[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:
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;
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;
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);
Deferral from future donations of donors who test
reactive;
Criteria for release or shipment of human blood or blood
components prior to completion of testing under limited circumstances;
[[Page 31147]]
Restrictions on shipment or use of human blood or blood
components that test reactive when screened for evidence of infection;
and
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:
For blood and blood components from autologous donors when
labeled as required in Sec. 610.40(d);
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);
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;
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
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]]
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;
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);
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;
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;
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
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
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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
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\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.
Recommendations for the Management of Donors and Units
that are Initially Reactive for Hepatitis B Surface Antigen (HBsAg);
December 2, 1987
HTLV-I Antibody Testing; November 29, 1988
FDA Recommendations Concerning Testing for Antibody to
Hepatitis B Core Antigen (Anti-HBc); September 10, 1991
Clarification of FDA Recommendations for Donor Deferral
and Product Distribution Based on the Results of Syphilis Testing;
December 12, 1991
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
Revised Recommendations for the Prevention of Human
Immunodeficiency Virus (HIV) Transmission by Blood and Blood Products;
April 23, 1992
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
Donor Suitability Related to Laboratory Testing for Viral
Hepatitis and a History of Viral Hepatitis; December 22, 1993
Recommendations for Donor Screening with a Licensed Test
for HIV-1 Antigen; August 8, 1995
Additional Recommendations for Donor Screening with a
Licensed Test Kit for HIV-1 Antigen [Supplements previous guidance
August 8, 1995]; March 14, 1996
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
Guidance for Industry: Donor Screening for Antibodies to
HTLV-II; August 15, 1997
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.
When FDA provides written approval for the shipment or
use;
When such human blood and blood components are labeled as
required under Sec. 606.121 or Sec. 640.70 and with the ``BIOHAZARD''
legend;
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);
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;
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]]
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 Burden1
----------------------------------------------------------------------------------------------------------------
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 Burden1
----------------------------------------------------------------------------------------------------------------
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