyte donors; parent to child donations of plasma or red blood 
cells).
    We agree with this comment. We believe that donations from 
dedicated donors should be treated alike in regards to communicable 
disease testing. Accordingly, the agency has extended the exception 
allowing testing for evidence of infection due to communicable disease 
agents to the first donation in each 30-day period for all donations of 
blood and blood components from dedicated donors to a single, 
identified recipient. Syphilis testing is required, at a minimum, for 
the first donation in each 30-day period in addition to the other 
communicable disease agents listed in Sec. 610.40(a).
    (Comment 12) One comment also calls for extending the exemption to 
other non-infectious tests required for donations from dedicated 
apheresis

[[Page 31153]]

donors, such as ABO, Rh, red cell antibody screening.
    We disagree with this comment. Tests such as ABO, Rh, and red cell 
antibody screening are part of matching the donation to the donor and, 
therefore, part of quality assurance processes.
    (Comment 13) One comment suggests that subsequent donations from 
dedicated apheresis donors should not be labeled as untested since the 
test results from the first donation should apply to subsequent 
donations.
    We agree with this comment. We are requiring that donations 
subsequent to the first tested donation in each 30-day period from 
dedicated donors, including apheresis donors, be labeled ``DONOR TESTED 
WITHIN THE LAST 30 DAYS.''
    We are aware that there may be occasions where the dedicated 
donations are no longer needed by the identified recipient. When an 
untested donation is to be used for transfusion to another recipient or 
for further manufacturing, the establishment must assure that all 
suitability criteria under Sec. 640.3 are met and that testing required 
under Sec. 610.40 is completed and that the donation tests nonreactive 
before use.

C. Supplemental Testing

    In proposed Sec. 610.40(c), we would require that each donation 
found to be reactive by a screening test for evidence of infection due 
to communicable disease agents be further tested whenever a 
supplemental (additional, more specific) test has been approved for 
such use by FDA.
    (Comment 14) Three comments support our proposal to further test 
reactive donations whenever a supplemental (additional, more specific) 
test has been approved for such use by FDA. These comments point out 
that this information is relevant to the donor and part of the usual 
and customary business practice for blood centers to provide. One of 
these comments also suggests that requiring such testing will provide 
test kit manufacturers with the economic incentive to develop 
supplemental tests for less common viruses for which donors are 
screened.
    Four comments oppose our mandating supplemental testing. These 
comments argue that there is not a sufficient public health concern and 
that the costs are too burdensome. The comments suggest that our 
regulatory concerns should be limited to deferring reactive donors and 
labeling positive donations. Several of these comments argue that 
supplemental testing has no impact on blood safety and is a medical 
decision to be made by the donor's physician. Others suggest that blood 
centers do supplemental testing voluntarily if they intend to reenter 
donors; so supplemental testing should not be required.
    Historically, we have recommended in guidance supplemental testing 
of reactive samples and, for HIV, we have required supplemental testing 
in Sec. 610.46(b). We consider supplemental testing as part of 
communicable disease control, necessary in protecting public health. 
Screening tests are designed to be highly specific for the tested 
marker. Nevertheless, false positives occur due to sample 
contamination, cross-reactivity, or nonspecific causes. In 
Sec. 610.40(e), we are requiring that reactive samples be further 
tested by a supplemental (additional, more specific) test, when 
available, that has been approved for such use by FDA. Although a donor 
must be deferred based on a reactive screening test, the blood and 
plasma establishment should use the information obtained through 
supplemental testing to notify and counsel the deferred donor. 
Providing donors with accurate information about their communicable 
disease status and deferral as soon as possible helps ensure a healthy 
donor population. Blood and plasma establishments also can use 
information from supplemental testing to evaluate the donor for 
possible reentry into the donor pool. Requalification of donors 
contributes to blood availability, which also is a public health 
concern. Therefore, FDA believes supplemental testing has a direct 
impact on blood safety in preventing communicable disease transmission 
and in optimizing blood availability.
    (Comment 15) Several comments object to HCV supplemental testing in 
particular because there is currently no requirement for lookback or 
product retrieval and there is no reentry algorithm in place.
    We disagree with the comments. We consider supplemental testing 
part of blood safety by providing deferred donors with accurate, timely 
information regarding their deferred status and possible transmission 
of communicable disease. Currently, we allow reentry of donors who test 
reactive by a multiantigen screening test for HCV. Reentry into the 
donor population must follow a method or process approved by FDA. This 
process includes the use of a supplemental test, e.g., recombinant 
immunoblot assay 3.0 (RIBA 3.0). We have issued draft guidance on our 
current thinking on HCV ``lookback'' (see section IV of this document 
for description on how to access the draft guidance document); we 
intend to finalize this guidance and to propose new regulations in a 
future rulemaking for ``lookback'' when donors test reactive for HCV.
    (Comment 16) One comment objects to supplemental testing of 
autologous donations. The comment objected, in part, because of the 
costs associated with testing each donation from autologous donors.
    Under the final rule, we require testing of autologous donations 
only where there is a public health risk, i.e., where an establishment 
has a program allowing the use of autologous donations for allogeneic 
transfusion, or where a collecting establishment ships autologous 
donations. For those donations of autologous blood and blood components 
that are required to be tested, we also are requiring blood 
establishments to further test such donations using supplemental tests. 
If an autologous donation is reactive in screening tests, blood 
establishments are required to defer the autologous donor from future 
allogeneic donations. The deferred autologous donor has the same need 
as the deferred allogeneic donor for accurate information regarding his 
or her possible infectious status, and the information from 
supplemental testing may prevent the donor from spreading the 
infection. Thus, we believe that supplemental testing of autologous 
donations is just as necessary to blood safety and public health as 
supplemental testing of allogeneic donations. For those autologous 
donors with a record of a positive supplemental test for a specific 
communicable disease agent, the establishment is not required to 
perform the supplemental test again.
    (Comment 17) Two comments argue that the approved supplemental 
tests are not always the best method of confirmatory testing, pointing 
to nucleic-acid-based testing (NAT) for HCV and HIV. The comments also 
suggest allowing blood establishments to use NAT testing and leave the 
decision to the donor's physician whether other supplemental tests are 
warranted medically.
    In structuring the proposed rule, we intended to allow for 
advancements in testing technology without further rulemaking. We built 
into the requirement for supplemental testing of reactive donations the 
ability for blood and plasma establishments to use different testing 
methods as long as those tests have been approved by the agency. NAT is 
not yet available as a supplemental testing method and cannot now be 
used in lieu of licensed or approved tests. However, we expect further 
development in NAT, both as a screening and supplemental test, and 
intend to issue guidance on the use of such testing in the future.

[[Page 31154]]

    (Comment 18) Three comments suggest that to reduce costs and delays 
supplemental tests need be performed only on the first reactive 
donation in a series of donations.
    Supplemental testing, when available, is required for each donation 
that tests reactive for evidence of infection due to a communicable 
disease agent(s) listed in Sec. 610.40. We agree with the comments in 
part, and applied the suggestion to autologous donors. We are making 
two exceptions to performing supplemental testing on each reactive 
donation. The first exception requires, at a minimum, that supplemental 
testing be performed on the first reactive autologous donation in each 
30-day period. The second exception is when an autologous donor has a 
positive supplemental test of record. In that instance, the 
supplemental test is not required to be performed on subsequent 
autologous donations.

D. Release or Shipment Prior To Testing

    In proposed Sec. 610.40(e), we would allow the use or shipment 
prior to test results of human blood or blood components under two 
circumstances: Appropriately documented medical emergency situations; 
or when approved in writing by FDA. Use or shipment prior to test 
results may occur, provided the consignee is notified that test results 
are not available, the tests for evidence of infection due to 
communicable disease agents are performed as soon as possible after 
release or shipment, and the results are provided promptly to the 
consignee.
    (Comment 19) Several comments support allowing use or shipment of 
donations prior to testing in medical emergencies and routine shipment 
for further manufacturing use. One comment opposes any use or shipment 
prior to testing.
    We believe these exceptions are necessary to ensure the continued 
availability of blood products in emergency situations and when 
products require rapid preparation, e.g., Source Leukocytes. In either 
instance, the completion of testing prior to shipment or use may not be 
feasible. The regulations require the blood or plasma establishment to 
document the emergency release or shipment of blood or blood components 
prior to completion of testing. If the blood or plasma establishment 
ships blood or blood components for further manufacturing use prior to 
completion of testing, the blood establishment must obtain prior 
approval from FDA. In either instance, the blood or plasma 
establishment must complete testing as soon as possible thereafter, and 
must notify the consignee of test results as soon as they are 
available.
    (Comment 20) One comment argues that a blood establishment should 
not be required to obtain approval from FDA before shipping untested 
blood or blood components for further manufacturing use. The comment 
contends that there is no public health concern since the blood or 
blood components are not released yet. The comment asserts that a 
request for FDA approval would delay manufacture of the biological 
product. The comment asks that any such requests be automatically 
approved 30 days after submission to FDA.
    We believe it is essential as a public health safeguard that blood 
or plasma establishments shipping blood and blood components for 
further manufacturing use prior to completion of testing obtain prior 
approval from FDA and submit their SOP's for review. However, the blood 
or plasma establishment must submit its SOP's and obtain prior approval 
only before its first shipment--not, as some comments seem to suggest, 
before each shipment. This requirement of a single submission will not 
delay the manufacture of a biological product. We believe that this 
provision will expedite the manufacturing process by allowing 
communicable disease testing to be completed after shipment, but before 
further manufacturing use. Prior approval is necessary to help ensure 
that a blood or plasma establishment is following proper procedures in 
shipping potentially infectious blood and blood components for further 
manufacturing use.
    (Comment 21) One comment asks FDA to clarify whether proposed 
Sec. 610.40(e)(2) addresses the transfer of untested donations within a 
multifacility manufacturer for labeling purposes.
    Requests to ship blood and blood components prior to testing 
between facilities within a multifacility manufacturer for labeling 
purposes should be submitted through the license application for that 
product. FDA will review those applications on a case-by-case basis.

E. Donor Deferral

    In proposed Sec. 610.41, we would require donors testing reactive 
for evidence of infection due to a communicable disease agent or 
reactive for a serological test for syphilis be deferred from future 
donations of blood and blood components. Proposed exceptions to this 
requirement are: (1) Autologous donors; (2) plasmapheresis donors with 
a reactive serological test for syphilis under Sec. 640.65; (3) donors 
who test reactive for anti-HTLV, types I or II, or anti-Hepatitis B 
core (anti-HBc) on only one occasion; (4) donors who test reactive for 
anti-HTLV, types I or II, or anti-HBc may serve as donors of Source 
Plasma; (5) deferred donors testing reactive for evidence of infection 
due to a communicable disease agent may serve as donors for blood or 
blood components when used following the requirements for restriction 
on shipment or use; (6) deferred donors showing evidence of infection 
due to hepatitis B virus when previously tested, may donate blood or 
blood components in the preparation of Hepatitis B Immune Globulin 
(Human) provided their current donations test negative for HBsAg and 
the donor is determined otherwise to be suitable; (7) donors testing 
reactive with a serological test for syphilis and found negative by an 
approved specific treponemal test; and (8) previously deferred donors 
later found to be suitable as donors of blood or blood components by a 
method or process acceptable for such purposes by FDA.
    (Comment 22) One comment supports and one comment opposes allowing 
donors testing reactive for anti-HTLV, type I or type II, or anti-HBc 
to serve as donors of Source Plasma.
    In the proposed rule, we explained that the communicable disease 
agents HTLV, types I and II, are highly cell-associated. It is well 
established that HTLV, types I and II infection may be transmitted to 
recipients by the transfusion of cellular blood components from 
infected donors. Conversely, HTLV transmission has not been 
demonstrated by the transfusion of Plasma or Cryoprecipitate or by the 
use of products made from Source Plasma. Donors testing reactive for 
anti-HBc also do not present a risk of transmitting hepatitis B to 
recipients of plasma derivatives made from Source Plasma. Although 
blood that is reactive for anti-HBc, even when negative for hepatitis B 
surface antigen (HBsAg), has a low risk of infectivity for HBV and 
would not be suitable for transfusion, the plasma from such blood would 
be suitable for manufacture into plasma derivatives. In most cases, 
blood that is negative for HBsAg, but is reactive for anti-HBc would be 
from a donor who has cleared a hepatitis B infection. Such a donor 
would still have circulating anti-HBc and presumably would also have 
circulating anti-hepatitis B surface antigen (anti-HB's), which is 
hepatitis B neutralizing antibody. This neutralizing antibody is 
thought to contribute to the safety of immune globulin products. 
Additionally, all licensed human plasma derivatives undergo procedures

[[Page 31155]]

that will inactivate HBV and HTLV. In the final rule, therefore, we 
continue to allow donors testing reactive for anti-HTLV, type I or type 
II, or anti-HBc to serve as donors of Source Plasma, consistent with 
the exemption that donors of Source Plasma need not be tested for anti-
HTLV, types I and II, and anti-HBc.
    (Comment 23) One comment suggests creating a temporary deferral 
category for donors found reactive with earlier generation EIA/
screening test, but negative by more specific tests and reenter those 
donors if they test negative two times 6 months apart by a later more 
specific/sensitive test for the same marker.
    We disagree with this comment on the basis that it is too specific 
for a regulation. The final rule contains a provision in 
Sec. 610.41(b), which allows donors deferred based on reactive 
screening tests to be reentered into the donor pool if their blood 
subsequently tests negative for the same communicable disease agent and 
the donor is shown to be suitable to donate by a method or process 
approved by FDA. We have identified such donor reentry algorithms in 
guidance documents for some of the communicable disease agents listed 
in Sec. 610.40 of the final rule. We expect, in the future, that blood 
and plasma establishments will submit for approval other reentry 
algorithms for the listed communicable disease agents.
    (Comment 24) One comment requests that FDA explicitly allow the use 
of newly developed technologies to reenter donors under proposed 
Sec. 610.40(f)(3).
    We are allowing for further advancements in testing methodologies 
by not identifying specific tests to be performed within this 
rulemaking. We will continue evaluating new technologies related to 
reentry of deferred donors. We intend to issue guidance concerning our 
views on the use of those new technologies in screening and 
confirmatory communicable disease testing and as part of reentry 
algorithms for donors deferred based on results of screening tests for 
infection due to communicable disease agents.
    (Comment 25) One comment stated that the exception to deferral in 
proposed Sec. 610.41(a) should apply to donors who test reactive for 
anti-HTLV, types I and II, or anti-HBc on only one occasion, unless 
further testing under proposed Sec. 610.40(c) is positive.
    We agree in part with this comment. Once a supplemental test for 
anti-HTLV, types I and II, or for anti-HBc is approved, deferral will 
occur after a reactive screening test on one occasion regardless of the 
outcome of the supplemental (additional, more specific) testing. When a 
supplemental test is approved, we intend to issue guidance on when 
donor requalification is appropriate. Until such time, deferral will be 
based on reactive test results on two occasions.
    (Comment 26) One comment requests clarification of the rule's 
impact on anti-HBc testing of blood and blood components for further 
manufacturing use.
    The final rule does not require blood and plasma establishments to 
test blood and blood components for further manufacturing use 
(including Source Plasma) for anti-HBc. The rule does not prohibit 
establishments that choose to test such products for anti-HBc from 
using reactive blood or blood components in fractionation products and 
in in-vitro diagnostic products. A guidance issued to all registered 
blood establishments addresses labeling for injectable and non-
injectable products using anti-HBc reactive blood components. (See the 
list of documents in section IV of this document (dated September 9, 
1991).)
    (Comment 27) For the manufacture of Hepatitis B Immune Globulin 
(Human) (HBIG), one comment supports the use of donors immunized to 
hepatitis B virus, as an alternative to using donors previously showing 
evidence of infection due to hepatitis B virus. The comment contends 
that this change would expand the possible supply. Another comment 
opposes the sole use of blood from donors immunized to hepatitis B 
virus in manufacture of HBIG for reasons related to protecting the 
public health.
    We disagree with the first comment, and accept the second. In the 
final rule, we have permitted deferred donors previously showing 
evidence of infection due to hepatitis B virus to donate blood or blood 
components for use in the preparation of HBIG, provided that the 
current donations test nonreactive for HBsAg and that the donor is 
otherwise suitable. The agency has concluded that donors with 
antibodies to HBsAg should not be excluded. Donors having detectable 
antibodies to HBsAg have a spectrum of antibodies to different epitopes 
of the hepatitis B virus and, therefore, are acceptable or even 
desirable as donors for HBIG. Blood or blood components from such 
donors also may provide better protection against future mutations of 
the hepatitis B virus. We believe that HBIG prepared from the blood and 
blood components of donors previously showing evidence of infection 
would produce a more effective product.

F. Syphilis

    In the proposed rule, we requested comments on continuing the 
requirement for testing each donation of blood and blood components for 
syphilis. We also requested data supporting their conclusion.
    (Comment 28) The majority of comments that responded to the issue 
of testing for syphilis support eliminating such testing. These 
comments argue that there has been no reported case of transfusion 
transmitted syphilis in 30 years; that studies show treponemes don't 
survive in blood stored at 4 \1/2\C and positive treponenemal DNA/RNA 
is not present in test positive donations based on studies using 
polymerase chain reaction (PCR ) (ARCNET study); that there are no 
relevant case reports of platelet transfusion transmission; and that 
recent studies indicate testing for syphilis has limited value as a 
surrogate marker for other communicable disease agents or high risk 
behavior. The comments also point out that syphilis testing has 
unnecessarily constricted the blood supply and eroded donor trust as 
otherwise qualified donors are deferred based on what turns out to be 
treated previous infection. Those comments that oppose eliminating the 
syphilis requirements criticize the recent ARCNET study's methodology 
and conclusions and argue that there is not sufficient information to 
eliminate testing requirements.
    After reviewing the comments and submitted study in addition to 
other scientific data, we have determined that the comments did not 
provide sufficient supporting data to justify eliminating the 
requirements to test blood and blood components with a serological test 
for syphilis. Preliminary results from ongoing studies indicate that 
the infectivity of seroreactive donors remains the subject of 
scientific debate. (See the transcript of the 67th Blood Product 
Advisory Committee Meeting, September 15, 2000). We will continue to 
consider this issue including any further studies that address the 
issues of transfusion related syphilis infection or testing for 
syphilis as a surrogate marker for other communicable diseases. We 
remain interested in receiving data supporting the elimination of the 
requirement for syphilis testing. Blood and plasma establishments must 
continue to test donations of blood and blood components for syphilis 
under Secs. 640.5(a), 640.14, 640.23(a), 640.33(a), 640.53(a), and 
640.65(b)(2) and references to these sections are inserted into the 
codified language in Secs. 610.40

[[Page 31156]]

and 610.41. The final rule requires that blood and plasma 
establishments defer donors who test reactive for a serologic test for 
syphilis unless a specific treponemal antibody test is negative or the 
donation is used for further manufacturing into control serum for a 
serological test for syphilis.
    In Sec. 610.40(h)(2)(vi) and (vii), we added language describing 
current requirements for the use of human blood, blood components, and 
Source Plasma with a reactive screening test for syphilis that is 
determined to be a biological false positive. Human blood and blood 
components may be used if the reactive screening test is further tested 
by an adequate and appropriate test demonstrating that the reactive 
screening test is a biological false positive. (See the list of 
documents in section IV of this document (dated December 12, 1991)). 
Such donations must be labeled with both test results. Source Plasma 
may be used from a donor with a reactive screening test for syphilis if 
the donor meets the requirements of Sec. 640.65(b)(2).

VI. Effective Date

    This final rule becomes effective December 10, 2001. All blood and 
blood components collected on and after the effective date must be in 
compliance with the new requirements. Labeling required by 
Secs. 610.40(c)(3)(ii) and (h)(2)(ii), and 610.42 must be submitted to 
FDA as part of a supplement submission requesting FDA approval prior to 
distribution of a product under Sec. 601.12(f)(1) (21 601.12(f)(1)). 
All other labeling changes must be submitted in an annual report under 
Sec. 601.12(f)(3).

VII. Analysis of Impacts

    FDA has examined the impacts of the rule under Executive Order 
12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
under the Unfunded Mandates Reform Act(2 U.S.C. 1501 et seq.). 
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 impacts; and equity). The Regulatory 
Flexibility Act requires agencies to analyze whether a rule may have a 
significant impact on a substantial number of small entities and, if it 
does, to analyze regulatory options that would minimize the impact. 
Section 202(a) of the Unfunded Mandates Reform Act requires that 
agencies prepare a written statement of anticipated costs and benefits 
before proposing any rule that may result in an expenditure in any one 
year by State, local, and tribal governments, in the aggregate, or by 
the private sector, of $100 million (adjusted annually for inflation).
    The Office of Management and Budget (OMB) has determined that the 
rule is a significant regulatory action as defined by the Executive 
Order and so is subject to review. Because the rule does not impose any 
mandates on State, local, or tribal governments, or the private sector, 
that will result in any one year of $100 million or more, FDA is not 
required to perform a cost-benefit analysis according to the Unfunded 
Mandates Reform Act.
    The Regulatory Flexibility Act requires agencies to prepare a 
Regulatory Flexibility Analysis for each rule unless the agency 
certifies that the rule will not have a significant economic impact on 
a substantial number of small entities. Although the rule is not 
expected to have a significant economic impact on a substantial number 
of small business entities, a precise impact is uncertain. Therefore, 
the agency has prepared a Regulatory Flexibility Analysis.

A. Objectives and Basis of the Action

    The basis for this rule is to help protect the safety and ensure 
the quality of the Nation's blood supply, and to promote consistency in 
the industry. The safety of the Nation's blood supply is enhanced when 
donors whose test results indicate evidence of infection due to 
communicable disease agents are excluded from donating blood and blood 
components. Under the biologics licensing and quarantine provisions of 
sections 351-361 of the Public Health Service Act (PHS Act) (42 U.S.C. 
262-264) and the drug, device, and the general administrative 
provisions of sections 501-503, 505-519, and 701-704 of the Federal 
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 351-353, 355-360i, 
and 371-374), FDA has the authority to issue regulations designed to 
protect the public from unsafe or ineffective biological products and 
to issue regulations necessary to prevent the transmission of 
communicable diseases into the United States or from one State to 
another. Under these statutory authorities, the agency is: (1) 
Requiring supplemental (additional, more specific) testing of all 
donations that are reactive by screening tests for which there are 
supplementary tests; and (2) codifying as requirements those 
recommendations that FDA has issued that are necessary to ensure blood 
safety, including testing for evidence of infection due to HIV, HBV, 
HCV, and HTLV.

B. Nature of the Impact

    The rule requires that each donation of human blood or blood 
component, including those intended for use as a component of, or used 
to prepare, a medical device, but not including those intended for 
autologous use, unless shipped or used for allogeneic transfusion, be 
tested for evidence of infection due to HIV, types 1 and 2; HBV; HCV; 
and HTLV, types I and II. Each donation that is reactive when tested 
for evidence of infection due to any of the disease agents would be 
required to be further tested whenever a supplemental (additional, more 
specific) test has been approved for such use by FDA. FDA is requiring 
that the testing be done by a laboratory that is registered with FDA 
and CLIA-certified or meeting equivalent requirements as determined by 
HCFA. The rule also contains provisions for appropriate deferral of 
donors based on test results, and exemptions for Source Plasma from 
being tested for evidence of infection from HTLV, types I and II. Under 
the rule, allogeneic donations that test reactive shall not be shipped 
except in situations specifically approved by FDA. Autologous donations 
may be shipped as long as they are properly labeled.
    This rule also requires manufacturers of tests kits, approved for 
use in testing donations of human blood and blood components for these 
disease agents, to verify an acceptable sensitivity and specificity of 
each lot of test kit, using a reference panel obtained from CBER or an 
FDA designated source, when available.
1. The Type and Number of Entities Affected
    The testing of donations from allogeneic and certain autologous 
donors of blood and blood components will affect all blood and plasma 
establishments that collect blood and blood components from such 
donors. FDA's registration database has record of 981 registered blood 
establishments that collect blood and blood components and 60 licensed 
plasma centers with approximately 370 locations that collect Source 
Plasma. Whole Blood donors in the United States are volunteers. By 
contrast, most Source Plasma centers are commercial establishments with 
paid donors. Based on information published by the American Association 
of Blood Banks (AABB) regarding allogeneic donations (Ref. 1), and 
communications with experts in the blood banking industry

[[Page 31157]]

regarding the testing of autologous donations, FDA believes that all of 
the 12 million blood donations (not including 643,000 autologous 
donations) currently collected annually by the regional and community 
blood centers and hospitals are already being tested for the specific 
disease agents as usual and customary business practice. FDA further 
estimates that autologous donations that are shipped are already being 
tested for HIV, types 1 and 2, HBV, HCV, HTLV, types I and II, and 
syphilis as usual and customary business practice. It is also usual and 
customary business practice for hospitals to solely use autologous 
donations for autologous use and not allow autologous donations to be 
used for allogeneic transfusion. Therefore, we estimate that since 
industry practices are currently the same as FDA requirements for 
testing shipped autologous donations, and are more stringent than FDA 
requirements for use of autologous donations for allogeneic 
transfusion, then additional costs to blood establishments collecting 
autologous blood and blood components will be minimal, if any.
    In 1997, the Government Accounting Office (GAO) estimated that 
approximately 12 million donations of Source Plasma were collected by 
plasma centers (Ref. 2). Although the precise number of those donations 
currently tested for HIV, types 1 and 2, HBV, and HCV is not reported, 
FDA assumes that virtually all donations are currently being initially 
screened for the communicable disease agents specified for plasma 
donations in the rule. However, based on GAO reported variations in the 
plasma industry's confirmatory testing of repeat reactive donations, it 
is also assumed that supplemental testing for HCV is not widely 
practiced at present.
    The requirements for lot testing of approved test kits by 
manufacturers will entail use of CBER regulatory reference panels to 
provide verification of the specificity and sensitivity of each lot of 
test kits approved for use in testing donations of human blood. This 
release criterion would be applied to lots of test kits produced by 
licensed manufacturers or lots produced by manufacturers pursuing 
licensure of such tests. FDA estimates that the number of manufacturers 
of kits for the four disease agents specified in the rule currently 
ranges from six to seven establishments per disease agent. It is also 
possible that some additional number of manufacturers may pursue 
licensure of such kits in future years, although the total number is 
likely to remain small because of the expected limits of demand for 
such tests.
    FDA currently has reference panels available for all of the disease 
agents specified in the rule, and has made the panels available to all 
currently licensed manufacturers of test kits. To the agency's 
knowledge, all currently licensed manufacturers covered by the rule are 
already performing the tests to comply with their own quality assurance 
standards. The rule is therefore expected to introduce no substantial 
impact on these establishments.
2. Estimated Impact of Requirements for Donor Testing
    The rule provisions for donation testing, appropriate handling, 
labeling, and distribution will involve a one-time effort by all blood 
and plasma establishments to review and modify current blood and plasma 
donor testing, handling, and recordkeeping protocols to comply with the 
rule. While the rule does establish test requirements, these are not 
expected to increase the yearly cost of donor screening testing.
    The one-time effort to review and modify current SOP's is expected 
to take approximately 8 hours of staff time to reconcile the 
regulations against the facility's current standards. This process 
could be performed by a technical specialist who works as a regulatory 
reviewer or manager of quality assurance. Based on the total average 
hourly compensation of $25.67 for professional specialty and technical 
occupations in the health services industry, as reported by Bureau of 
Labor Statistics for March 1997, the cost would be approximately $205, 
for each of the blood and plasma collecting establishments. Because 
this final rule does not require that all blood centers test all 
autologous donations, it is a lesser burden that what was in the 
proposed rule. FDA assumes that the cost will be the same for all 
facilities, whether or not they currently test all autologous 
donations. It is also assumed that all facilities already perform 
careful labeling and keep records of test results for evidence of 
infection due to communicable disease agents. Thus, the total one-time 
cost for the industry is estimated to be $276,955 ((370 + 981 
establishments) x $205).
    (Comment 29) Ten comments asserted that testing of autologous 
donations is costly to facilities and patients.
    We have considered these comments and we are limiting the 
requirement to test autologous donations to two occasions when risk of 
exposure is increased, i.e., when autologous donations are used for 
allogeneic transfusion or when they are shipped. It is assumed that 
there will be very little testing that was not already being done, and 
that the requirement to test autologous donations when used for 
allogeneic transfusion or shipped will not impose additional cost.
    The rule also allows that multiple donations of blood and blood 
components from single donors dedicated to a single identified 
recipient be tested once at the beginning of a 30-day period. These 
dedicated donations, however, are relatively uncommon and are believed 
to generally undergo testing by all facilities that is at least as 
frequent as the rule requires.
    (Comment 30) Two comments contend that supplemental testing should 
be required only for HIV and HBsAg. Four additional comments noted that 
supplemental testing is expensive.
    The agency believes that while there are costs to supplemental 
testing, the costs imposed by this rule are mitigated because a 
substantial fraction of facilities already perform supplemental 
testing. In addition, the ability to obtain more precise information on 
donors testing reactive will improve public health by providing these 
donors with accurate health information.
    Currently, blood and plasma establishments are required under 
Sec. 610.46(b) to further test donations that test reactive by a 
screening test for HIV. Anti-HBc and anti-HTLV, types I and II, do not 
have supplemental (additional, more specific) tests approved for such 
use by FDA at this time. Therefore, the yearly increase in cost imposed 
by this final rule is based on the assumption that blood and plasma 
collecting establishments will need to begin supplemental (additional, 
more specific) testing on donations that test reactive for HCV and 
HBsAg. Assuming: (1) An average 0.18 percent (0.0018) rate of HCV 
reactive donations; (2) an average 0.05 percent (0.0005) rate of HBsAg 
reactive donations; and (3) an annual volume of approximately 24 
million blood and plasma donations, and the cost for a supplemental 
(additional, more specific) test for HCV and HbsAg is approximately 
$144.50 and $8.00 respectively (Ref. 3), then the annual cost is 
estimated to be no greater than $5,946,400 ((24,000,000 x 0.0018) x 
$114.50 + (24,000,000 x 0.0005) x $8.00).
    In summary, the rule would result in an estimated one-time cost of 
$276,955, and a total annual cost of $5,042,400 to the blood and plasma 
industries.

[[Page 31158]]

3. Expected Benefits of the Rule
    The rule is intended to increase the safety of all blood and blood 
component products by providing recipients with increased protection 
against communicable disease transmission. The rule addresses exposures 
that may occur through errors in administration of autologous as well 
as allogeneic blood units. For example, AABB Anonymous Survey Report 
included reports of erroneous transfusions (1.2 percent of 
respondents), untested recovered plasma salvaged (3.7 percent), units 
lost in transit (12.3 percent), units broken in the lab (33.6 percent), 
and units broken outside the lab (32.2 percent), as well as other 
errors (9.8 percent) (Ref. 4). The reduction in communicable disease 
risk already achieved among allogeneic blood transfusions as a result 
of infectious disease testing of donors has been quite dramatic. For 
example, as a result of the expansion of blood donor screening and 
improved laboratory tests, it is now estimated that the chances of 
transfusion-related HIV infection have decreased to between 1 in 
450,000 to 660,000 per unit of blood (Ref. 5). HCV and HBV transfusion 
risks have also declined. In 1990, prior to specific testing, HCV was 
transmitted by 0.2 to 0.5 percent of transfusions, compared with the 
current rate of approximately 0.0005 percent. The risk of HBV 
transfusion transmission is currently estimated to be 1 in 500,000 
transfused units.
    The gravity of the disease risks addressed by the rule is widely 
recognized. Transfusion of HIV, the virus that causes AIDS, continues 
to cause great concern. Human T-cell leukemia/lymphoma viruses types I 
and II ,were identified in the early 1980's. Infection with the virus 
is associated with tropical spastic paraparesis, adult T-cell leukemia/
lymphoma, and some inflammatory disorders (Lapane et al.). Although the 
virus is primarily transmitted by sexual contact and intravenous drug 
abuse, it can also be transmitted through blood transfusion.
    HBV is a major cause of acute and chronic hepatitis, cirrhosis, and 
primary hepatocellular carcinoma worldwide. The Centers for Disease 
Control and Prevention (CDC) estimated that in 1985 approximately 
300,000 persons became infected with HBV. Prior to the development of 
hepatitis screening tests, transfusion-related risks were significant. 
A retrospective testing of blood donors using first generation tests 
for the presence of HBsAg found that over half of recipients of HBsAg 
positive blood developed hepatitis (Ref. 6). Of the current pool of 1 
to 1.25 million HBV carriers, approximately 25 percent will develop 
chronic hepatitis which will progress to cirrhosis and carriers will 
have a risk of liver cancer that is 12 to 300 times higher than the 
risk to non-carriers. An estimated 4,000 persons die each year from 
hepatitis B-related cirrhosis, and more than 800 die from primary 
hepatocellular carcinoma (PHC). The lifetime medical cost per case of 
PHC and cirrhosis is estimated to be $96,500 (Ref. 7).
    Epidemiologic and experimental studies indicate that HCV is 
primarily transmitted by the parenteral route. Persons at increased 
risk of acquiring hepatitis C include parenteral drug users; health-
care workers with occupational exposure to blood; hemodialysis 
patients; and recipients of Whole Blood, blood cellular components, or 
Plasma. Transfusion of blood or blood products, which accounted for a 
substantial proportion of HCV infections acquired more than 10 years 
ago, is now an uncommon means of transmission. CDC estimates that 
150,000 to 170,000 new HCV infections occur annually in the United 
States (Ref. 8). Of patients with transfusion-associated chronic non-A, 
non-B hepatitis who undergo biopsy within 5 years after onset, at least 
40 percent have histological evidence of chronic active hepatitis and 
10 to 20 percent have evidence of cirrhosis (Ref. 9). An estimated 30 
percent of those infected will eventually die of liver-related causes, 
an estimated 8,000 patients per year. Although some HCV patients have 
been found to respond to interferon therapy, the average cost of care 
per year for persons with liver disease from chronic hepatitis C is 
estimated to range from $24,600 for patients without interferon-alpha 
therapy to $26,500 per year for those receiving a 12-month course of 
therapy. The latter has been estimated to provide patients with an 
additional 0.37 quality-adjusted life years (Ref. 10). As described 
previously, the requirement of HIV, types 1 and 2; HBV; HCV; HTLV, 
types I and II; and syphilis testing for blood and blood component 
donations significantly reduces the U.S. population's exposure to the 
morbidity and mortality risks associated with these diseases, and their 
attendant costs.
4. Small Entity Impact
    The information available to characterize the relevant volumes of 
affected blood and plasma products is limited. Although the rule is not 
expected to have a significant impact on a substantial number of small 
entities, the impact on blood and plasma establishments that might 
qualify as small entities is uncertain. FDA has therefore prepared a 
Regulatory Flexibility Analysis. The blood and plasma establishments 
affected by the rule are included under the major Standard Industry 
Code (SIC) group 80 for providers of health services. According to 
section 601 of the Regulatory Flexibility Act of 1980, the term ``small 
entity'' encompasses the terms ``small business,'' ``small 
organization,'' and ``small governmental jurisdiction.'' ``Small 
governmental jurisdiction'' generally means governments of cities, 
counties, towns, townships, villages, school districts, or special 
districts with a population of less than 50,000.
    The extent of the small business impact is uncertain. Although the 
details of blood collection at hospitals are not available, FDA 
examined other data to develop a preliminary assessment of small 
business impact. The size of U.S. hospitals varies substantially. The 
1998 American Hospital Association (AHA) survey data (Ref. 11) indicate 
a total of 5,134 U.S. registered community hospitals grouped into 8 
bedsize categories. The average annual revenues for facilities in these 
bedsize categories range from approximately $5.5 million to $513 
million. However, since many hospitals are not-for-profit or are 
operated by State and local governments, the Small Business Association 
(SBA) annual receipts criteria for small businesses would not apply to 
these facilities. Of the 5,134 U.S. community hospitals included in the 
AHA report, 1,330 are under the control of State and local government, 
3,045 are nonprofit institutions, and the remaining 759 are reported to 
be investor-owned. (Note that while there are over 5,000 community 
hospitals in this small entity impact analysis, not all 5,000 hospitals 
are collecting facilities. Therefore, this does not invalidate the 
estimate of 60 licensed plasma centers with 370 locations and 981 
registered blood establishments affected by the rule.)
    The number of hospitals that would meet at least one of the various 
SBA definitions for small entities is uncertain. According to the AHA 
statistics for 1998, the smallest reported hospital size category 
includes 262 hospitals with 6 to 24 beds, and total gross revenues of 
$1.43 billion, yielding average revenues of $5.46 million. FDA assumes 
that the 11 facilities reported to be investor-owned within this 
bedsize category could qualify as small entities. Although it is 
possible that all nonprofit hospitals may qualify as small entities, it 
appears that a number of facilities

[[Page 31159]]

might be excluded from that definition because they are reported to be 
hospitals in a system. According to the AHA survey definition, 
``hospitals belonging to a corporate body that owns and/or manages 
health provider facilities or health-related subsidiaries; the system 
may also own non-health-related facilities.'' The AHA currently has 
record of 1,592 hospitals that are nonFederal and nonprofit (including 
State and local government controlled) that are hospitals in a system. 
If these facilities were excluded, FDA estimates that 2,783 [1,330 
State and local + 3,045 nonprofit--1,592 in-a-system] non-federal, 
nonprofit hospitals may qualify as small entities. Although, a total of 
2,794 [2,783 + 11] hospitals might qualify as small entities, not all 
such hospitals collect blood and blood components, and some would be 
transfusion services only.
    Approximately 75 of the 981 registered blood establishments that 
collect blood and blood components are responsible for collecting 65 
percent of the blood supply (7.8 million donations). The remaining 906 
registered blood establishments assumed to operate as small entities 
would collect 45 percent of the blood supply (5.4 million donations). 
If the estimated 5.4 million donations of blood and blood components 
were evenly distributed over the 906 registered blood collection 
establishments, each establishment would average 5,960 donations 
annually, of which approximately 11 (0.0018 x 5,960) might test 
reactive for HCV and approximately 3 (0.0005 x 5,960) of which might 
test reactive for HBsAg, and require supplemental testing. The expected 
cost of the additional testing would then be $1,283.50 (($114.50 x 11) 
+ ($8.00 x 3)) per establishment per year.
    The number of plasma facilities that would qualify as small 
entities is also uncertain. According to the General Accounting Office 
(Ref. 12) approximately 370 paid plasma collection locations annually 
collect about 12 million plasma donations, the vast majority of which 
is processed by 8 companies. FDA estimates that approximately 90 
percent of these plasma collection locations are owned by companies 
that operate multiple facilities. Although the agency is uncertain 
about the level of revenues for these companies, it is considered 
likely that most would have annual receipts of $5 million or more per 
year. The remaining 10 percent of paid plasma collection locations (37 
locations) may qualify as small business establishments. The potential 
impact on these facilities will be a function of the number of donors 
and the HCV and HBsAg reactive findings among donors at their facility. 
If the estimated 12 million plasma donations were evenly distributed 
over the collection centers, each center would average 25,000 
donations. Assuming approximately 8 units per plasma donor per year 
(Ref. 12), each center would average 3,125 donors, approximately 6 
(0.0018 x 3,125) of whom might test reactive for HCV and approximately 
2 (0.0005 x 3,125) of whom might test reactive for HBsAg, and require 
supplemental testing. The expected cost of the additional testing would 
then be $703 (($114.50 x 6) + ($8.00 x 2)) per center per year.
    In addition to these for-profit establishments, the remaining 
plasma collection centers function within blood collection centers that 
are operated by the American National Red Cross, or are independently 
operated. The independently operated, not-for-profit blood collection 
centers would likely qualify as small entities. The added impact of the 
rule on plasma collection performed at blood collection facilities is 
expected to be small, however, because the required testing would 
already be performed for Whole Blood donation.
    FDA has considered alternatives for lessening the burden on small 
entities. The proposed rule proposed that all autologous blood be 
tested. By choosing this less costly alternative that does not require 
autologous blood testing, FDA is lessening the burden on small 
entities.

VIII. The Paperwork Reduction Act of 1995

    This final rule contains information collection requirements that 
are subject to review by OMB under the Paperwork Reduction Act of 1995 
(the PRA) (44 U.S.C. 3501-3520). The title, description, and respondent 
description of the information collection provisions are shown below 
with an estimate of the annual reporting and recordkeeping burden. 
Included in the estimate is the time for reviewing instructions, 
searching existing data sources, gathering and maintaining the data 
needed, and completing and reviewing each collection of information.
    Title: Recordkeeping and Reporting Requirements for Testing Human 
Blood Donors for Evidence of Infection Due to Communicable Disease 
Agents.
    Description: FDA is revising the test requirements in part 610 
subpart E issued under the authorities of the act and the PHS Act. 
Section 610.40 of the final rule requires screening tests for evidence 
of infection due to communicable disease agents, HIV, types 1 and 2; 
HBV; HCV; HTLV, types I and II, be performed on each donation of human 
blood and blood component. Certain exceptions to performing screening 
tests are described elsewhere in this rule.
    In Sec. 610.40(c)(1)(ii), each dedicated donation must be labeled 
as required under Sec. 606.121 and with a label entitled ``INTENDED 
RECIPIENT INFORMATION LABEL'' containing the name and identifying 
information of the recipient. Each donation that is untested in the 30-
day period must be labeled ``DONOR TESTED WITHIN THE LAST 30 DAYS.''
    In Sec. 610.40(d)(4), each autologous donation must be labeled as 
required under Sec. 606.121 and with the following label, as 
appropriate. If the donation is: (1) Untested, label with ``UNTESTED;'' 
(2) negative, label as required under Sec. 606.121; (3) reactive on the 
current collection or in the last 30 days, label with ``BIOHAZARD'' 
legend; and (4) tested negative within the last 30 days, label with 
``DONOR TESTED WITHIN THE LAST 30 DAYS.''
    Under Sec. 610.40(g), each donation that may be released or shipped 
prior to testing must be labeled as required under Sec. 606.121(h) and 
the test results must be provided promptly to the consignee. Section 
610.40(g)(1) permits release or shipment prior to completion of testing 
in documented medical emergencies, and Sec. 610.40(g)(2) permits 
release or shipment prior to completion of testing when FDA provides 
written approval for the shipment or use.
    In Sec. 610.40(h)(2)(ii), human blood or blood components intended 
for further manufacturing use may be shipped or used under the 
following conditions.
    <bullet> When FDA provides written approval for the shipment or 
use;
    <bullet> When such human blood and blood components are labeled as 
required under Sec. 606.121 or Sec. 640.70 and with the ``BIOHAZARD'' 
legend;
    <bullet> When such human blood and blood components are labeled 
reactive for the appropriate screening test for evidence of infection 
due to the identified communicable disease agent(s);
    <bullet> When such human blood and blood components are intended 
for further manufacturing use into injectable products, and a statement 
indicating the exempted use specifically approved by FDA is included on 
the container label;
    <bullet> When such human blood and blood components are intended 
solely as a component of, or used to prepare, a medical device and the 
statement ``Caution: For Further Manufacturing Use As a Component of a 
Medical Device For Which There Are No Alternative Sources;'' and

[[Page 31160]]

    <bullet> When such human blood and blood components are intended 
for in vitro use and the statement ``Caution: For Further Manufacturing 
Into In Vitro Diagnostic Reagents For Which There Are No Alternative 
Sources'' is included.
    In Sec. 610.40(h)(2)(vi) and (h)(2)(vii), we added language 
describing current practice on the use of human blood and blood 
components, and Source Plasma, with a reactive screening test for 
syphilis that is determined to be a biological false positive.
    In Sec. 610.42(a), medical devices containing or used to prepare 
human blood or blood components that are reactive for syphilis or by a 
screening test for evidence of infection due to a communicable disease 
agent(s) must include, in addition to appropriate labeling requirements 
in subchapter H (Medical Devices), a statement of warning that the 
product was manufactured from a donation testing reactive for the 
identified communicable disease agent(s).
    Description of Respondents: Establishments that collect blood and 
blood components.
    As required by section 3506(c)(2)(B) of the PRA, FDA provided an 
opportunity for public comment on the information collection 
requirements of the proposed rule (64 FR 67207). In accordance with the 
PRA, OMB reserved approval of the information collection burden in the 
proposed rule stating they will make an assessment in light of public 
comments received on the proposed rule. No letters of comment on the 
information collection requirements were submitted to OMB or the 
docket.
    Based on current information retrieved from FDA's registration data 
base, there are approximately 60 licensed plasma collection facilities 
and approximately 981 registered blood collection facilities for a 
total of 1,041 establishments. These facilities collect annually an 
estimated 24.6 million donations: 12 million donations of Source Plasma 
and 12.6 million donations of Whole Blood, including 643,000 
autologous.

Annual Reporting Burden (Table 3)

    Section 610.40(c)(1)(ii) requires that each dedicated donation be 
labeled as required under Sec. 606.121 (OMB No. 0910-0116) and with a 
label containing the name and identifying information of the recipient. 
FDA estimates that approximately 5 percent (10,250) of the 205,000 
donations that are donated specifically for the use of an identified 
recipient would be tested under the dedicated donors testing provisions 
in Sec. 610.40(c). FDA estimates that the remaining 95 percent would be 
tested as allogeneic donations in accordance with Sec. 610.40(a), (b), 
and (e) because most such donors do not donate more often than once in 
a 30-day period, and because most establishments choose to test every 
donation. We estimate that each establishment expends approximately 5 
minutes to insert the name of the recipient and identifying information 
on each label.
    In Sec. 610.40(g)(2) and (h)(2)(ii)(A), a manufacturer must obtain 
written approval from FDA when a manufacturer seeks to: (1) Ship human 
blood or blood components for further manufacturing use prior to 
completion of testing; or (2) ship human blood or blood components 
found to be reactive by a screening test for evidence of a communicable 
disease agent(s) or collect from a donor with a record of a reactive 
screening test, respectively. The only product currently shipped prior 
to completion of testing is a licensed product, Source Leukocytes, used 
in the manufacture of interferon, which requires rapid preparation from 
blood. Shipment of Source Leukocytes are preapproved under a product 
license application and each shipment does not have to be reported to 
the agency. To obtain approval from FDA as described in 
Sec. 610.40(g)(2), we expect the manufacturer(s) to submit specific 
procedures for collection, shipment, and quarantine of a product before 
testing is completed, and the completion of testing as soon as possible 
after shipping. In addition, the manufacturer must promptly communicate 
the test results to the consignee. FDA has received two applications 
from the manufacturers of Source Leukocytes during fiscal year (FY) 95, 
FY 96, and FY 97. Therefore, we estimate receiving an average of two 
annually.
    According to information from industry, a license application of 
this type would contain safety and effectiveness information and would 
take approximately 1,600 hours to prepare. The information that a 
manufacturer would need to put together for the request is typically 
part of an Biologics License Application (BLA) submission. Therefore, 
we estimate that approximately 1 hour of the estimated 1,600 hours 
would be used in preparing the request for FDA's approval to ship a 
product prior to completion of testing.
    Under Sec. 610.40(h)(2)(ii)(C) and (h)(2)(ii)(D), industry 
estimates that each manufacturer would ship an estimated 10 blood or 
blood components per month that would require 2 labels; one as reactive 
for the appropriate screening test under paragraph (C), and the other 
stating the exempted use specifically approved by FDA under paragraph 
(D). According to FDA's database, there are approximately 300 licensed 
manufacturers that ship known reactive blood or blood components. 
Industry also estimates that it would take approximately 10 minutes per 
blood or blood component to affix the labels.
    In Sec. 610.40(h)(2)(vi), each donation of human blood or blood 
component that tests reactive by a screening test for syphilis and is 
determined to be a biological false positive, must be labeled with both 
test results. After reviewing information from industry, we estimate 
that approximately 15,120 donations annually test reactive by a 
screening test for syphilis, and are determined to be biological false 
positives by additional testing. We also estimate that the 
establishment would expend approximately 5 minutes to label the blood 
or blood component with the results of both tests.
    Section 610.42(a) requires a warning statement, including the 
identity of the communicable disease agent, on medical devices 
containing human blood or blood components found to be reactive by a 
screening test for evidence of infection due to a communicable disease 
agent(s) or syphilis. Human blood or a blood component with a reactive 
screening test, as a component of a medical device, is an integral part 
of the medical device, e.g., a positive control for an in vitro 
diagnostic testing kit. It is usual and customary business practice for 
manufacturers to include on the container label a warning statement 
that identifies the communicable disease agent. In addition, on the 
rare occasion when a human blood or blood component with a reactive 
screening test is the only component available for a medical device 
that does not require a reactive component, then a statement of warning 
is required to be affixed to the medical device. To account for this 
rare occasion we estimate that the warning statement would be necessary 
no more than once a year and we estimate the manufacturer would need to 
expend 1 hour to complete the labeling requirement.

Annual Recordkeeping Burden (Table 4)

    Under Sec. 610.40(g)(1), we are permitting in rare emergency 
circumstances, the release or shipment of human blood or blood 
components prior to the completion of testing for evidence of infection 
due to communicable disease agents. Such emergencies include, e.g., 
where a patient's need for blood is so acute as to preclude any 
communicable disease

[[Page 31161]]

testing of the blood. We have concluded that the use of untested or 
incompletely tested blood in such medical emergencies should not be 
prohibited. Release of blood or blood components due to a medical 
emergency prior to completion of required testing must be appropriately 
documented. We estimate the recordkeeping to be minimal with one or 
less occurrence per year. Documentation of the medical emergency should 
take a half-hour or less. The reporting of test results to the 
consignee in Sec. 610.40(g) does not create a new burden for 
respondents because it is the usual and customary business practice or 
procedure to finish the testing and provide the results to the 
manufacturer responsible for labeling the blood products.

                                  Table 3.--Estimated Annual Reporting Burden<SUP>1</SUP>
----------------------------------------------------------------------------------------------------------------
   21 CFR                          Annual Frequency      Total Annual          Hours per
   Section    No. of Respondents     per Response          Responses           Response           Total Hours
----------------------------------------------------------------------------------------------------------------
610.40(c)(1)      1,041                   9              10,250                    .08              820
 (ii)
610.40(g)(2)          2                   1                   2                   1                   2
610.40(h)(2)          2                   1                   2                   1                   2
 (ii)(A)
610.40(h)(2)        300                  10               3,000                   0.2               600
 (ii)(C) and
 (h)(2)(ii)(
 D)
610.40(h)(2)      1,041                  15              15,120                   0.08            1,210
 (vi)
610.42(a)             1                   1                   1                   1                   1
Total                                                                                             2,635
----------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.


                                Table 4.--Estimated Annual Recordkeeping Burden<SUP>1</SUP>
----------------------------------------------------------------------------------------------------------------
   21 CFR           No. of         Annual Frequency      Total Annual          Hours per
   Section       Recordkeepers     per Recordkeeping        Records          Recordkeeper         Total Hours
----------------------------------------------------------------------------------------------------------------
610.40(g)(1)        981                   1                 981                   0.5               490.5
----------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.

    Under section 1320.3(c)(2) of the PRA, the labeling requirements in 
Sec. 610.40(c)(3)(ii), (d)(4), and (h)(2)(ii)(B) and (h)(2)(ii)(E) do 
not constitute collection of information because information required 
to be on the labeling is originally supplied by the Federal Government 
to the manufacturers for the purpose of disclosure to the public in 
order to keep the blood supply safe and protect public health.
    The information collection provisions of this final rule have been 
submitted to OMB for review.
    Prior to the effective date of this final rule, FDA will publish a 
notice in the Federal Register announcing OMB's decision to approve, 
modify, or disapprove the information collection provisions in this 
final rule. An agency may not conduct or sponsor, and a person is not 
required to respond to, a collection of information unless it displays 
a currently valid OMB number.

IX. Environmental Impact

    The agency has determined under 21 CFR 25.30(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.

X. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, the agency has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the order and, consequently, a federalism 
summary impact statement is not required.

XI. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. American Association of Blood Banks, Facts About Blood and Blood 
Banking, ``http://www.aabb.org''.
    2. General Accounting Office, ``Blood Safety: Enhancing Safeguards 
Would Strengthen the Nation's Blood Supply,'' GAO-HEHS-97-143, June 
1997.
    3. Lapane, K. L., A. F. Jakiche, D. Sugano, C. S. Wayne Weng, and 
W. D. Carey, ``Hepatitis C Infection Risk Analysis: Who Should Be 
Screened? Comparison of Multiple Screening Strategies Based on the 
National Hepatitis Surveillance Program,'' The American Journal of 
Gastroenterology, vol. 93, no. 4, pp. 591-596, 1998.
    4. American Association of Blood Banks (AABB) Association Bulletin 
No. 95-4: AABB Position on Testing of Autologous Units. Attachment 1: 
AABB Anonymous Autologous Survey Request, May 9, 1999.
    5. Podnos, Y. D. and R. A. Williams, Current Risks for Blood Borne 
Viral Illness in Blood Transfusion, Western Journal of Medicine, vol. 
168, no. 1, pp. 36-37, January 1998.
    6. Public Health Service Inter-Agency Guidelines for Screening 
Donors of Blood, Plasma, Organs, Tissues, and Semen for Evidence of 
Hepatitis B and Hepatitis C, Morbidity and Mortality Weekly Report 40 
(RR-4) April 19, 1991.
    7. Margolis, H. S., P. J. Coleman, R. E. Brown, E. E. Mast, S. H. 
Sheingold, and J. A. Arevalo, ``Prevention of Hepatitis B Virus 
Transmission by Immunization: an Economic Analysis of Current 
Recommendations,'' Journal of the American Medical Association, vol. 
274, no. 15, October 1995.
    8. U.S. Centers for Disease Control and Prevention, 1997, 
``www.cdc.gov/ncidod/diseases/hepatitis''.
    9. Morbidity and Mortality Weekly Report, 40 (RR-4) April 19, 1991.
    10. Kim, W. R., J. J. Peterucha, J. E. Hermans, T. M. Therneau, E. 
R. Dickson, R. W. Evans, and J. B. Gross,

[[Page 31162]]

``Cost-Effectiveness of 6 and 12 Months of Interferon Therapy for 
Chronic Hepatitis C,'' Annals of Internal Medicine, vol. 127, no. 10, 
November 1997.
    11. Healthcare InfoSource, Inc., a subsidiary of the American 
Hospital Association, Hospital Statistics, 1998 ed., Chicago, IL.
    12. General Accounting Office, ``Blood Plasma Safety: Plasma 
Product Risks Are Low if Good Manufacturing Practices Are Followed.'' 
GAO-HEHS-98-205, September 1998.

List of Subjects

21 CFR Part 606

    Blood, Labeling, Laboratories, Reporting and recordkeeping 
requirements.

21 CFR Part 607

    Blood.

21 CFR Parts 610 and 660

    Biologics, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 640

    Blood, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 809

    Labeling, Medical devices.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and the 
Public Health Service Act, and under the authority delegated to the 
Commissioner of Food and Drugs, 21 CFR parts 606, 607, 610, 640, 660, 
and 809 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 606.121 is amended by revising paragraph (e)(5)(ii), by 
removing and reserving paragraph (g), and in paragraphs (h)(2) and 
(h)(3) by removing ``610.45,'' to read as follows:


Sec. 606.121  Container label.

* * * * *
    (e) * * *
    (5) * * *
    (ii) The statement as applicable: ``Caution: For Manufacturing Use 
Only''; or ``Caution: For Use in Manufacturing Noninjectable Products 
Only.'' If the recovered plasma has a reactive screening test for 
evidence of infection due to a communicable disease agent(s) under 
Sec. 610.40 of this chapter, or is collected from a donor with a 
previous record of a reactive screening test for evidence of infection 
due to a communicable disease agent(s) under Sec. 610.40 of this 
chapter, the recovered plasma must be labeled as required under 
Sec. 610.40(h)(2)(ii)(E) of this chapter.
* * * * *

PART 607--ESTABLISHMENT REGISTRATION AND PRODUCT LISTING FOR 
MANUFACTURERS OF HUMAN BLOOD AND BLOOD PRODUCTS

    3. The authority citation for 21 CFR part 607 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 371, 374; 42 
U.S.C. 216, 262.


Sec. 607.65  [Amended]

    4. Section 607.65 Exemption for blood product establishments is 
amended by removing paragraph (g).

PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS

    5. The authority citation for 21 CFR part 610 is revised to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 
360d, 360h, 360i, 371, 372, 374, 381; 42 U.S.C. 216, 262, 263, 263a, 
264.
    6.-7. The heading of subpart E is revised to read as follows:

Subpart E--Testing Requirements for Communicable Disease Agents

    8. Section 610.40 is revised to read as follows:


Sec. 610.40  Test requirements.

    (a) Human blood and blood components. Except as specified in 
paragraphs (c) and (d) of this section, you, an establishment that 
collects blood or blood components, must test each donation of human 
blood or blood component intended for use in preparing a product, 
including donations intended as a component of, or used to prepare, a 
medical device, for evidence of infection due to the following 
communicable disease agents:
    (1) Human immunodeficiency virus, type 1;
    (2) Human immunodeficiency virus, type 2;
    (3) Hepatitis B virus;
    (4) Hepatitis C virus;
    (5) Human T-lymphotropic virus, type I; and
    (6) Human T-lymphotropic virus, type II.
    (b) Testing using one or more approved screening tests. To test for 
evidence of infection due to communicable disease agents designated in 
paragraph (a) of this section, you must use screening tests that the 
Food and Drug Administration (FDA) has approved for such use, in 
accordance with the manufacturer's instructions. You must perform one 
or more such tests as necessary to reduce adequately and appropriately 
the risk of transmission of communicable disease.
    (c) Exceptions to testing for allogeneic transfusion or further 
manufacturing use.
    (1) Dedicated donations. (i) You must test donations of human blood 
and blood components from a donor whose donations are dedicated to and 
used solely by a single identified recipient under paragraphs (a), (b), 
and (e) of this section; except that, if the donor makes multiple 
donations for a single identified recipient, you may perform such 
testing only on the first donation in each 30-day period. If an 
untested dedicated donation is made available for any use other than 
transfusion to the single, identified recipient, then this exemption 
from the testing required under this section no longer applies.
    (ii) Each donation must be labeled as required under Sec. 606.121 
of this chapter and with a label entitled ``INTENDED RECIPIENT 
INFORMATION LABEL'' containing the name and identifying information of 
the recipient. Each donation must also have the following label, as 
appropriate:

 
------------------------------------------------------------------------
        Donor Testing Status                        Label
------------------------------------------------------------------------
Tests negative                       Label as required under Sec.
                                      606.121
Tested negative within the last 30   ``DONOR TESTED WITHIN THE LAST 30
 days                                 DAYS''
------------------------------------------------------------------------


[[Page 31163]]

    (2) Source Plasma. You are not required to test donations of Source 
Plasma for evidence of infection due to the communicable disease agents 
listed in paragraphs (a)(5) and (a)(6) of this section.
    (3) Medical device. (i) You are not required to test donations of 
human blood or blood components intended solely as a component of, or 
used to prepare, a medical device for evidence of infection due to the 
communicable disease agents listed in paragraphs (a)(5) and (a)(6) of 
this section unless the final device contains viable leukocytes.
    (ii) Donations of human blood and blood components intended solely 
as a component of, or used to prepare, a medical device must be labeled 
``Caution: For Further Manufacturing Use as a Component of, or to 
Prepare, a Medical Device.''
    (4) Samples. You are not required to test samples of blood, blood 
components, plasma, or sera if used or distributed for clinical 
laboratory testing or research purposes and not intended for 
administration to humans or in the manufacture of a product.
    (d) Autologous donations. You, an establishment that collects human 
blood or blood components from autologous donors, or you, an 
establishment that is a consignee of a collecting establishment, are 
not required to test donations of human blood or blood components from 
autologous donors for evidence of infection due to communicable disease 
agents listed in paragraph (a) of this section or by a serological test 
for syphilis under paragraph (i) of this section, except:
    (1) If you allow any autologous donation to be used for allogeneic 
transfusion, you must assure that all autologous donations are tested 
under this section.
    (2) If you ship autologous donations to another establishment that 
allows autologous donations to be used for allogeneic transfusion, you 
must assure that all autologous donations shipped to that establishment 
are tested under this section.
    (3) If you ship autologous donations to another establishment that 
does not allow autologous donations to be used for allogeneic 
transfusion, you must assure that, at a minimum, the first donation in 
each 30-day period is tested under this section.
    (4) Each autologous donation must be labeled as required under 
Sec. 606.121 of this chapter and with the following label, as 
appropriate:

 
----------------------------------------------------------------------------------------------------------------
                  Donor Testing Status                                            Label
----------------------------------------------------------------------------------------------------------------
Untested                                                 ``DONOR UNTESTED''
Tests negative                                           Label as required under Sec.  606.121
Reactive on current collection/reactive in the last 30   ``BIOHAZARD'' legend in Sec.  610.40(h)(2)(ii)(B)
 days
Tested negative within the last 30 days                  ``DONOR TESTED WITHIN THE LAST 30 DAYS''
----------------------------------------------------------------------------------------------------------------

    (e) Further testing. You must further test each donation, including 
autologous donations, found to be reactive by a screening test 
performed under paragraphs (a) and (b) of this section, whenever a 
supplemental (additional, more specific) test has been approved for 
such use by FDA, except:
    (1) For autologous donations, you must further test under this 
paragraph, at a minimum, the first reactive donation in each 30-day 
period; or
    (2) If you have a record for that donor of a positive result on a 
supplemental (additional, more specific) test approved for such use by 
FDA, you do not have to further test an autologous donation.
    (f) Testing responsibility. Required testing under this section, 
must be performed by a laboratory registered in accordance with part 
607 of this chapter and either certified to perform such testing on 
human specimens under the Clinical Laboratory Improvement Amendments of 
1988 (42 U.S.C. 263a) under 42 CFR part 493 or has met equivalent 
requirements as determined by the Health Care Financing Administration 
in accordance with those provisions.
    (g) Release or shipment prior to testing. Human blood or blood 
components that are required to be tested for evidence of infection due 
to communicable disease agents designated in paragraphs (a) and (i) of 
this section may be released or shipped prior to completion of testing 
in the following circumstances provided that you label the blood or 
blood components under Sec. 606.121(h) of this chapter, you complete 
the tests for evidence of infection due to communicable disease agents 
as soon as possible after release or shipment, and that you provide the 
results promptly to the consignee:
    (1) Only in appropriately documented medical emergency situations; 
or
    (2) For further manufacturing use as approved in writing by FDA.
    (h) Restrictions on shipment or use--(1) Reactive screening test. 
You must not ship or use human blood or blood components that have a 
reactive screening test for evidence of infection due to a communicable 
disease agent(s) designated in paragraphs (a) and (i) of this section 
or that are collected from a donor with a previous record of a reactive 
screening test for evidence of infection due to a communicable disease 
agent(s) designated in paragraphs (a) and (i) of this section, except 
as provided in paragraphs (h)(2)(i) through (h)(2)(vii) of this 
section.
    (2) Exceptions. (i) You may ship or use blood or blood components 
intended for autologous use, including reactive donations, as described 
in paragraph (d) of this section.
    (ii) You must not ship or use human blood or blood components that 
have a reactive screening test for evidence of infection due to a 
communicable disease agent(s) designated in paragraph (a) of this 
section or that are collected from a donor deferred under 
Sec. 610.41(a) unless you meet the following conditions:
    (A) Except for autologous donations, you must obtain from FDA 
written approval for the shipment or use;
    (B) You must appropriately label such blood or blood components as 
required under Sec. 606.121, or Sec. 640.70 of this chapter, and with 
the ``BIOHAZARD'' legend;
[GRAPHIC] [TIFF OMITTED] TR11JN01.000

    (C) Except for autologous donations, you must label such human 
blood and blood components as reactive for the appropriate screening 
test for evidence of infection due to the identified communicable 
disease agent(s);
    (D) If the blood or blood components are intended for further 
manufacturing

[[Page 31164]]

use into injectable products, you must include a statement on the 
container label indicating the exempted use specifically approved by 
FDA.
    (E) Each blood or blood component with a reactive screening test 
and intended solely as a component of, or used to prepare a medical 
device, must be labeled with the following label, as appropriate:

 
----------------------------------------------------------------------------------------------------------------
                 Type of Medical Device                                           Label
----------------------------------------------------------------------------------------------------------------
A medical device other than an in vitro diagnostic       ``Caution: For Further Manufacturing Use as a Component
 reagent                                                  of a Medical Device For Which There Are No Alternative
                                                          Sources''
An in vitro diagnostic reagent                           ``Caution: For Further Manufacturing Into In Vitro
                                                          Diagnostic Reagents For Which There Are No Alternative
                                                          Sources''
----------------------------------------------------------------------------------------------------------------

    (iii) The restrictions on shipment or use do not apply to samples 
of blood, blood components, plasma, or sera if used or distributed for 
clinical laboratory testing or research purposes, and not intended for 
administration in humans or in the manufacture of a product.
    (iv) You may use human blood or blood components from a donor with 
a previous record of a reactive screening test(s) for evidence of 
infection due to a communicable disease agent(s) designated in 
paragraph (a) of this section, if:
    (A) At the time of donation, the donor is shown or was previously 
shown to be suitable by a requalification method or process found 
acceptable for such purposes by FDA under Sec. 610.41(b); and
    (B) tests performed under paragraphs (a) and (b) of this section 
are nonreactive.
    (v) Anti-HBc reactive donations, otherwise nonreactive when tested 
as required under this section, may be used for further manufacturing 
into plasma derivatives without prior FDA approval or a ``BIOHAZARD'' 
legend as required under paragraphs (h)(2)(ii)(A) and (h)(2)(ii)(B) of 
this section.
    (vi) You may use human blood or blood components, excluding Source 
Plasma, that test reactive by a screening test for syphilis as required 
under paragraph (i) of this section if, consistent with Sec. 640.5 of 
this chapter, the donation is further tested by an adequate and 
appropriate test which demonstrates that the reactive screening test is 
a biological false positive. You must label the blood or blood 
components with both test results.
    (vii) You may use Source Plasma from a donor who tests reactive by 
a screening test for syphilis as required under Sec. 610.40(i) of this 
chapter, if the donor meets the requirements of Sec. 640.65(b)(2) of 
this chapter.
    (i) Syphilis testing. In addition to the testing otherwise required 
under this section, you must test by a serological test for syphilis 
under Secs. 640.5(a), 640.14, 640.23(a), 640.33(a), 640.53(a), and 
640.65(b)(2) of this chapter.
    9. Section 610.41 is revised to read as follows:


Sec. 610.41  Donor deferral.

    (a) You, an establishment that collects human blood or blood 
components, must defer donors testing reactive by a screening test for 
evidence of infection due to a communicable disease agent(s) listed in 
Sec. 610.40(a) or reactive for a serological test for syphilis under 
Sec. 610.40(i), from future donations of human blood and blood 
components, except:
    (1) You are not required to defer a donor who tests reactive for 
anti-HBc or anti-HTLV, types I or II, on only one occasion. When a 
supplemental (additional, more specific) test for anti-HBc or anti-
HTLV, types I and II, has been approved for use under Sec. 610.40(e) by 
FDA, such a donor must be deferred;
    (2) A deferred donor who tests reactive for evidence of infection 
due to a communicable disease agent(s) listed in Sec. 610.40(a) may 
serve as a donor for blood or blood components shipped or used under 
Sec. 610.40(h)(2)(ii);
    (3) A deferred donor who showed evidence of infection due to 
hepatitis B surface antigen (HBsAg) when previously tested under 
Sec. 610.40(a), (b), and (e) subsequently may donate Source Plasma for 
use in the preparation of Hepatitis B Immune Globulin (Human) provided 
the current donation tests nonreactive for HBsAg and the donor is 
otherwise determined to be suitable;
    (4) A deferred donor, who otherwise is determined to be suitable 
for donation and tests reactive for anti-HBc or for evidence of 
infection due to HTLV, types I and II, may serve as a donor of Source 
Plasma;
    (5) A deferred donor who tests reactive for a communicable disease 
agent(s) described under Sec. 610.40(a) or reactive with a serological 
test for syphilis under Sec. 610.40(i), may serve as an autologous 
donor under Sec. 610.40(d).
    (b) A deferred donor subsequently may be found to be suitable as a 
donor of blood or blood components by a requalification method or 
process found acceptable for such purposes by FDA. Such a donor is 
considered no longer deferred.
    10. Section 610.42 is added to subpart E to read as follows:


Sec. 610.42  Restrictions on use for further manufacture of medical 
devices.

    (a) In addition to labeling requirements in subchapter H of this 
chapter, when a medical device contains human blood or a blood 
component as a component of the final device, and the human blood or 
blood component was found to be reactive by a screening test performed 
under Sec. 610.40(a) and (b) or reactive for syphilis under 
Sec. 610.40(i), then you must include in the device labeling a 
statement of warning indicating that the product was manufactured from 
a donation found to be reactive by a screening test for evidence of 
infection due to the identified communicable disease agent(s).
    (b) FDA may approve an exception or alternative to the statement of 
warning required in paragraph (a) of this section based on evidence 
that the reactivity of the human blood or blood component in the 
medical device presents no significant health risk through use of the 
medical device.
    11. Section 610.44 is added to subpart E to read as follows:


Sec. 610.44  Use of reference panels by manufacturers of test kits.

    (a) When available and appropriate to verify acceptable sensitivity 
and specificity, you, a manufacturer of test kits, must use a reference 
panel you obtain from FDA or from an FDA designated source to test lots 
of the following products. You must test each lot of the following 
products, unless FDA informs you that less frequent testing is 
appropriate, based on your consistent prior production of products of 
acceptable sensitivity and specificity:
    (1) A test kit approved for use in testing donations of human blood 
and blood components for evidence of

[[Page 31165]]

infection due to communicable disease agents listed in Sec. 610.40(a); 
and
    (2) Human immunodeficiency virus (HIV) test kit approved for use in 
the diagnosis, prognosis, or monitoring of this communicable disease 
agent.
    (b) You must not distribute a lot that is found to be not 
acceptable for sensitivity and specificity under Sec. 610.44(a). FDA 
may approve an exception or alternative to this requirement. Applicants 
must submit such requests in writing. However, in limited 
circumstances, such requests may be made orally and permission may be 
given orally by FDA. Oral requests and approvals must be promptly 
followed by written requests and written approvals.


Sec. 610.45  [Removed]

    12. Section 610.45 Human Immunodeficiency Virus (HIV) requirements 
is removed.

PART 640--ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS

    13. 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.


Sec. 640.2  [Amended]

    14. Section 640.2 General requirements is amended by removing 
paragraph (d).
    15. Section 640.5 is amended by revising paragraph (f).


Sec. 640.5  Testing the blood.

* * * * *
    (f) Test for communicable disease agents. Whole Blood shall be 
tested for evidence of infection due to communicable disease agents as 
required under Sec. 610.40 of this chapter.


Sec. 640.14  [Amended]

    16. Section 640.14 Testing the blood is amended by removing 
``Secs. 610.40 and 610.45'' and by adding in its place `` 
Sec. 610.40''.


Sec. 640.23  [Amended]

    17. Section 640.23 Testing the blood is amended in paragraph (a) by 
removing ``Secs. 610.40 and 610.45'' and by adding in its place 
``Sec. 610.40''.


Sec. 640.33  [Amended]

    18. Section 640.33 Testing the blood is amended in paragraph (a) by 
removing ``Secs. 610.40 and 610.45'' and by adding in its place 
``Sec. 610.40''.


Sec. 640.53  [Amended]

    19. Section 640.53 Testing the blood is amended in paragraph (a) by 
removing ``Secs. 610.40 and 610.45'' and by adding in its place 
``Sec. 610.40''.
    20. Section 640.67 is revised to read as follows:


Sec. 640.67  Laboratory tests.

    Each unit of Source Plasma shall be tested for evidence of 
infection due to communicable disease agents as required under 
Sec. 610.40 of this chapter.
    21. Section 640.70 is amended by revising paragraph (a)(2).


Sec. 640.70  Labeling.

    (a) * * *
    (2) The statement ``Caution: For Manufacturing Use Only'' for 
products intended for further manufacturing into injectable products, 
or the statement, ``Caution: For Use In Manufacturing Noninjectable 
Products Only'', for products intended for further manufacturing into 
noninjectable products. The statement shall follow the proper name in 
the same size and type of print as the proper name. If the Source 
Plasma has a reactive screening test for evidence of infection due to a 
communicable disease agent(s) under Sec. 610.40 of this chapter, or is 
collected from a donor with a previous record of a reactive screening 
test for evidence of infection due to a communicable disease agent(s) 
under Sec. 610.40 of this chapter, the Source Plasma must be labeled 
under Sec. 610.40(h)(2)(ii)(E) of this chapter.
* * * * *

PART 660--ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR 
LABORATORY TESTS

    22. The authority citation for 21 CFR part 660 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 
360d, 360h, 360i, 371, 372; 42 U.S.C. 216, 262, 263, 263a, 264.


Sec. 660.42  [Removed]

    23. Section 660.42 Reference panel is removed.

PART 809--IN VITRO DIAGNOSTIC PRODUCTS FOR HUMAN USE

    24. The authority citation for 21 CFR part 809 continues to read as 
follows:

    Authority: 21 U.S.C. 331, 351, 352, 355, 360b, 360c, 360d, 360h, 
360i, 360j, 371, 372, 374, 381.
    25. Section 809.20 is amended by revising paragraph (b).


Sec. 809.20  General requirements for manufacturers and producers of in 
vitro diagnostic products.

* * * * *
    (b) Compliance with good manufacturing practices. In vitro 
diagnostic products shall be manufactured in accordance with the good 
manufacturing practices requirements found in part 820 of this chapter 
and, if applicable, with Sec. 610.44 of this chapter.

    Dated: June 1, 2001.
Bernard A. Schwetz,
Acting Principal Deputy Commissioner.
[FR Doc. 01-14408 Filed 6-8-01; 8:45 am]
BILLING CODE 4160-01-F