[Federal Register Volume 80, Number 99 (Friday, May 22, 2015)]
[Rules and Regulations]
[Pages 29842-29906]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-12228]
[[Page 29841]]
Vol. 80
Friday,
No. 99
May 22, 2015
Part III
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Parts 606, 610, 630, et al.
Requirements for Blood and Blood Components Intended for Transfusion or
for Further Manufacturing Use; Final Rule
Federal Register / Vol. 80, No. 99 / Friday, May 22, 2015 / Rules and
Regulations
[[Page 29842]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 606, 610, 630, 640, 660, and 820
[Docket No. FDA-2006-N-0040 (formerly Docket No. 2006N-0221)]
RIN 0910-AG87
Requirements for Blood and Blood Components Intended for
Transfusion or for Further Manufacturing Use
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending the
regulations applicable to blood and blood components, including Source
Plasma, to make the donor eligibility and testing requirements more
consistent with current practices in the blood industry, to more
closely align the regulations with current FDA recommendations, and to
provide flexibility to accommodate advancing technology. In order to
better assure the safety of the nation's blood supply and to help
protect donor health, FDA is revising the requirements for blood
establishments to test donors for infectious disease, and to determine
that donors are eligible to donate and that donations are suitable for
transfusion or further manufacture. FDA is also requiring
establishments to evaluate donors for factors that may adversely affect
the safety, purity, and potency of blood and blood components or the
health of a donor during the donation process. Accordingly, these
regulations establish requirements for donor education, donor history,
and donor testing. These regulations also implement a flexible
framework to help both FDA and industry to more effectively respond to
new or emerging infectious agents that may affect blood product safety.
DATES: This rule is effective May 23, 2016.
FOR FURTHER INFORMATION CONTACT: Valerie A. Butler, Center for
Biologics Evaluation and Research, Food and Drug Administration, 10903
New Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002,
240-402-7911; or Jonathan R. McKnight, Center for Biologics Evaluation
and Research, Food and Drug Administration, 10903 New Hampshire Ave.,
Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002, 240-402-7911.
SUPPLEMENTARY INFORMATION:
Executive Summary
Purpose of the Final Rule
The final rule helps to protect donors of blood and blood
components by requiring establishments to evaluate donors for factors
that may cause donation to adversely affect their health. In addition,
the final rule is being issued to assure the safety, purity, and
potency of the blood and blood component products used for transfusion
and for further manufacture.
The final rule applies to establishments that collect and/or
process blood and blood components, including transfusion services.
This rule requires establishments to assess a donor's medical history
to determine that the donor is in good health and to screen the donor
for factors that can adversely affect the safety, purity, or potency of
blood and blood components. In addition, the rule provides requirements
for testing donations for relevant transfusion-transmitted infections.
This rule revises and updates existing regulations.
FDA is issuing this rule under the authority of sections 351 and
361 of the Public Health Service Act (PHS Act) (42 U.S.C. 262 and 264),
and certain provisions of the Federal Food, Drug, and Cosmetic Act (the
FD&C Act) that apply to drugs and devices (21 U.S.C. 201 et seq.).
Summary of the Major Provisions of the Final Rule
Consistent with the proposed rule, in Sec. 630.3(l)), we define
transfusion-transmitted infection as a disease or disease agent that:
(1) Could be fatal or life-threatening, could result in permanent
impairment of a body function or permanent damage to body structure, or
could necessitate medical or surgical intervention to preclude
permanent impairment of body function or permanent damage to a body
structure and (2) for which there may be a risk of transmission by
blood or blood components, or by a blood derivative product
manufactured from blood or blood components, because the disease or
disease agent is potentially transmissible by that blood, blood
component or blood derivative product.
Sometimes, a transfusion-transmitted infection will also meet the
definition of a relevant transfusion-transmitted infection. We define
relevant transfusion-transmitted infection in Sec. 630.3(h) to include
two groups of transfusion-transmitted infections. The first group, in
Sec. 630.3(h)(1) is a list of 10 named transfusion-transmitted
infections: Human immunodeficiency virus, types 1 and 2 (referred to,
collectively as HIV); Hepatitis B virus (referred to as HBV); Hepatitis
C virus (referred to as HCV); Human T-lymphotropic virus, types I and
II (referred to, collectively, as HTLV); Treponema pallidum (referred
to as syphilis); West Nile virus; Trypanosoma cruzi (referred to as
Chagas disease); Creutzfeldt-Jakob disease (referred to as CJD);
Variant Creutzfeldt-Jakob disease (referred to as vCJD); and Plasmodium
species (referred to as malaria). In recognition of current industry
practices and in response to comments to the proposed rule, we included
West Nile virus and Chagas disease in the definition of relevant
transfusion-transmitted infection at Sec. 630.3(h)(1)(vi) and (vii),
respectively. Establishments currently perform donor screening for
these relevant transfusion-transmitted infections. Blood establishments
other than Source Plasma establishments already perform testing for the
first seven listed transfusion-transmitted infections, and Source
Plasma establishments already perform testing for HIV, HBV, HCV, and
more limited testing for syphilis. Testing requirements for Source
Plasma establishments are more limited because Source Plasma undergoes
further processing into blood derivative products, and those additional
manufacturing steps have been shown to inactivate or remove certain
infectious agents. We consider these donor testing and screening
practices to meet current standards, and would address any changes in
our recommendations for complying with the final rule in guidances
issued in accordance with good guidance practice (21 CFR 10.115). The
second part of the definition of relevant transfusion-transmitted
infections, Sec. 630.3(h)(2), establishes the criteria which will be
used to identify other transfusion-transmitted infections that may
present risks to the safety, purity, and potency of blood and blood
components in the future. A transfusion-transmitted infection will meet
the additional criteria for a relevant transfusion-transmitted
infection when the following conditions are met: (1) Appropriate
screening measures for the transfusion-transmitted infection have been
developed and/or an appropriate screening test has been licensed,
approved, or cleared for such use by FDA and is available and (2) the
disease or disease agent may have sufficient incidence and/or
prevalence to affect the potential donor population, or may have been
released accidentally or intentionally in a manner that could place
potential donors at risk of
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infection. Under the first prong of these criteria, a transfusion-
transmitted infection would become relevant only when an appropriate
intervention is available to prevent contamination of the blood supply.
Under the second prong, the disease or disease agent must also meet one
of the following two criteria: (1) It may have sufficient incidence
and/or prevalence to affect the potential donor population or (2) it
may have been released accidentally or intentionally in a manner that
could place potential donors at risk of infection.
In the event that circumstances have changed, and that a
transfusion-transmitted infection meets the definition of a relevant
transfusion-transmitted infection, FDA intends to issue guidance in
accordance with good guidance practices to advise stakeholders of FDA's
assessment of how the transfusion-transmitted infection now meets the
definition of relevant transfusion-transmitted infection. In the same
guidance, we would also address appropriate donor screening measures,
including medical history assessments, in accordance with Sec.
630.10(e), and any appropriate donor testing in accordance with Sec.
610.40(a)(3) (21 CFR 610.40(a)(3)). We may also address educational
materials in accordance with Sec. 630.10(b).
We are finalizing minor changes to the requirements in Sec.
606.100(b) (21 CFR 606.100(b)) to maintain standard operating
procedures largely as proposed. In addition, final Sec. 606.100(b)(22)
more explicitly requires establishments to have procedures to control
the risks of bacterial contamination of platelets, including all steps
required under Sec. 606.145.
We address requirements for establishments to take steps to control
bacterial contamination of platelets in Sec. 606.145, which is located
in the part entitled ``Current Good Manufacturing Practice for Blood
and Blood Components'' instead of in Sec. 630.30(a)(5), as proposed.
This placement more clearly reflects the importance of these steps to
current good manufacturing practice. Section 606.145 requires
establishments to assure that the risks of bacterial contamination of
platelets are adequately controlled using FDA approved or cleared
devices or other adequate and appropriate methods found acceptable for
this purpose by FDA, and explicitly addresses the responsibility of
transfusion services to comply with this current good manufacturing
practice. Establishments must take appropriate steps to identify the
contaminating organism, and in the event that the organism is
identified, the responsible physician for the collection establishment
must determine whether that organism is likely to be associated with a
bacterial infection that is endogenous to the bloodstream of the donor.
Such a determination would lead to donor deferral and notification.
In response to comments, we have significantly narrowed the
recordkeeping requirement that we proposed in Sec. 606.160(e) (21 CFR
606.160(e)). Instead of requiring collection establishments to share a
record of all ineligible donors with appropriate personnel at all
locations operating under the same license or under common management,
final Sec. 606.160(e) requires establishments to maintain two records:
(1) A record of all donors found to be ineligible or deferred at the
collection location and (2) a cumulative record of donors deferred from
donation at all locations operating under the same license or under
common management because their tests were reactive for evidence of
infection due to HIV, HBV, or HCV. Establishments other than Source
Plasma establishments must include donors deferred for evidence of
infection due to HTLV and Chagas disease. A related provision, Sec.
630.10(d), sets out requirements for establishments to consult these
records before collection. If a pre-collection review of the cumulative
record is not feasible, establishments must review it before releasing
blood or blood components.
We maintain current testing requirements in Sec. 610.40, and
include additional provisions. In Sec. 610.40(a), we address testing
for Chagas disease, West Nile virus, and syphilis. This section would
also require testing for additional relevant transfusion-transmitted-
infections in the event that donor screening tests are licensed,
approved, or cleared, and are available, and that such testing is
necessary to reduce adequately and appropriately the risk of
transmission of the relevant transfusion-transmitted infection by blood
or blood components. In addition, this section provides that, under
appropriate conditions and for certain relevant transfusion-transmitted
infections, it may become appropriate to test at a frequency other than
at each donation, or, when the conditions in the regulations are met,
even to stop testing for that relevant transfusion-transmitted
infection. Section 610.40(a)(4) describes types of evidence that may
support such a determination.
In Sec. 610.40(e), we are maintaining the existing requirement for
further testing when a donation tests reactive for a relevant
transfusion-transmitted infection. When a licensed, approved, or
cleared supplemental test is not available, the rule provides greater
flexibility for the use of licensed, approved, or cleared tests to
provide additional information concerning the reactive donor's
infection. This section also requires establishments to perform
additional testing of a donation found reactive by a non-treponemal
donor screening test for syphilis.
Final Sec. 630.5 provides requirements for medical supervision of
collection activities, such as determining the eligibility of a donor
of blood or blood components, including Source Plasma, collecting blood
or blood components, and for performing other donor procedures such as
returning red blood cells during apheresis, or immunizing Source Plasma
donors as part of an approved immunization program. This section
requires establishments to establish, maintain, and follow standard
operating procedures for obtaining rapid emergency medical services for
donors when medically necessary, and must assure that a person who is
currently certified in cardiopulmonary resuscitation is located on the
premises whenever collections are performed.
Section 630.10 establishes general donor eligibility requirements
and consolidates most donor eligibility requirements for Whole Blood
and Source Plasma into a single section. A donor is not eligible and
must be deferred if the donor is not in good health or if the
establishment identifies any factor that may cause the donation to
adversely affect the health of the donor or the safety, purity, or
potency of the blood or blood component. This section requires the
establishment to provide the donor with educational material related to
a relevant transfusion-transmitted infection when donor education about
that infection is necessary to assure the safety, purity, and potency
of blood and blood components, to consult records of deferred donors,
to assess the donor for risk factors for relevant transfusion-
transmitted infections and other factors that might adversely affect
the donation or the donor's health, and to obtain proof of the donor's
identity and a postal address where the donor may be contacted for 8
weeks after donation.
Section 630.10(f) requires establishments to perform a limited
physical assessment of the donor. This assessment must include donor
temperature, blood pressure, pulse, minimum weight, condition of the
skin at phlebotomy site and on arms, and hemoglobin or hematocrit
levels. The rule maintains current requirements for hemoglobin and
hematocrit levels for
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female donors, but since lower levels are also within the normal range
for women, the rule would authorize collection from female donors with
levels no lower than 12.0 grams of hemoglobin per deciliter of blood,
or a hematocrit value no lower than 36 percent, provided that the
establishment has taken additional steps to assure that the alternative
standard is adequate to assure donor safety, in accordance with a
procedure that has been found acceptable for this purpose by FDA. The
rule raises the minimum standard for male donors from 12.5 grams of
hemoglobin per deciliter of blood, or a hematocrit value that is equal
to or greater than 38 percent, to 13 grams and 39 percent,
respectively.
Under Sec. 630.10(g)(2) establishments must obtain the donor's
acknowledgement that the donor has reviewed educational material
required to be provided under this section as well as information about
the risks and hazards of the specific donation procedure. In the
proposed rule, this was called the ``Donor's written statement of
understanding.''
Section 630.15 establishes additional donor eligibility
requirements for the collection of Whole Blood and Red Blood Cells
collected by apheresis and Source Plasma and Plasma collected by
plasmapheresis. For donors of Whole Blood and Red Blood Cells collected
by apheresis, Sec. 630.15(a) requires that donation frequency be
consistent with protecting the donor's health, describes minimum
intervals between donations (typically 8 weeks, and 16 weeks for a
double Red Blood Cell donation), and addresses donations by donors
undergoing therapeutic phlebotomy.
The requirements in Sec. 630.15(b) applicable to donors of Source
Plasma and Plasma collected by plasmapheresis are largely consistent
with current regulations and practices. The responsible physician,
subject to delegation in accordance with Sec. 630.5(c), must conduct
an appropriate medical history and physical examination of the donor at
least annually, and must defer a donor found to have a medical
condition that would place the donor at risk from plasmapheresis, and
for red blood cell loss, as described in the rule. This section also
addresses informed consent requirements for donors of Source Plasma and
Plasma collected by plasmapheresis. These requirements complement other
requirements for the collection of plasma by plasmapheresis in parts
630 and 640 (21 CFR parts 630 and 640), including restrictions on
frequency of collection specified in Sec. Sec. 640.32 and 640.65).
Section 630.20 permits, under certain circumstances, the collection
of blood and blood components from individuals who are ineligible under
one or more of the eligibility requirements under Sec. Sec. 630.10 and
630.15. This section provides exceptions for autologous donors and
donors who are participants in an approved plasmapheresis program for
products for which there are no alternative sources, and for dedicated
donations where there is documented exceptional medical need. For all
collections authorized under this section, we have clarified the
responsible physician's role and responsibilities in these collections.
We are finalizing Sec. 630.25 largely as proposed. This section
modifies certain requirements in Sec. Sec. 630.15(b) and 640.65(b) as
they are applicable to the collection of plasma from infrequent plasma
donors. For greater clarity, we have included a definition of
``infrequent plasma donor'' in new Sec. 630.3(e) and we use that
defined term in this section.
We have finalized requirements in Sec. 630.30(a) to define when a
donation is suitable. Section 630.30(b) expressly prohibits an
establishment from releasing an unsuitable donation for transfusion or
further manufacturing use unless it is an autologous donation, or an
exception is provided. It further requires a blood establishment to
defer the donor of an unsuitable donation, although final Sec.
630.30(b)(2) requires deferral of donors of platelets found to be
bacterially contaminated only when the establishment determines in
accordance with Sec. 606.145 that the bacterial contamination shows
evidence of bacteria endogenous to the bloodstream of the donor. This
is because we recognize that a frequent cause of bacterial
contamination in platelets is due to the passage of the collection
needle through the donor's skin, which is not sterile. For this reason,
the presence of bacteria that are common skin flora does not warrant
deferral of the donor.
We have finalized the donor notification provisions in Sec.
630.40. Consistent with the proposed rule, Sec. 630.40(a) requires
establishments to notify donors whose platelet component has tested
positive for a bacterial contamination that is likely due to an
infection endogenous to the bloodstream of the donor, such as
Streptococcus bovis. Identification of this bacterium indicates that
the donor may have a serious health condition such as colon cancer.
Section 640.21 addresses eligibility of donors of platelets.
Consistent with the proposed rule, Sec. 640.21(b) provides that a
plateletpheresis donor must not serve as the source of Platelets for
transfusion if the donor has recently ingested a drug that adversely
affects platelet function. We have modified this requirement for donors
of Whole Blood that is the source of Platelets for transfusion. Section
640.21(c) requires that a Whole Blood donor must not serve as the
source of Platelets for transfusion if the donor has recently ingested
a drug that adversely affects platelet function unless the unit is
labeled to identify the ingested drug that adversely affects platelet
function. Section 640.21(g) incorporates existing informed consent
requirements.
Based on comments to the proposed rule, we have finalized the
requirements for collection of Platelets by plateletpheresis to be
consistent with ``Guidance for Industry and FDA Review Staff:
Collection of Platelets by Automated Methods,'' dated December 2007.
These provisions address donor platelet counts, frequency and size of
plateletpheresis collection, and deferral for red blood cell loss.
We are finalizing the limits on distribution of Source Plasma in
Sec. 640.69(e) with minor changes. The final rule now provides that
establishments must establish a paid Source Plasma donor's
qualification by determining on at least two occasions in the past 6
months that the donor is eligible under Sec. 630.10(e) and that the
donor's results are negative on all tests required under Sec.
610.40(a). Consistent with current industry standards, we have also
finalized the inventory hold provision proposed in Sec. 640.69(f) to
require establishments to hold Source Plasma donated by paid donors in
quarantine for a minimum of 60 days. In addition, we clarify the
conditions that would prevent an establishment from distributing Source
Plasma from quarantine.
We are not finalizing proposed Sec. 640.73, ``Reporting of donor
reactions'', in this rule. Instead, FDA intends to finalize this
section when FDA finalizes the proposed Safety Reporting Requirements
for Human Drug and Biologicals (68 FR 12406, March 14, 2003). We will
address in that final rule the comments on proposed Sec. 640.73.
We are finalizing Sec. 640.120 largely as proposed. Final Sec.
640.120(b) authorizes the Director of the Center for Biologics
Evaluation and Research (CBER) ``to respond to a public health need''
by issuing an exception or alternative to any requirement in subchapter
F of chapter I of title 21 of the CFR if necessary to provide for
appropriate donor screening and testing or to assure
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that blood, blood components, or blood products will be available in a
specified location or locations to address an urgent and immediate need
for blood, blood components, or blood products. Under these provisions,
this authority will be available to FDA to assure the availability of
blood and blood components that are safe, pure, and potent.
Analysis of Impacts
FDA has examined the impacts of the final rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612) and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). This final rule is not a significant regulatory action under
the Executive orders, and it will not have an economic impact, or
require expenditures, at magnitudes warranting review under those
statutory provisions.
Costs and Benefits
This rule sets forth requirements for donor eligibility and
donation suitability to ensure the safety, purity, and potency of the
blood and blood components used for transfusion or for further
manufacture. Costs estimated in this analysis include costs related to
the standard operating procedures and bacterial testing requirements
for blood collection establishments and transfusion services. The total
upfront costs are $16,042,628, and include costs related to the review,
modification, and creation of standard operation procedures. The mean
annual costs of $892,233 include costs related to the bacterial testing
of single units of Whole Blood-derived platelets and speciation of
bacterially contaminated platelets. We anticipate that this final rule
will preserve the safety, purity, and potency of blood and blood
components by preventing unsafe units of blood or blood components from
entering the blood supply, and by providing recipients with increased
protection against communicable disease transmission. The requirements
set forth in this rule will also help to decrease the number of blood
transfusion related fatalities that are associated with the bacterial
contamination of platelets. The annual value of additional fatalities
averted related by testing of Whole Blood-derived platelets is
estimated to be approximately $27 million to $90 million and the annual
value of averted nonfatal sepsis infections is estimated to be $3.19
million to $4.91 million.
Table of Contents
I. Introduction
II. Comments on the Proposed Rule and FDA's Responses
A. General
B. Definitions (Sec. Sec. 606.3, 610.39, 630.3, 640.125)
C. Standard Operating Procedures (Sec. 606.100)
D. Control of Bacterial Contamination of Platelets (Sec.
606.145)
E. Records (Sec. 606.160)
F. Test Requirements (Sec. Sec. 610.40, 640.5, 640.71(a))
G. Donor Deferral (Sec. 610.41)
H. Purpose and Scope (Sec. 630.1)
I. Medical Supervision (Sec. Sec. 630.5, 640.130)
J. General Donor Eligibility Requirements (Sec. 630.10)
K. Donor Eligibility Requirements Specific to Whole Blood, Red
Blood Cells and Plasma Collected by Apheresis (Sec. 630.15)
L. Exceptions for Certain Ineligible Donors (Sec. 630.20)
M. Exceptions from Certain Donor Eligibility Requirements for
Infrequent Plasma Donors (Sec. 630.25)
N. Donation Suitability Requirements (Sec. 630.30)
O. Requalification of Previously Deferred Donors (Sec. 630.35)
P. Requirements for Notifying Deferred Donors (Sec. 630.40)
Q. Platelets: Eligibility of Donors (Sec. 640.21)
R. Source Plasma: Plasmapheresis (Sec. 640.65(b))
S. Source Plasma: General Requirements (Sec. 640.69)
T. Source Plasma: Records (Sec. 640.72)
U. Source Plasma: Reporting of Donor Reactions (Sec. 640.73)
V. Alternative Procedures (Sec. 640.120)
W. Reagent Red Blood Cells (Sec. Sec. 660.31, 660.32)
X. Quality System Regulation: Scope (Sec. 820.1)
Y. Technical Amendments
III. Legal Authority
IV. Analysis of Impacts
V. Environmental Impact
VI. Federalism
VII. The Paperwork Reduction Act of 1995
VIII. References
I. Introduction
In the Federal Register of November 8, 2007 (72 FR 63416), FDA
published the proposed rule ``Requirements for Human Blood and Blood
Components Intended for Transfusion or for Further Manufacturing Use''
to amend the regulations for blood and blood components, including
Source Plasma and Source Leukocytes, by adding donor eligibility and
donation suitability requirements that are consistent with current
practices in the blood industry, and to more closely align the
regulations with current FDA recommendations. We proposed this rule to
help ensure the safety of the nation's blood supply and to help protect
the health of donors by requiring establishments to evaluate donors for
factors that may adversely affect the safety, purity, and potency of
blood and blood components or the health of a donor.
This effort was undertaken as part of the Department of Health and
Human Services Blood Action Plan (Ref. 1). The Blood Action Plan was
developed in response to recommendations from Congress and other groups
including the Government Accountability Office (previously the General
Accounting Office) and the Institute of Medicine (Refs. 2, 3). This
rulemaking is one of the final remaining action items under the Blood
Action Plan.
In response to numerous requests, we extended the comment period
for the proposed rule, initially scheduled to close on February 8,
2008, for an additional 180 days to August 4, 2008 (73 FR 1983, January
11, 2008). FDA received 29 letters of comment on the proposed rule,
most of which raised multiple issues. Some comments responded to
questions that we solicited in the preamble to the proposed rule in
order to obtain additional information and data for this rulemaking.
For example, we solicited comments on testing for bacterial
contamination in platelets (72 FR 63416 at 63421) and requested data
addressing the continued need for syphilis testing to address the risks
of transfusion-related syphilis infection, and its value as a surrogate
marker for other communicable diseases (72 FR 63416 at 63422).
II. Comments on the Proposed Rule and FDA's Responses
We received 29 letters containing multiple comments from blood
establishments, biologics manufacturers, industry trade associations,
and other interested persons. In this section, we respond first to
general comments and then, in the corresponding section of this
preamble, to those on specific provisions of the proposed rule. To make
it easier to identify the comments and our responses, the word
``Comment,'' in parentheses, will appear before the comment's
description, and the word ``Response,'' in parentheses, will appear
before our response. We have also numbered each comment in the order in
which we discuss it. The number assigned to each comment is purely for
organizational purposes and does not signify the comment's value or
importance or the order in which it was received. Certain comments were
grouped together because the subject matter of the comments was
similar.
A. General
(Comment 1) One comment commended FDA's efforts to update the
regulations for blood and blood components to accommodate scientific
and industry advances. These advances are vital to assuring the safety,
purity
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and potency of the blood supply. Another comment stated that they fully
support the intent of the proposed rule to help assure the safety of
the blood supply and to help protect donor health.
(Response) We acknowledge and appreciate these supportive comments.
(Comment 2) One comment applauded and supported FDA efforts to
streamline the regulations and bring them up-to-date with current
recommendations and current FDA guidance documents. The comment stated
that appropriate standards will afford the medical community the
ability to alleviate blood shortages, contribute to the success of
public health initiatives, and contribute to quality medical care.
(Response) We appreciate the comment. We revised and updated the
regulations applicable to blood and blood components, including Source
Plasma and Source Leukocytes, with the goal of ensuring optimal donor
safety measures as well as assuring that the public will continue to
have access to safe, pure and potent blood and blood components.
B. Definitions (Sec. Sec. 606.3, 610.39, 630.3, 640.125)
We have combined our discussion of the definitions contained in
Sec. Sec. 606.3, 610.39, 630.3, and 640.125 in this section of the
preamble. An understanding of the terms we define is important to an
understanding of other sections of this rule that use those terms. We
hope to help the reader by discussing these foundational definitions
early in this preamble, before we discuss the substantive provisions
using those terms.
We are finalizing the definition of blood in Sec. Sec. 606.3(a)
and 630.3(a) as a product that is a fluid containing dissolved and
suspended elements which was collected from the vascular system of a
human. We received no comments on the proposed definition. The
definition in the final rule differs from the proposal only in the
reference to ``a fluid'' instead of ``the fluid,'' and the substitution
of the phrase ``was collected from'' for ``circulates in.'' We made
these minor changes for accuracy, and to reflect the practical fact
that when blood becomes a ``product'' it is no longer circulating in a
human vascular system, but has been collected from the human vascular
system. We are finalizing without change the proposed definition of
blood component in Sec. Sec. 606.3(b) and 630.3(b) as ``a product
containing a part of human blood separated by physical or mechanical
means.'' We had proposed to modify the definition of blood component in
proposed Sec. 1270.3(b) (21 CFR 1270.3(b)). We are not finalizing that
provision because, due to the Agency's issuance of new regulations
applicable to human cellular and tissue based products (21 CFR part
1271), the regulations in part 1270 (21 CFR part 1270), including the
definition we proposed to amend, now apply only to human tissue
recovered before May 25, 2005. (See Sec. 1270.3(j)). For this reason,
it is unnecessary to finalize proposed Sec. 1270.3(b).
We are also finalizing as proposed the definitions of donor (Sec.
630.3(c)), eligibility of a donor (Sec. 630.3(d)), and suitability of
the donation (Sec. 630.3(j)).
In Sec. 630.3(e), we have added a definition of infrequent plasma
donor, which means a donor who has not donated plasma by plasmapheresis
or a co-collection of plasma with another blood component in the
preceding 4 weeks, and has not donated more than 12.0 liters of plasma
(14.4 liters of plasma for donors weighing more than 175 pounds) in the
past year. We provided a similar definition in the preamble to the
proposed rule, and are adding it to the codified section in order to
make the definition more accessible and clear. The preamble described
an infrequent plasma donor as a donor: (1) Who has not donated Whole
Blood in the preceding 8 weeks or plasma by apheresis in the preceding
4 weeks, or participated in a double Red Blood Cells unit collection
program within the preceding 16 weeks; (2) who has not donated more
than 12.0 liters of plasma in the past year (14.4 liters of plasma for
donors weighing more than 175 pounds); (3) who is determined by the
responsible physician to be in good health; and (4) who is not
participating in an immunization program for the production of high-
titer plasma. Under proposed Sec. 630.25(a), exceptions from certain
donor eligibility requirements could apply to such donors who have not
donated within the preceding 4 weeks. The definition of infrequent
plasma donor in the final rule focuses on the donor's prior donations
of plasma and co-collections of plasma because deferral for Whole Blood
and Red Blood Cell donation and requirements for donor health are
addressed in other sections of this rule (Sec. Sec. 630.10 and
630.15), and final Sec. 630.25 states that the exceptions in Sec.
630.25 are applicable only for infrequent plasma donors who are not
participating in an immunization program. The final rule defines an
infrequent plasma donor as a donor who has not donated plasma by
plasmapheresis or a co-collection of plasma with another blood
component in the preceding 4 weeks, and has not donated more than 12.0
liters of plasma (14.4 liters of plasma for donors weighing more than
175 pounds) in the past year. This definition makes clear that for
purpose of this exception, co-collection of plasma with another blood
component is considered in the same way as collection of plasma. We
decided to make this reference to co-collection by apheresis of plasma
more explicit in response to comments discussed in comment 115, which
asked FDA to harmonize deferral periods after red blood cell loss for
apheresis donors of plasma and of apheresis donors of plasma co-
collected with platelets.
Due to the addition of this new definition in Sec. 630.3(e), we
have redesignated the remaining definitions alphabetically, beginning
with intimate contact with risk for a relevant transfusion-transmitted
infection (now final Sec. 630.3(f)), through transfusion-transmitted
infection (now final Sec. 630.3(l)). Several of these definitions use
the term transfusion-transmitted infection, which is alphabetically
last. To help the reader understand the definitions that incorporate
the term transfusion-transmitted infection, we will first explain the
term transfusion-transmitted infection.
Consistent with the proposed rule, we define transfusion-
transmitted infection, final Sec. 630.3(l), as a disease or disease
agent: (1) That could be fatal or life-threatening, could result in
permanent impairment of a body function or permanent damage to body
structure, or could necessitate medical or surgical intervention to
preclude permanent impairment of body function or permanent damage to a
body structure and (2) for which there may be a risk of transmission by
blood or blood components or by a blood derivative product manufactured
from blood or blood components, because the disease or disease agent is
potentially transmissible by that blood, blood component or blood
derivative product.
Sometimes, a transfusion-transmitted infection will meet the
additional criteria established in the definition of a relevant
transfusion-transmitted infection. We define relevant transfusion-
transmitted infection in Sec. 630.3(h) to include two groups of
transfusion-transmitted infections. The first group, in Sec.
630.3(h)(1) is a list of 10 named transfusion-transmitted infections:
HIV; HBV; HCV; HTLV; syphilis; West Nile virus; Chagas disease;
Creutzfeldt-Jakob disease (CJD); variant Creutzfeldt-Jakob disease
(vCJD); and Plasmodium species (malaria). In recognition of current
industry practices and in response to comments received on the proposed
rule, West Nile virus
[[Page 29847]]
and Chagas disease are included in the definition of relevant
transfusion-transmitted infection at Sec. 630.3(h)(1)(vi) and (vii),
respectively. Establishments currently perform donor screening for
these relevant transfusion-transmitted infections. Blood establishments
other than Source Plasma establishments already perform testing for the
first seven listed transfusion-transmitted infections, and Source
Plasma establishments already perform testing for HIV, HBV, HCV, and
more limited testing for syphilis. Testing requirements for Source
Plasma establishments are more limited because Source Plasma undergoes
further processing into blood derivative products, and those additional
manufacturing steps have been shown to inactivate or remove certain
infectious agents. We consider these donor testing and screening
practices to meet current standards, and would address any changes in
our recommendations for complying with the final rule in guidances
issued in accordance with good guidance practice.
The second part of the definition of relevant transfusion-
transmitted infections, Sec. 630.3(h)(2), establishes the criteria
which will be used to identify other transfusion-transmitted infections
that present risks to the safety, purity, and potency of blood and
blood components at some time in the future. Under these criteria, a
transfusion-transmitted infection will be identified as a relevant
transfusion-transmitted infection when the following conditions are
met: (1) Appropriate screening measures for the transfusion-transmitted
infection have been developed and/or an appropriate screening test has
been licensed, approved, or cleared for such use by FDA and is
available and (2) the disease or disease agent may have sufficient
incidence and/or prevalence to affect the potential donor population,
or may have been released accidentally or intentionally in a manner
that could place potential donors at risk of infection. Under the first
prong of these criteria, a transfusion-transmitted infection could be
identified as a relevant transfusion-transmitted infection only when an
intervention is available to prevent infection of the blood supply.
This intervention could be a donor screening measure such as questions
during the medical history interview about medical history, travel, or
other behaviors, or a donor screening test to detect the disease or
disease agent or evidence of the infection. Under the second prong, the
transfusion-transmitted infection must be relevant to the donor
population, either because it may have sufficient incidence and/or
prevalence to affect the donor population, or because it may have been
released in a manner that could place potential donors at risk of
infection.
In the event that FDA determines that, under current conditions, a
transfusion-transmitted infection now meets the definition of a
relevant transfusion-transmitted infection, FDA intends to issue
guidance in accordance with good guidance practices to advise
stakeholders of FDA's assessment of how the transfusion-transmitted
infection now meets the definition of relevant transfusion-transmitted
infection. In the same guidance, we would also address appropriate
screening measures, including medical history assessments, in
accordance with Sec. 630.10(e), and any appropriate donor testing for
relevant transfusion-transmitted infections in accordance with Sec.
610.40(a)(3). We anticipate issuing such guidance initially as a draft
for comment, unless, due to urgent circumstances, it is not feasible or
appropriate to issue the document first in draft. Under those
circumstances we would invite comment on the final guidance, and revise
it as appropriate.
We note that members of the Transfusion Transmitted Diseases
Committee of AABB, formerly the American Association of Blood Banks,
published an article in 2009 identifying 68 emerging infectious disease
agents that are potentially transmitted by blood (Ref. 4) and recently
updated this list of potential threats (Ref. 5). We recognize the value
of such scientific assessments to the recognition and management of
emerging infections among blood donors and blood recipients, and note
that blood establishments already exercise medical judgment in
implementing measures to respond to emerging infectious diseases.
However, FDA intends to enforce requirements for screening and/or
testing in this final rule with respect to an emerging infectious
disease agent that is newly identified as meeting the definition of
relevant transfusion-transmitted infection only after FDA issues a
final guidance identifying the disease or disease agent as a relevant
transfusion-transmitted infection under the criteria in this final
rule, and recommends appropriate screening and/or testing measures.
Transfusion-transmitted infections that may, due to changed
circumstances, meet the definition of relevant transfusion-transmitted
infections in the future include dengue viruses or babesia. These
infections meet the definition of transfusion-transmitted infection
because they are life-threatening and are known to be transmitted by
blood or blood components. We are continuing to monitor the incidence
and prevalence of these infections in the donor population, as well as
the development and availability of screening measures and screening
tests. As discussed in the previous paragraph, if we determine at a
future time that one of these transfusion-transmitted infections meets
the criteria for a relevant transfusion-transmitted infection, we would
issue guidance to explain our assessment. We would also address in that
guidance appropriate screening and/or testing measures under Sec. Sec.
630.10(e) and 610.40(a)(3).
We revised the defined term intimate contact in the proposed rule
to intimate contact with risk for a relevant transfusion-transmitted
infection (Sec. 630.3(f)). This term means having engaged in an
activity that could result in the transfer of potentially infectious
body fluids from one person to another. By including the phrase ``with
risk for a relevant transfusion-transmitted infection'' in the term, we
have clarified that the term applies to only those body fluids
potentially infectious for infections that are or have been determined
to be relevant transfusion-transmitted infections. Also, in response to
several comments, discussed in more detail in comment 7, we deleted the
reference to the exchange of ``blood or saliva'' from the definition.
We define physician substitute in Sec. 630.3(g), responsible
physician in Sec. 630.3(i) and trained person in Sec. 630.3(k). These
definitions describe the qualifications an individual must possess to
perform certain donor eligibility assessments and blood and blood
component collection procedures as described in Sec. 630.5. The
physician substitute definition is unchanged from the proposed, except
that instead of requiring, among other criteria, that the individual be
``trained and authorized to perform specified functions under the
direction of the responsible physician,'' the final rule specifies that
the individual be ``trained and authorized under State law, and/or
local law when applicable, to perform the specified functions under the
direction of the responsible physician.'' We make this change to
clarify that authorization under existing and applicable state and
local law, such as compliance with state practice limitations, is
required. The definition of responsible physician is unchanged from the
proposed rule. For clarity we substituted the non-plural term trained
person, for the term trained
[[Page 29848]]
personnel, which was used in the proposed rule. We have also specified
that a trained person must be ``authorized under State law, and/or
local law when applicable.''
We did not receive any comments to the proposed definition of you
as ``an establishment that collects blood and blood components''
(proposed Sec. 630.3(l)). However, we are not finalizing that proposed
definition. We did not intend to limit the term you to establishments
that collect blood and blood components. In fact, we intended the term
also to apply to establishments that perform other manufacturing steps,
such as testing laboratories and transfusion services. Accordingly, we
concluded that including you as a defined term was confusing, and we
are not finalizing the proposed definition.
Finally, in new Sec. 610.39, we have added a cross-reference to
the definitions in Sec. 630.3 to make clear that when these terms are
used in part 610, subpart E (Sec. Sec. 610.40 through 610.48), the
definitions in Sec. 630.3 apply. Although our practice in subpart E
has been to cross-reference specific sections, express incorporation of
these definitions into the subpart will support the clarity of these
provisions. Similarly, we have added new Sec. 640.125 to new subpart M
in part 640, entitled ``Definitions and Medical Supervision.'' Section
640.125 provides a cross-reference to the definitions in Sec. 630.3,
making those definitions applicable when those terms are used in part
640. This provision is consistent with the proposed rule, which stated
in the introductory paragraph to proposed Sec. 630.3 that the
definitions were applicable in part 630 and in part 640.
(Comment 3) One comment recommended that the definition of blood
component in proposed Sec. Sec. 606.3(c) and 630.3(b) should include a
cross-reference to the regulations in which specific blood components
(such as Red Blood Cells and Platelets) are defined. The comment stated
that the proposed definition fails to impart the complexity of
different blood components and their intended uses, that there is
little similarity between blood components intended for transfusion and
Source Plasma, and that the requirements for donor eligibility and
testing are unique for Source Plasma. Another comment proposed that a
comprehensive definition be provided for Source Plasma.
(Response) All blood components contain risks for transmission of
infectious agents, and collection of donations presents risks for donor
safety regardless of the intended use of the donation. There is
significant consistency among donor eligibility requirements for all
types of blood components; these are addressed in Sec. 630.10. In
addition, different types of blood components may present different
issues, both for the safety, purity, and potency of the collection, and
for the safety of the donor. The regulations have long included
requirements specific to Source Plasma, Platelets, Red Blood Cells, and
other blood components, and we maintain many of those requirements in
the final rule. However, we disagree that the definition of blood
component, which includes all products derived from human blood
separated by physical or mechanical means, will be improved by cross-
references to the sections that address requirements for specific types
of blood components. Instead, we address requirements applicable to a
specific type of blood component in the sections applicable to those
blood components. For example, in part 640, subpart B (Sec. Sec.
640.10 through 640.17) addresses Red Blood Cells and contains standards
for those blood components, as subparts C (Sec. Sec. 640.20 through
640.27), D (Sec. Sec. 640.30 through 640.34), and G (Sec. Sec. 640.60
through 640.76) do for Platelets, Plasma, and Source Plasma,
respectively. Finally, we reviewed the current definition of Source
Plasma in Sec. 640.60, which states that ``the fluid portion of human
blood collected by plasmapheresis and intended as source material for
further manufacturing use. The definition excludes single donor plasma
products intended for intravenous use.'' We conclude that it is
sufficiently comprehensive.
(Comment 4) One comment questioned FDA's inclusion of a person who
``presents as a potential candidate for such donation'' in the
definition of donor. The comment requested clarification on when a
person ``presents'' to donate, and asked whether a donor ``presents''
simply by walking through the door, or whether a donor ``presents''
when the blood establishment starts the donor interview to assess the
donor's eligibility under the regulations. The comment stated that
certain blood establishments collect blood from donors who have
specific characteristics unrelated to donor eligibility, such as a
history of a specific disease. The comment stated that preliminary
interviews to determine whether an individual has such a characteristic
should not be considered to be interviews with a ``donor.'' The comment
asserted that requirements to maintain donor records in Sec.
606.160(b)(1) (21 CFR 606.160(b)(1)) should not apply to records of
these preliminary interviews because the specialty centers determine
specialty information before assessing the general eligibility of the
potential candidate. The comment proposed the following definition,
``Donor means a person who: (1) Donates blood or blood components for
transfusion or for further manufacturing or (2) a potential candidate
who has begun the interactive assessment of eligibility by center
personnel.''
(Response) Under the definition of donor in final Sec. 630.3(c),
an individual would be a ``donor'' once the establishment begins any of
the interactions that are required under this rule. Accordingly, an
individual who has not yet donated, but has received educational
material in accordance with Sec. 630.10(b), or started to provide
donor information related to medical history under Sec. 630.10(e),
would be a donor. For example, questioning of the ``donor'' regarding
travel history or risk behaviors that could lead to deferral under
Sec. Sec. 630.10(e)(2)(iii) and 630.10(e)(1)(i), respectively, would
be considered part of determining donor eligibility. However, other
interactions not required under this rule, such as taking a blood
sample at a health fair to identify rare blood types or unique antigens
or antibodies could be considered preliminary interactions, provided
that an interaction required under this rule (such as testing for a
relevant transfusion-transmitted infection) was not also initiated
during the same encounter. If an establishment's interactions with an
individual are only preliminary and are not otherwise required under
these regulations, the individual would not yet be considered a
``donor.''
(Comment 5) One comment recommended that FDA adopt terminology that
excludes paid donors from the definition of a donor. The comment stated
that people being paid to have their plasma collected are not giving a
donation.
(Response) We decline to accept the recommendation. Consistent with
the general use of the term in blood collection establishments, FDA
uses the term donor to apply to all donors, whether or not they are
paid. FDA regulations do not preclude paid donations for blood for
transfusion or for further manufacture. We acknowledge that the
existing regulations have specific provisions applicable to paid
donors. For example, FDA requires the container label of blood and
blood components intended for transfusion to include the statement
``paid donor'' or ``volunteer donor.'' Section 606.121(c)(8)(v)(A)
defines a
[[Page 29849]]
paid donor as a person who receives monetary payment for a blood
donation. We do not require that Source Plasma be labeled in this way
because it is widely understood that Source Plasma is collected
predominantly from paid donors.
(Comment 6) Several comments agreed with the definitions of
eligibility of a donor and suitability of the donation in proposed
Sec. 630.3(d) and (i), respectively. The comments stated the terms are
helpful in clarifying many requirements.
(Response) We agree, and have finalized the definitions as proposed
in Sec. 630.3(d) and (j), respectively.
(Comment 7) Several comments stated that the definition of intimate
contact, designated in the final rule at Sec. 630.3(f), should be
reworded to describe an activity (sexual contact or living with) that
could result in an exchange of blood with another individual.
(Response) As stated earlier, we revised the term from intimate
contact to intimate contact with risk for a relevant transfusion-
transmitted infection. The term means having engaged in an activity
that could result in the transfer of potentially infectious body fluids
from one person to another. The new definition does not reference blood
or saliva specifically; it also does not define the specific activity
that could result in the transfer of potentially infectious body
fluids. The definition applies only when intimate contact presents
risks for transmission of a relevant transfusion-transmitted infection.
This definition of intimate contact with risk for a relevant
transfusion-transmitted infection and the associated requirement in
Sec. 630.10(e)(1)(v) to assess donors for this risk replaces current
Sec. 640.3(c)(2), which requires deferral of donors who have a history
of close contact within 12 months of donation with an individual having
viral hepatitis. The new provisions refine the current requirement, and
we note that the donor history questionnaires prepared by AABB and the
Plasma Protein Therapeutic Association, which have been recognized as
acceptable by FDA for screening donors of blood, blood components and
Source Plasma, already address the risk of transmission of HBV and HCV
by including questions about the donor's ``sexual contact'' and
``living with'' individuals with hepatitis (Refs. 6, 7, 8).
We also note that FDA has recommended that a donor be deferred on
the basis of sexual contact with an individual infected with HIV.
Questions related to sexual contact with an individual infected with
HIV are also included in the donor history questionnaires found
acceptable by FDA (Refs. 6, 7, 8). FDA intends to issue guidance as
needed to identify other relevant transfusion-transmitted infections
where we consider intimate contact to present significant risks for
transmission of such infection.
(Comment 8) Several comments stated that the proposed definition of
intimate contact was not consistent with public health messages that
the risk of transmission of HIV transmission through kissing is remote.
(Response) We agree with this comment in part and have revised the
proposed definition. Public health messages have not identified casual
kissing as a risk for HIV. However, CDC has identified open-mouth
kissing with an HIV infected person as a risk if there are breaks in
the skin or tongue (Ref. 9). FDA's guidance for donor deferral is
limited to ``having sexual contact with an HIV infected individual''
(Ref. 10). It does not recommend deferral for kissing.
(Comment 9) One comment agreed with the proposed definition of
physician substitute; however, the comment stated that the term could
be misleading for the general public and could imply that physician
substitutes can perform all duties of a licensed physician at the
Source Plasma establishments.
(Response) We disagree that the term physician substitute implies
that physician substitutes can perform all the duties of a licensed
physician. We believe the definition in Sec. 630.3(g) describes
sufficiently the training and qualifications of a physician substitute,
who must be a graduate of an education program for healthcare workers
that includes clinical training, currently licensed or certified as a
health care worker in the jurisdiction where the collection
establishment is located, and currently certified in cardiopulmonary
resuscitation. Moreover, the definition now makes explicit that a
physician substitute must be trained and authorized under State law,
and/or local law when applicable, to perform specified functions under
the direction of the responsible physician. Finally, Sec. 630.5
describes the activities the responsible physician may delegate to the
physician substitute, and those the responsible physician is not
authorized to delegate.
(Comment 10) Several comments stated that syphilis and CJD should
not be included in the definition of relevant transfusion-transmitted
infection.
(Response) We disagree with the comments. Syphilis is a relevant
transfusion-transmitted infection which screening tests have long been
used to detect. As discussed in our response to comment 31, we continue
to review data to determine whether it is still necessary to perform
screening tests for this infection. However, data submitted to date do
not justify a determination that testing to identify syphilis infection
is no longer needed to protect the blood supply. Accordingly, we have
included syphilis in the definition of a relevant transfusion-
transmitted infection at final Sec. 630.3(h)(1)(v).
We have also determined that CJD and vCJD are relevant transfusion-
transmitted infections because of the risks they present. Screening
tests are not yet available for CJD and vCJD. It is current practice
for establishments to perform screening by means of a medical history
interview, and FDA has issued guidance recommending donor screening for
these diseases (Ref. 11). Consistent with these current practices, we
have included CJD and vCJD in the definition of a relevant transfusion-
transmitted infection at Sec. 630.3(h)(1)(viii) and (ix),
respectively.
However, our inclusion of certain transfusion-transmitted
infections within the definition of relevant transfusion-transmitted
infection does not necessarily mean an establishment will always be
required to perform donor history screening, or donor testing for that
relevant transfusion-transmitted infection. Specifically, in line with
the more flexible testing paradigm and criteria we have adopted in
final Sec. 610.40(a), it is possible that testing for syphilis will no
longer be necessary to reduce adequately and appropriately the risk of
transmission of syphilis by blood or blood components. The same applies
to CJD and vCJD, and to relevant transfusion-transmitted infections
other than HIV, HBV, and HCV. New Sec. 610.40(a)(4) describes the
evidence that may be used to support such a determination.
(Comment 11) One comment recommended the inclusion of West Nile
virus, Chagas disease, and bacteria in the definition of relevant
transfusion-transmitted infection, noting that blood components are
routinely tested for West Nile virus and Chagas disease.
(Response) We agree that West Nile virus and Chagas disease present
significant risks to the safety, purity, and potency of the blood
supply, and that the performance of screening tests for these
transfusion-transmitted infections has become routine. Accordingly, we
have added these two infections to the definition of relevant
transfusion-transmitted infections in this final rule. However, testing
or screening of blood donors to identify
[[Page 29850]]
specific bacterial infections is not routinely performed for donors of
all blood components, although under final Sec. 630.10(e)(2)(i)
establishments must assess all donors for symptoms of a recent or
current illness. We decline to add bacteria to the definition of
relevant transfusion-transmitted infection at this time, but we have
addressed bacterial testing of platelets in Sec. 606.145 of this rule.
(Comment 12) One comment recommended that responsible physician be
defined to differentiate between the duties of a physician overseeing
blood collection at an individual facility and a corporate physician
with broader oversight responsibilities. Another comment stated that
regional responsible physicians should be responsible for endorsing
standard operating procedures (SOPs), and for supervising employees'
compliance with those SOPs. Locally based physicians should not control
or approve SOPs as this would lead to inconsistency in operations.
(Response) We decline to provide distinct definitions for
``corporate responsible physician'' and ``locally based physician''. As
discussed in section II.C of this preamble, Sec. 606.100(b) requires
blood establishments to establish, maintain, and follow written SOPs
for all steps in the collection, processing, compatibility testing,
storage, and distribution of blood and blood components. These
regulations do not prescribe the roles of corporate and locally based
physicians in developing and approving SOPs. In fact, one process for
establishing SOPs may be appropriate for one type of blood
establishment, such as a licensed blood establishment that collects
blood and blood components in multiple states, but inappropriate for a
smaller blood establishment that collects and distributes blood and
blood components within a limited geographic area.
C. Standard Operating Procedures (Sec. 606.100)
We are finalizing Sec. 606.100(b), on which we received no
comments, largely as proposed. In this section we revised the
requirements for SOPs to require more specifically that blood
establishments follow those procedures, to distinguish transfusions as
either ``allogeneic'' or ``autologous,'' and to require more explicitly
that establishments establish, maintain, and follow written standard
operating procedures for investigating product deviations and for
recordkeeping related to current good manufacturing practice
requirements and other applicable requirements and standards. We are
also finalizing as proposed Sec. 606.100(b)(20) and (b)(21), which
require procedures for donor deferral as prescribed in Sec. 610.41,
and procedures, including appropriate follow up, for notification of
donors under Sec. 630.40, and, for autologous donors, their referring
physicians. We have also added Sec. 606.100(b)(22), which requires
establishments to have procedures to control the risks of bacterial
contamination of platelets, including all steps required under Sec.
606.145. We are including this provision to clarify that taking steps
to control bacterial contamination of platelets is a step in the
collection, processing, storage, and distribution of platelets, for
which SOPs are required. Our discussion of comments received regarding
bacterial testing of platelets can be found at comments 13 through 24
in section II.D.
D. Control of Bacterial Contamination of Platelets (Sec. 606.145)
We have finalized in new Sec. 606.145 the requirement we proposed
as Sec. 630.30(a)(5), which, for platelet components, would have
required establishments who collect blood and blood components to
``take adequate steps to assure that the donation is tested for
bacterial contamination and found negative.'' We are finalizing this in
part 606 in order to underscore the importance of including methods to
control the risk of the proliferation of bacteria in platelets as
current good manufacturing practice for blood and blood components.
Unlike other blood components, platelets do not function optimally
following refrigeration. They are stored at room temperature, an
environment conducive to the growth of bacteria. If the platelet unit
is contaminated, bacteria can flourish and grow quickly in the warm,
nutrient-rich platelet storage bag. Bacterial contamination is
estimated to occur in as many as 1/1,000 to 1/3,000 platelet
collections (Refs. 12, 13). The transfusion of bacterially contaminated
platelets puts recipients at risk, with reactions varying due to a
number of factors, including the pathogenicity of the bacteria, the
quantity of the bacteria transfused, and the immune status of the
recipient. Reactions range from no obvious clinical effects to severe
and life-threatening infections (Ref. 14). Under current regulations
(Sec. 606.170(b)), blood collection establishments and transfusion
services are only required to report to FDA when adverse reactions
related to blood collection or transfusion are confirmed to be fatal.
Deaths due to bacterial contamination of platelets have been reported
to FDA in recent years as follows: in 2008, there were two fatalities
reported as complications of platelet transfusions, with subsequent
reports of five in 2009, one in 2010, three in 2011, and two in 2012
(Ref. 15).
The final rule requires blood collection establishments and
transfusion services to assure that the risks of bacterial
contamination of platelets are adequately controlled using FDA approved
or cleared devices or other adequate and appropriate methods found
acceptable for this purpose by FDA. This final rule requires these
manufacturers to meet this standard, and, unlike the language in the
proposed rule, does not necessarily require that components be ``tested
. . . and found negative.'' Even though testing of platelet components
using an FDA approved or cleared test would currently meet this
requirement, the standard setting language used in the final rule would
provide for appropriate use of new technologies in the future. For
example, if pathogen reduction technology is approved or cleared and
available in the future, then use of pathogen reduction technology may
also meet the requirements of this provision. We intend to issue
guidance addressing how establishments would use FDA approved or
cleared devices or methods that FDA has determined to be adequate to
assure that the risks of bacterial contamination of platelets are
adequately controlled.
Transfusion services are manufacturers that release platelet
components for transfusion to an identified recipient but do not
routinely collect blood and blood components. Under this rule,
transfusion services may rely on the steps taken by the blood
collection establishment to assure that the risks of bacterial
contamination of a platelet component are controlled, as long as those
methods adequately control risks from the growth of bacteria until the
transfusion service releases the product for transfusion. If the
collection establishment did not take steps to control the risk of
bacterial contamination, then the transfusion service must do so. We
note that collection establishments currently take steps to control the
risk of bacterial contamination in most platelet components, and expect
that transfusion services will have to take steps to control the risk
of bacterial contamination only for limited numbers and types of
platelet components. For example, a transfusion service may intend to
release for transfusion a platelet component derived from a single unit
of whole blood. Collection
[[Page 29851]]
establishments do not typically subject such components to testing by
culture-based methods, in part because the volume of the sample
required for currently available culture tests would significantly
deplete the volume of the component. For such platelet components,
Sec. 606.145 would require the transfusion service to take steps, such
as the performance of an FDA-cleared rapid test, to assure that the
risk of bacterial contamination is adequately controlled.
In the proposed rule (72 FR 63416 at 63421), FDA asked for comments
on the following additional points related to testing for bacterial
contamination: (1) Whether to require the identification of the species
of the bacterial contaminant; (2) whether to require donor deferral and
notification when identification of the contaminant indicates possible
endogenous bacteremia, and not contamination during collection and
processing; and (3) whether to extend bacterial testing requirements to
other transfusable blood components. We discuss the first issue at
comments 18 through 21, and the second issue at comments 103 through
106, related to Sec. Sec. 630.30 and 630.40. With respect to the third
issue, as discussed at comment 24, we have decided not to codify a
requirement for bacterial testing of other blood components in this
rule.
(Comment 13) One comment supported requirements for bacterial
testing of platelets prior to transfusion in order to reduce the risk
of post-transfusion infection, sepsis, or mortality.
(Response) We appreciate this support for bacterial testing of
platelets.
(Comment 14) Several comments opposed a requirement to obtain a
negative test result prior to determining a platelet donation to be
suitable. Two comments noted that this standard is difficult to apply
when a culture-based method is used. The comments stated that in
current practice, cultured platelets are released as negative-to-date
while incubation is continued. The comments asked FDA not to finalize
the proposed requirement.
(Response) We agree that the proposed requirement that platelets be
``tested for bacterial contamination and found negative'' may have been
too prescriptive. Accordingly, Sec. 606.145(a) requires manufacturers
to assure that the risks of bacterial contamination of platelets are
adequately controlled using FDA approved or cleared devices or other
adequate and appropriate methods found acceptable for this purpose by
FDA. This could permit release on the basis of an adequate culture test
method that is ``negative-to-date'' on the date of release, even if the
establishment continues to incubate the culture. In some circumstances,
the culture may later indicate the presence of bacteria in a platelet
component that was appropriately released as ``negative-to-date''. In
that event, the establishment would initiate appropriate action under
21 CFR 606.100(c) and part 7, which may include notifying consignees
and retrieving transfusable blood components prepared from that
collection.
(Comment 15) Some comments expressed concern that the testing
requirement in this provision would be difficult for blood centers to
implement because there are currently no cleared or approved release
tests for bacterial testing of platelet products. One of the two
cleared quality control tests does not report a single negative result,
only a negative-to-date reading. The comment recommended that FDA not
finalize these requirements and, instead, provide separate guidance
after FDA approves a release test to identify bacteria in platelets.
(Response) We decline to delay establishing a requirement that
establishments assure that the risk of bacterial contamination of
platelets is adequately controlled. Some manufacturers have been
conducting bacterial testing on platelet components for over a decade.
We note that the College of American Pathologists has established
bacterial testing of platelets as an accreditation standard (Ref. 16).
In March 2004, AABB established an accreditation standard requiring
accredited blood banks and transfusion services to have methods to
limit and detect bacterial contamination in all platelet components
(Ref. 17). We have modified the language in the proposed rule so that
we require manufacturers to assure that the risks of bacterial
contamination of platelets are controlled using FDA approved or cleared
devices or other adequate and appropriate methods found acceptable for
this purpose by FDA. We intend to issue guidance addressing the use of
methods that FDA has determined to be acceptable for this purpose.
(Comment 16) One comment asserted that a requirement for negative
test results could become outdated. Methods for bacterial testing
continue to evolve and the possibility exists that a pathogen reduction
procedure will obviate the need for bacterial screening.
(Response) We recognize that, as technology develops, new methods,
including pathogen reduction, may become adequate to satisfy the
requirements in Sec. 606.145(a), and may replace testing. We
anticipate that, in the future, we will recognize such developments by
updating our guidance on the methods that would meet the requirements
of Sec. 606.145(a).
(Comment 17) One comment requests that the Agency add a requirement
that bacterial contamination testing be performed in a laboratory
certified under the Clinical Laboratory Improvement Amendments of 1988
(42 U.S.C. 263a) (CLIA) to perform the testing. The comment asserts
that the CLIA requirements complement FDA requirements and lead to
higher quality laboratory testing.
(Response) We appreciate the comment. However, we note that final
Sec. 606.145(a) requires manufacturers to ``assure that the risks of
bacterial contamination of platelets are adequately controlled using
FDA approved or cleared devices or other adequate and appropriate
methods found acceptable for this purpose by FDA.'' In the future,
technology may develop adequate methods that do not include testing,
instead incorporating, for example, pathogen reduction technology.
Under these circumstances, laboratory testing may no longer be
necessary to assure platelet safety from bacterial contamination. For
this reason, we are not specifying a specific requirement to ``test''
in the final rule, and do not require that ``tests'' be performed in a
laboratory certified under CLIA.
(Comment 18) One comment observed that bacterial speciation may be
viewed as an important part of an investigation of a failed product
quality control test. Species identification assists in isolating the
source of the contamination, such as when the species is associated
with environmental contamination, skin flora, or is an enteric
organism. Furthermore, species identification permits appropriate
investigation and donor counseling to take place. The comment noted
that the identification of certain skin bacteria may raise questions
about adequate performance of skin preparation procedures, and may
support further examination of the donor's antecubital areas for
scarring and pitting at the donor's next donation. The identification
of enteric organisms such as Streptococcus bovis may be an indication
of an underlying illness in the donor.
(Response) We agree with these observations. Bacteria may be
introduced into a platelet component by means that do not indicate any
illness in the donor, such as passage of the collection needle through
the donor's non-sterile skin, or other environmental factors. However,
in rare cases, the presence of bacteria is due to its
[[Page 29852]]
endogenous presence in the donor's bloodstream. This can reveal a
serious illness in the donor (Ref. 18). For example, the presence of
Streptococcus bovis in the blood is associated with colonic pathology,
including malignancy (Refs. 18, 19). Speciation of bacteria can provide
information valuable to the processing establishment about deficiencies
in platelet collection and processing methods, and may provide
information that may be important to the donor's health. To assure
blood safety, final Sec. 606.145(b) requires that, in the event that a
blood collection establishment identifies platelets as bacterially
contaminated, that establishment may not release for transfusion the
platelets or any other component prepared from the same collection, and
must take appropriate steps to identify the organism. Final Sec.
606.145(c) requires that, in the event that a transfusion service
identifies platelets as bacterially contaminated, the transfusion
service must not release the platelets, and must notify the blood
collection establishment that provided the platelets. The transfusion
service must take appropriate steps to identify the organism; these
steps may include contracting with the collection establishment or a
laboratory to identify the organism. The transfusion service must
further notify the blood collection establishment either by providing
information about the species of the contaminating organism when the
transfusion service has been able to identify it, or by advising the
blood collection establishment when the transfusion service has
determined that the species cannot be identified. Final Sec.
606.145(d) provides that in the event that a contaminating organism is
identified under Sec. 606.145(b) or (c), the responsible physician for
the collection establishment must determine whether the contaminating
organism is likely to be associated with a bacterial infection that is
endogenous to the bloodstream of the donor, in accordance with a
standard operating procedure developed under Sec. 606.100(b)(22). This
determination may not be further delegated.
Finally, we note that requirements to take appropriate steps to
identify contaminating organisms apply only when bacterial
contamination is found. In the event that approved or cleared devices
or other methods that employ pathogen reduction technology, rather than
relying on identifying contamination, are determined to be adequate and
appropriate, the use of such technologies may eventually limit the
situations where establishments would need to identify the presence of
contaminating bacteria. If fewer instances of contamination are
identified due to widespread use of pathogen reduction technologies,
the instances where establishments are required to identify the
contaminating organisms would also be reduced in number.
(Comment 19) Several comments stated that they consider the
decision whether to identify the species of the bacterial contaminant
to fall within the purview of the collection facility's medical
director. Some stated that the standard of care already includes
speciation of isolated bacteria and donor notification when felt to be
medically appropriate, and regulation is not required in this area. One
comment stated that, consistent with the College of American
Pathologists and AABB accreditation standards, blood establishments
should have a defined policy for how to investigate and handle
bacterial contamination. However, this policy represents medical
decision making that should not be addressed in regulation.
(Response) Current good manufacturing practices applicable to the
manufacture of drugs, including transfusable platelet components,
already require a manufacturer to thoroughly investigate the failure of
a batch or any of its components to meet any of its specifications (21
CFR 211.192). Identifying the species of contaminating bacteria can
provide information concerning the likely pathway that permitted the
bacteria to enter the contaminated component. That information may then
permit a manufacturer to determine whether, and how, a deficient
manufacturing practice (for example, poor arm preparation, non-sterile
docking, or contamination of the collection container) allowed the
contamination to occur. Such a determination could enable the
manufacturer to take appropriate corrective actions, which may include,
for example, additional training of personnel. Because speciation of
bacteria provides information that is important to a manufacturer's
investigation of the failure of a platelet component to be free of
bacteria, a decision concerning whether or not to identify the species
of contaminating bacteria is not solely for the medical director to
make. Instead, it falls within the province of production and process
controls. For this reason, we have included in Sec. 606.145 an
explicit current good manufacturing practice requirement for
manufacturers to take appropriate steps to identify the organism. In
addition, in the event that the contaminating organism is identified,
Sec. 606.145(d) requires the responsible physician for the collection
establishment to determine whether the contaminating organism is likely
to be associated with a bacterial infection that is endogenous to the
bloodstream of the donor, in accordance with a standard operating
procedure developed under Sec. 606.100(b)(22).
(Comment 20) Some comments noted that FDA did not provide a
definition of an endogenous bacterial infection, and stated that they
are not aware of any bright line dividing an endogenous bacteremia from
contamination, since the organisms involved overlap significantly.
(Response) The proposed rule referenced ``endogenous'' bacteria in
proposed Sec. 630.40(a), which would have required notification of a
donor ``whose platelet component has tested positive for an endogenous
bacterial contamination.'' In Sec. 606.145(d), we now require the
responsible physician for the collection establishment to determine
whether the contaminating organism is likely to be associated with a
bacterial infection that is endogenous to the bloodstream of the donor,
in accordance with a standard operating procedure. Examples of
contaminating organisms that the responsible physician, based on his or
her medical judgment, may determine to be likely to be associated with
a bacterial infection that is endogenous to the bloodstream of the
donor include Streptococcus bovis, Streptococcus veridins, and
Salmonella. We require the responsible physician to make this
determination in accordance with a standard operating procedure.
(Comment 21) Another comment stated that FDA should not require
testing for a contaminating organism until the Agency approves a test
specifically for that purpose. The comment supported the introduction
of bacterial screening when assays become available that are accurate,
rapid, and economically feasible.
(Response) We believe that, consistent with current standards of
the College of American Pathologists and AABB, a majority of collection
establishments are currently using bacterial detection methods such as
culture to identify the contaminating organism. Section 606.145(b) and
(c) require that blood collection establishments and transfusion
centers take appropriate steps to identify the organism. To satisfy
this requirement, an establishment would use adequate and currently
available technologies, which may include appropriate culture methods.
As we noted in our response to comment 15, we intend to issue guidance
[[Page 29853]]
addressing how establishments would use FDA approved or cleared devices
or methods that FDA has determined to be adequate to assure that the
risks of bacterial contamination of platelets are adequately
controlled.
(Comment 22) Some comments noted that, when a transfusion service
pools platelets separated from Whole Blood with other units of Whole
Blood-derived platelets immediately before releasing the pooled
platelet component for transfusion, there is not enough time to use
culture methods to assess the pooled unit for bacterial contamination.
The comments stated that the proposed rulemaking would, as a practical
matter, prohibit the use of components prepared from platelets
separated from Whole Blood and then pooled immediately prior to
transfusion. The comments further stated that while systems exist that
allow Whole Blood-derived platelets to be pooled by a collection
facility before storage and tested for bacteria using culture-based
methods, these systems are not used by most collection facility
component laboratories.
(Response) We disagree that the requirements in final Sec. 606.145
will prohibit the use of platelet components prepared at the
transfusion service by pooling units of Whole Blood-derived platelets,
and note that practices have evolved since the comment raised these
objections. Since the proposed rule published, FDA has cleared rapid
bacterial detection devices that detect bacteria in platelets. These
devices do not use culture-based methods, and provide a result in less
than 1 hour. The transfusion service may use such devices to control
the risks of bacterial contamination before releasing a pooled platelet
unit for transfusion. We also note that pre-storage pooling has become
the prevailing practice for platelet units derived from Whole Blood.
Based on data presented at the July 2012 AABB Workshop (Ref. 20),
currently about 65 percent of Whole Blood-derived platelets are
cultured by collection establishments as pre-stored pools. About 35
percent of those platelet components are tested as pools constituted
within 4 hours prior to transfusion using an FDA-cleared rapid test
(Ref. 20).
(Comment 23) Some comments stated that the standards requiring
testing for platelet contamination, such as those of AABB, do not
currently apply to Whole Blood-derived platelets. Transfusion services
may not subject the platelet components they pool to bacterial testing,
and instead use, at the time of release for transfusion, surrogate
methods such as pH meters, to assess whether bacterial contamination is
likely.
(Response) Testing using surrogate methods such as pH meters is
inadequate to determine whether platelets are bacterially contaminated.
Studies have shown that pH does not constitute an adequate surrogate
marker for bacterial contamination in platelets, and has poor
sensitivity and poor positive predictive value (Ref. 13). Other FDA
cleared devices, including rapid tests, are available for use by a
transfusion service to identify the presence of bacterial
contamination. The use of such devices can help assure the safety of
the platelet component, and protect the recipient from bacterial
infections. Accordingly, final Sec. 606.145(a) requires blood
collection establishments and transfusion services to assure that the
risks of bacterial contamination of platelets are adequately controlled
using FDA approved or cleared devices or other adequate and appropriate
methods found acceptable for this purpose by FDA.
(Comment 24) Some comments stated that it is not appropriate to
extend requirements addressing bacterial contamination of platelets to
the manufacture of other transfusable blood components. They note that
the rate of reported septic reactions to Red Blood Cells and plasma
products is very low, and methods to identify bacterial contamination
in these products are not well developed. Furthermore, there appears to
be little rationale for requiring bacterial testing of blood products
that, unlike platelets, are stored at cold temperatures that do not
promote bacterial growth.
(Response) We agree that transfusable blood components other than
platelets are stored at cold temperatures that do not promote bacterial
growth, and that the rate of septic reactions to these products is very
low. The final rule includes requirements specific to bacterial
contamination of platelet components, and also provides that, in the
event that a blood collection establishment or transfusion service
identifies platelets as bacterially contaminated, that establishment
must not release the product or any other component prepared from the
same collection. In the event of technological changes, or significant
evidence that transfusion recipients are at greater risk from bacterial
contamination of Red Blood Cell and Plasma products than is presently
considered to exist, we will consider again whether additional
requirements specific to blood components other than platelets are
necessary.
E. Records (Sec. 606.160)
The final rule makes the conforming changes described in proposed
Sec. 606.160(b)(1)(ix) and (xi), now identified as Sec.
606.160(b)(1)(x) and (xi). These changes relate to the move of the
donor notification provisions from Sec. 630.6 to Sec. 630.40. Current
Sec. 606.160(b)(1)(x) is redesignated as Sec. 606.160(b)(1)(ix). We
also inserted the word ``postal'' before the word ``address'' in the
current requirement, so that the recordkeeping requirement would
closely track the requirement in final Sec. 630.10(g)(1) to obtain a
``postal address.''
In response to comments, we have significantly narrowed the
requirements we proposed in Sec. 606.160(e). We have not finalized a
requirement to share a record of all ineligible donors with appropriate
personnel at all locations operating under the same license or under
common management. Instead, final Sec. 606.160(e)(1) requires
establishments to maintain at each location a record of all donors
found to be ineligible or deferred at that location, so that blood and
blood components from such individuals are not collected or distributed
while they are ineligible or deferred. This provision is related to
current Sec. 606.160(e), which requires that ``A record shall be
available from which unsuitable donors may be identified so that
products from such individuals will not be distributed.'' Final Sec.
606.160(e)(2) through (4) requires establishments to maintain a
cumulative record of donors deferred from donation under Sec. 610.41
based on their reactive tests for evidence of infection due to HIV,
HBV, or HCV. In addition, establishments other than Source Plasma
establishments must include in this cumulative record donors deferred
from donation for evidence of infection due to HTLV or Chagas disease.
Establishments must maintain the cumulative record of deferred donors
at all locations operating under the same license or under common
management, must update the cumulative record at least monthly, and
revise the cumulative record for donors who are requalified under Sec.
610.41(b). Final Sec. 630.10(d) sets out requirements for
establishments to consult the cumulative record of deferred donors
before collection, or if pre-collection review is not feasible, before
release of any blood or blood component prepared from the collection.
(Comment 25) We received several comments objecting to the scope of
donor deferrals that would be included in the list of ineligible donors
described in the proposed rule.
[[Page 29854]]
(Response) We agree that the types of donor deferrals that were
proposed to trigger inclusion in the list of ineligible donors were
broad, and that requiring extensive deferral records to be updated and
consulted at the donation site before collection could be unduly
burdensome. The final rule requires establishments to enter into the
cumulative list only those donors who were deferred under Sec. 610.41
due to reactive test results for HIV, HBV, or HCV, as well as HTLV or
Chagas disease for donors other than Source Plasma donors.
(Comment 26) We received several comments objecting to a
requirement for a common donor deferral registry to be used by all
donor screening locations operating under a single operating license or
common management. Some expressed concern that it would be
technologically difficult to make this information available to all
locations under a single operating license or under common management.
(Response) Under the final rule establishments must enter into the
cumulative list only those donors who were deferred under Sec. 610.41
due to reactive screening test results for HIV, HBV, or HCV, as well as
HTLV or Chagas disease for donors other than Source Plasma donors. We
believe that it is a current industry practice to maintain such lists
(Refs. 21, 22). In the final rule, we have significantly narrowed the
scope of information subject to this requirement in a manner that is
consistent with this industry practice, and to reduce the technological
challenges of making reliable information available.
We disagree with the suggestion that it is technologically
difficult for facilities operating under a single license, or under
common management, to make this more limited cumulative record of
deferred donors available at collection sites for consultation by all
facilities operating under a single operating license or under common
management. The cumulative record is now required to list only a subset
of deferred donors, who are identified by very specific and objective
criteria. This information may be made available by providing a copy of
the cumulative record of deferred donors at each collection site.
Establishments may also comply with this requirement by providing for a
pre-collection query of a centrally maintained cumulative record of
deferred donors. In the event that pre-collection review is not
feasible, Sec. 630.10(d)(1) requires establishments to consult the
cumulative record prior to release of any blood or blood component
prepared from the collection.
(Comment 27) In the preamble to the proposed rule we also solicited
comments on the feasibility of sharing donor deferral lists among
licensed and registered establishments. Such shared lists are known as
national donor deferral registries, and are already in use among
establishments collecting Source Plasma. We received several comments
opposing a requirement for a national donor deferral registry. Some
described national donor deferral registries as unnecessary or
burdensome. One comment emphasized differences between Source Plasma
and collections of Whole Blood and other blood components, and stated
that the Source Plasma donor deferral registry would be a poor model
for other collection establishments. The comment cited technical
limitations such as computer down times and connectivity from remote
locations, and stated that the creation of a national donor deferral
system for whole blood donors would be burdensome and time-consuming.
(Response) As noted, it is currently the practice of most Source
Plasma collection establishments to determine whether a donor is
permanently deferred because the donor tested reactive for HIV, HBV, or
HCV by accessing a shared list of deferred donors called the National
Donor Deferral Registry (NDDR). We recognize that the NDDR is a
voluntary, self-regulating initiative by the Source Plasma collection
industry that is operated by a third party administrator. We agree it
is an important industry practice to ensure the safety of plasma-
derived therapies. Moreover, we are aware that, to increase efficiency
and to protect donor confidentiality and proprietary information across
non-affiliated Source Plasma establishments, information entered into
the NDDR is coded as to infectious disease test result. This rule is
not intended to interfere with that practice. We believe that the
current NDDR goes beyond the requirements in the final rule, since it
is a national list of donors deferred by multiple licensed
establishments (Ref. 23). For Source Plasma establishments, we believe
that participation in the NDDR would meet the requirements under this
section. If a Source Plasma establishment does not participate in the
NDDR, the establishment must establish its own cumulative record of
deferred donors with all other establishments operating under common
management or a single license, as required under this section.
We are not requiring blood collection establishments to share donor
deferral information in a national donor deferral registry.
(Comment 28) In the preamble of the proposed rule (72 FR 63416 at
63420), we stated that we were considering whether to include, in the
final rule, a provision requiring that the donor deferral records be
used and disclosed only for purposes consistent with subchapter F of 21
CFR Chapter I. One comment expressed concern about the importance of
protecting donor information. Another comment explained why additional
protections are not needed. For example, the NDDR used by Source Plasma
collectors is never available in its entirety to its users. When an
NDDR check is performed, the database is queried to determine whether a
record for the potential donor is present. If a record is present, the
establishment performing the check is informed that a record exists. No
other information is shared. One comment stated confidentiality of
information is of extraordinary importance to the industry. The comment
stated that each company uses its own best methods for handling
confidential information consistent with its operational policies and
procedures in submitting relevant information to the NDDR. One comment
stated that in their current system, unique donor identifiers such as
social security numbers are not available.
(Response) As we discussed earlier in this section, we are not
requiring establishments to participate in a national donor deferral
registry system, and we are not requiring the sharing of information
outside a single license or outside common management.
F. Test Requirements (Sec. Sec. 610.40, 640.5, 640.71(a))
We have modified proposed Sec. 610.40(a), (b), and (e) in order to
address concerns that the proposed rule did not permit an adequately
flexible approach to donor testing. Although the testing for HIV, HBV,
HCV, and HTLV that is required under current Sec. 610.40(a) would
continue under the new rule, we have also provided additional
flexibility for FDA to permit testing less frequently than at every
donation, or as appropriate, to stop testing, for relevant transfusion-
transmitted infections other than HIV, HBV, and HCV, provided that the
practices are supported by evidence related to the risk of transmission
of such infection, such as epidemiological data and developments in
risk reduction technology. In Sec. 610.40(a), we have clarified
requirements for Chagas disease and West Nile virus testing and have
continued the existing requirement
[[Page 29855]]
to test donations for evidence of syphilis. We have also provided
requirements for testing for infectious agents that may be identified
in the future as relevant transfusion-transmitted infections, in the
event that testing becomes necessary to ensure blood safety.
Final Sec. 610.40(b) clarifies that the tests performed to comply
with Sec. 610.40(a) must be ``licensed, approved, or cleared screening
tests''; current Sec. 610.40(b) refers only to ``approved screening
tests''. We made this change because Sec. 610.40(b) is now applicable
to syphilis testing, and syphilis screening tests are generally
``cleared,'' and not licensed or approved.
The final rule contains a different heading for Sec. 610.40(c).
Instead of ``Exceptions to testing for allogeneic transfusion or
further manufacturing use,'' which is used in current Sec. 610.40(c),
the heading is now ``Exceptions to testing for dedicated donations,
medical devices, and samples.'' We made this change because the
exception from testing for HTLV is now addressed in Sec.
610.40(a)(2)(ii) and (iii), and we are removing the exception for HTLV
now found in current Sec. 610.40(c)(2). Since Sec. 610.40(c) no
longer addresses Source Plasma (the most commonly identifiable blood
component collected for further manufacturing use) the new heading is
more accurate.
In Sec. 610.40(e), we are maintaining the existing requirement for
further testing when a donation tests reactive for a relevant
transfusion-transmitted infection. When a licensed, approved, or
cleared supplemental test is not available, the rule provides greater
flexibility to allow the use of licensed, approved, or cleared tests,
as adequate and appropriate to determine the reactive donor's infection
status. We address further testing for donations reactive for syphilis
in Sec. 610.40(e)(2).
Under the proposed rule, existing testing practices for HIV, HBV,
HCV, and HTLV would continue. In addition, we proposed that, when a
test for the disease or disease agent is approved or cleared for donor
screening and FDA determines that testing is necessary to reduce the
risk of transmission of the relevant transfusion-transmitted infection
by the blood or blood component, blood collection establishments would
be required to test for CJD, vCJD, and malaria, which were identified
as relevant transfusion-transmitted infections in proposed Sec.
630.3(g)(1)(vi) through (viii). We further proposed that, when the
conditions concerning the availability and necessity of testing were
met, establishments would be required to test for other relevant
transfusion-transmitted infections meeting the standard in proposed
Sec. 630.3(g)(2).
We also solicited comments with supporting data on whether to
discontinue the requirement for testing for syphilis, and we indicated
that we might drop the requirement for syphilis testing if sufficient
data were submitted (72 FR 63416 at 63422). We stated that testing for
a relevant transfusion-transmitted infection may not be required if
viral inactivation or removal procedures have been validated to ensure
inactivation or removal of the infectious agent and screening for risk
factors is available, unless the risk of harm from transmission is too
great to rely solely on viral inactivation procedures and screening for
risk factors. We are finalizing this provision using the concepts
proposed, but have provided greater flexibility to permit
establishments to stop testing, or vary testing frequency, when the
evidence shows testing each donation intended for transfusion is no
longer necessary to reduce the risk of transmission of the relevant
transfusion-transmitted infection by the blood or blood component. Such
changes must be made in accordance with procedures found acceptable for
this purpose by FDA. We have retained requirements for syphilis testing
of blood and blood components for transfusion, since we did not receive
data sufficient to support their elimination. However, if such evidence
is developed in the future, the rule would allow establishments to
change their testing practices in accordance with procedures found
acceptable for this purpose by FDA. We have removed existing Sec.
610.40(i), which required testing for syphilis, and address testing
transfusable blood and blood components for syphilis in Sec.
610.40(a). To reflect this new citation for the syphilis testing
requirement, we made conforming changes to Sec. Sec. 610.40(d), (g),
(h)(1), (h)(2)(vi), and (h)(2)(vii), 610.41 and 610.42.
Current Sec. 640.5 provides additional standards for testing Whole
Blood. We did not propose changes to Sec. 640.5 in the proposed rule.
However, based on comments received and discussed at comment 29, we
recognize that greater flexibility in testing schedules may be
appropriate, and that it may be adequate and appropriate to test donors
for certain relevant transfusion-transmitted infections less frequently
than at every donation, or while observing geographic or seasonal
limitations. Accordingly, we are making a related change to the
introductory paragraph of Sec. 640.5, which currently provides ``All
laboratory tests shall be made on a specimen of blood taken from the
donor at the time of collecting the unit of blood, and these tests
shall include the following.'' Because it may be appropriate to perform
testing other than on each collection, we are modifying this to state
``All laboratory tests shall be made on a specimen of blood taken from
the donor, and these tests shall include the following.''
We are also making one other minor conforming change, removing
current Sec. 640.5(a) which requires ``Whole Blood shall be negative
to a serological test for syphilis.'' This provision is duplicative of
the requirement to test for syphilis in new Sec. 610.40(a)(2), and to
avoid confusion we are deleting Sec. 640.5(a).
For similar reasons, we are amending the provisions of current
Sec. 640.71(a) which specify certain donor screening tests related to
Source Plasma. We are removing the phrase ``the following tests'' and
adding in its place ``testing performed in accordance with Sec. 610.40
of this chapter and Sec. 640.65(b)'' and we are removing the list of
tests set out in current Sec. 640.71(a)(1) through(4). We are making
these changes so that Sec. 640.71(a) will conform to final Sec.
610.40.
1. Section 610.40(a)
Final Sec. 610.40(a) addresses testing for the infectious agents
already required under current Sec. 610.40(a), and now identified in
Sec. 630.3(h)(1) as relevant transfusion-transmitted infections. We
continue to require testing of each donation for evidence of infection
due to HIV; HBV; and HCV. We also continue to require testing of each
donation, except Source Plasma, for evidence of infection due to HTLV
and syphilis. We are adding a requirement to test donations, except
Source Plasma, for West Nile virus and Chagas disease.
As in the existing regulations, testing requirements for certain
relevant transfusion-transmitted infections vary for Source Plasma. For
example, we have concluded that, in the absence of testing, the risk of
HTLV, a highly cell-associated pathogen, is sufficiently mitigated by
plasma derivative manufacturing steps, including validated viral
inactivation and removal procedures. These manufacturing procedures
therefore obviate the need to test individual donations of Source
Plasma for HTLV. We have further determined that these manufacturing
procedures obviate the need to test individual donations of Source
Plasma for West Nile virus and Chagas disease. Testing of Source Plasma
donors for syphilis must be performed every 4 months in accordance with
Sec. 640.65(b).
[[Page 29856]]
The final rule allows for the possibility that, in the future,
evidence related to the risk of transmission of HTLV, syphilis, West
Nile virus, and Chagas disease could support the conclusion that
testing of each donation is no longer necessary to reduce adequately
and appropriately the risk of transmission of that relevant
transfusion-transmitted infection by the blood or blood component.
Under final Sec. 610.40(a)(2)(iii)(A), if testing each donation is not
necessary to reduce adequately and appropriately the risk of
transmission of a relevant transfusion-transmitted infection, an
establishment may adopt an adequate and appropriate alternative testing
procedure that has been found acceptable for this purpose by FDA.
Section 610.40(a)(4) makes clear that an assessment that testing each
donation is not necessary could be based on, for example, changing
science, or epidemiological or other scientific data. It may also
include evidence related to seasonal or regional variations in the
activity of the relevant transfusion-transmitted infection. Under final
Sec. 610.40(a)(2)(iii)(A), following an assessment that testing each
donation is not necessary, establishments may adopt alternative
procedures that have been found acceptable for this purpose by FDA such
as initial or periodic testing of donations from the same donor due to
the epidemiology of the relevant transfusion-transmitted infection.
An example of such an alternative testing paradigm is FDA's current
recommendation contained in guidance for one-time testing of a donor
for Chagas disease, instead of testing the donor at each donation (Ref.
24). FDA made this recommendation after reviewing comments to the draft
guidance and consulting with the Blood Products Advisory Committee
(April 2009) (Ref. 25). Consistent with Sec. 610.40(a)(2)(iii)(A), we
continue to recognize this testing practice as an acceptable
alternative testing paradigm for Chagas disease. In the future, new
epidemiologic or other scientific data could demonstrate that a
different testing paradigm, including testing of the donor at each
donation, is needed to adequately and appropriately reduce the risk of
transmission of Chagas disease.
This rule also provides that establishments may stop testing blood
and blood components for HTLV, syphilis, West Nile virus, or Chagas
disease in the event that such testing is no longer necessary. Section
610.40(a)(2)(iii)(B) authorizes such an action taken in accordance with
procedures found acceptable for this purpose by FDA, when testing is no
longer necessary to reduce adequately and appropriately the risk of
transmission of such infection by blood or a blood component, based on
evidence related to the risk of transmission of that relevant
transfusion-transmitted infection. Section 610.40(a)(4) describes the
evidence that would support such a finding, such as a change in the
epidemiology of the relevant transfusion-transmitted infection, or the
implementation of pathogen reduction technology. We note that the rule
does not require establishments to test donors of Source Plasma for
these relevant transfusion-transmitted infections because of reduced
risk of transmission by fractionated products manufactured from Source
Plasma.
We recognize that there are no donor screening tests currently
licensed, approved, or cleared for the following relevant transfusion-
transmitted infections identified in Sec. 610.40(a)(3): CJD, vCJD, or
malaria. In the event that a donor screening test is licensed, approved
or cleared for one of these infections, the rule would require the use
of the test, if testing is necessary to reduce adequately and
appropriately the risk of transmission of that relevant transfusion-
transmitted infection.
Similarly, FDA has not yet identified any relevant transfusion-
transmitted infections under the criteria in Sec. 630.3(h)(2). In the
future, if a transfusion-transmitted infection is identified by FDA to
meet the criteria for a relevant transfusion-transmitted infection
under Sec. 630.3(h)(2), and FDA has licensed, approved or cleared a
donor screening test, FDA may seek advice from the Blood Products
Advisory Committee on the use of the donor screening test, and seek
public comment by issuing guidance in accordance with good guidance
practices. When a transfusion-transmitted infection has met both the
standards under final Sec. 630.3(h)(2) and Sec. 610.40(a)(3), such
that it now meets the criteria for a relevant transfusion-transmitted
infection and testing is necessary to reduce adequately and
appropriately the risk of transmission of that relevant transfusion-
transmitted infection, use of the test would be required. When testing
for a particular relevant transfusion-transmitted infection become
necessary under final Sec. 610.40(a)(2) or (a)(3), FDA intends to
enforce the testing requirements under this regulation only after
issuing a final guidance advising establishments and the public of the
Agency's assessment of the applicable criteria.
Should testing become necessary to reduce adequately and
appropriately the risk of transmission of a relevant transfusion-
transmitted infection under Sec. 610.40(a)(3), FDA will also consider
the application of Sec. 610.40(a)(3)(ii)(A), which we drafted to
parallel Sec. 610.40(a)(2)(iii)(A). Under this provision, if testing
each donation is no longer necessary to reduce adequately and
appropriately the risk of transmission of a relevant transfusion-
transmitted infection, an establishment may adopt an adequate and
appropriate alternative testing procedure that has been found
acceptable for this purpose by FDA. Under Sec. 610.40(a)(4), such
methods may address seasonal or regional variations in the activity of
the relevant transfusion-transmitted infection, or where, due to the
epidemiology of the relevant transfusion-transmitted infection, initial
or periodic testing of donations from the same donor (instead of
testing each donation) would be sufficient. In the event that the
standard set forth in Sec. 610.40(a)(3)(ii)(A) and (a)(4) is met, FDA
intends to reassess the applicability of alternative testing
procedures, and if needed, seek advice from the Blood Products Advisory
Committee and issue new guidance in accordance with good guidance
practices. Similarly, Sec. 610.40(a)(3)(ii)(B), which we drafted to
parallel Sec. 610.40(a)(2)(iii)(B), recognizes that, at some later
point in time, if evidence related to the risk of transmission of such
infection supports a determination that testing is no longer necessary
to adequately and appropriately reduce the risk of transmission of that
relevant transfusion-transmitted infection. When testing is not
necessary, establishments may stop such testing in accordance with
procedures found acceptable for this purpose by FDA. Sections
610.40(a)(3)(ii)(A) and (a)(3)(ii)(B) provide mechanisms for tailoring
testing requirements to more accurately address the risks presented by
a relevant transfusion-transmitted infection, while assuring that blood
establishments perform adequate and appropriate testing of blood
donations.
We recognize that greater flexibility in testing schedules may be
appropriate, and have incorporated these changes into this final rule.
Accordingly, we are making a related change to the introductory
paragraph of Sec. 640.5, which currently provides ``All laboratory
tests shall be made on a specimen of blood taken from the donor at the
time of collecting the unit of blood, and these tests shall include the
following.'' Because it may be appropriate to perform testing other
than on each collection, we are
[[Page 29857]]
modifying this to state ``All laboratory tests shall be made on a
specimen of blood taken from the donor, and these tests shall include
the following.''
(Comment 29) One comment supported a requirement to test for
relevant transfusion-transmitted infections that meet the definition
under proposed Sec. 630.3(g)(2), when such testing is available and is
necessary to reduce the risk of transmission of the relevant
transfusion-transmitted infection by the blood or blood component,
because of the need to identify and respond to current and future
agents.
(Response) We agree with this comment. We have drafted final Sec.
610.40(a)(3) to provide a framework for applying the rule's testing
provisions to infectious agents that may, in the future, meet the
standard for relevant transfusion-transmitted infection, as defined in
final Sec. 630.3(h)(2). For example, under Sec. 630.3(h)(2), a
transfusion-transmitted infection such as babesia or dengue virus may
meet the definition of a relevant transfusion-transmitted infection if
the disease or disease agent meets criteria for incidence and/or
prevalence or may have been accidentally or intentionally released, and
if appropriate screening measures have been developed and/or an
appropriate screening test has been licensed, approved, or cleared for
such use and is available. In the event that such a test has been
licensed, cleared, or approved, its use would be required under this
section when necessary to reduce the risk of transmission of the
relevant transfusion-transmitted infection. Whether testing is
necessary would depend on all the relevant circumstances, including,
for example, whether screening for travel history or another risk
factor would, by itself, adequately reduce the risk of transmission.
FDA intends to seek advice on relevant scientific issues from the Blood
Products Advisory Committee as appropriate.
(Comment 30) One comment suggested that testing be required for
West Nile virus, Chagas disease, and bacteria because testing for those
agents is currently conducted.
(Response) We agree that establishments should be required to
conduct testing for West Nile virus and Chagas disease for blood and
blood components for transfusion. Under the proposed rule, these
infectious agents would have been evaluated under the standards for
relevant transfusion-transmitted infection in proposed Sec.
630.3(g)(2). To provide greater clarity on this regulation, we have
specified these diseases by name in the definition of relevant
transfusion-transmitted infection at Sec. 630.3(h)(1)(vi) and (vii),
and testing for these agents is addressed in Sec. 610.40(a)(2). We
recognize that bacterial contamination of platelets presents
significant issues related to the safety, purity, and potency of
platelets. We have addressed the risk presented by bacterial
contamination of platelets in Sec. Sec. 606.145 (see comments 13
through 24), 630.30 (see comments 103 through 106), and 630.40 (see
comment 107). We address bacterial contamination of blood components
other than platelets in response to comment 24.
(Comment 31) Several comments stated that FDA should not require
that blood donors be tested for syphilis. One comment recommended that
testing for syphilis continue to be required, but for public health
reasons, rather than for its value in protecting blood safety.
(Response) We are continuing to require testing for syphilis at
this time. We note that in the proposed rule, FDA requested information
on the value of testing for syphilis as a marker of increased risk
behavior, as a surrogate test for other infectious diseases, and in
preventing the transmission of syphilis through blood transfusion. We
stated that if we received adequate data, FDA would eliminate or modify
this testing requirement in the final rule. This was the second time we
invited the submission of such data; we also invited it in an earlier
proposed rule, ``Requirements for Testing Human Blood Donors for
Evidence of Infection Due to Communicable Disease Agents'' (64 FR
45340, August 19, 1999). Syphilis testing was discussed at the
September 2000 Blood Products Advisory Committee meeting and studies
that might help determine that such testing would no longer be needed
were identified (Ref. 26). We have not received adequate scientific
data in response to our solicitations.
However, the final rule recognizes the possibility of discontinuing
the requirement for syphilis testing of blood and blood components
intended for transfusion. We have moved this requirement from Sec.
610.40(i) to Sec. 610.40(a). The more flexible framework found in
Sec. 610.40(a)(2)(iii) provides a mechanism under which an
establishment could stop testing for syphilis or adopt different
testing frequency, provided that evidence related to the risk of
transmission demonstrates that testing of each donation is no longer
necessary to reduce adequately and appropriately the risk of
transmission of syphilis, and provided that the change is made in
accordance with procedures found acceptable for this purpose by FDA. In
the event that the evidence supports such a determination under Sec.
610.40(a)(2)(iii)(B), FDA intends to issue guidance recognizing
procedures for ending syphilis testing of blood and blood components
for transfusion.
(Comment 32) Another comment asserted that current syphilis testing
practices are deficient, since many confirmed positives are in fact
false positives.
(Response) We recognize that syphilis screening tests, like other
screening tests, may yield false positive results on some donations.
However, Sec. 610.40(h)(2)(vi) permits the use of blood and blood
components that test reactive for syphilis if the donation is further
tested by an adequate and appropriate test which demonstrates that the
reactive screening test is a biologic false-positive. In addition,
consistent with the current regulation, the final rule permits the
reentry of positive donors who have been successfully requalified under
Sec. 610.41(b).
(Comment 33) Several comments stated that testing for CJD and vCJD
should not be required.
(Response) There are no currently licensed, approved, or cleared
donor screening tests for these agents. If and when donor screening
tests for CJD or vCJD become available, testing would be required under
this provision only if testing was necessary to adequately and
appropriately reduce the risk of transmission of CJD or vCJD, taking
into account the risks presented by donated blood and blood components.
(Comment 34) One comment stated that the use of the defined term
relevant transfusion-transmitted infection in the proposed rule (Sec.
630.3(g)) in Sec. 610.40(a) would require testing for agents such as
cytomegalovirus (CMV), even though screening of all donors for CMV is
not currently thought to be necessary.
(Response) We agree that, currently, it is not necessary to test
all donors for CMV. For this reason, donor screening testing for CMV is
not now required under Sec. 610.40 of the final rule, which in Sec.
610.40(b) requires testing only ``as necessary to reduce adequately and
appropriately the risk of transmission'' (emphasis added).
2. Section 610.40(e)
In this section, FDA is maintaining the requirement for further
testing when a donation tests reactive for a relevant transfusion-
transmitted infection. Consistent with the existing regulation and the
proposed rule, establishments must perform further testing using an
approved supplemental test when one is available. However, the final
rule now
[[Page 29858]]
recognizes that supplemental tests may be licensed, approved, or
cleared. We eliminated the term ``additional'' as unnecessary. When a
supplemental test is not available, the final rule requires the use of
other tests as adequate and appropriate to provide additional
information concerning the reactive donor's infection status. This
language provides greater clarity concerning the purpose of further
testing. Under this paradigm, if an approved supplemental test was not
available, or became unavailable, an establishment would conduct
further testing using, for example, an alternative algorithm to provide
additional information to the establishment concerning the donor's
infection status. For example, a testing algorithm that was adequate
and appropriate to determine the reactive donor's infection status
might include the use of multiple approved donor screening tests. We
intend to issue guidance on these issues as needed.
Section 610.40(e)(2) requires establishments to perform further
testing when a donation is reactive by a non-treponemal donor screening
test for syphilis. Previously, we did not require establishments to
perform any supplemental testing after a reactive test for syphilis.
However, further testing may help to rule out syphilis infection.
Additionally, a reactive test result on a non-treponemal syphilis test
may be a biologic false-positive result, which may potentially be
indicative of a serious illness in the donor, such as lupus
erythematosus (Ref. 27). In this setting, further testing will provide
important information for donor notification, including information
that is appropriate for medical follow up and counseling under Sec.
630.40(b)(4). Blood establishments must perform further testing using a
licensed, cleared, or approved supplemental test for syphilis, when
available. When no such supplemental test is available, FDA would
consider the use of a licensed, approved, or cleared treponemal test to
be adequate and appropriate to provide additional information
concerning the donor's infection status. Establishments are not
required to perform further testing of a donation found to be reactive
by a treponemal donor screening test for syphilis, since those tests do
not present similar risks of a biological false positive result.
(Comment 35) FDA received several comments raising concern about
the lack of availability of supplemental tests for certain infectious
agents for which FDA currently requires donor screening.
(Response) FDA recognizes the importance of confirming the
infection status of a deferred donor. This information is important to
donor notification, and in some instances determines whether a donor
should be entered into the cumulative record of deferred donors under
Sec. 606.160(e). Accordingly, we have revised this section to require,
when a supplemental test is not available, the use of one or more
licensed, approved, or cleared tests as adequate and appropriate to
provide additional information concerning the reactive donor's
infection status.
G. Donor Deferral (Sec. 610.41)
We have made conforming changes in final Sec. 610.41(a) to
incorporate the ``relevant transfusion-transmitted infection''
terminology, the inclusion of syphilis testing in Sec. 610.40(a)
instead of Sec. 610.40(i), and updated the term from ``supplemental''
testing to ``further'' testing, to reflect the change in Sec.
610.40(e). At the same time we clarified the meaning of the second
sentence of Sec. 610.41(a)(1), which now states, ``However, you must
defer the donor if further testing for HBV or HTLV has been performed
under Sec. 610.40(e) and the donor is found to be positive, or if a
second, licensed, cleared, or approved, screening test for HBV or HTLV
has been performed on the same donation under Sec. 610.40(a) and is
reactive, or if the donor tests reactive for anti-HBc or anti-HTLV,
types I and II on more than one occasion.'' Previously this provision
stated, ``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.'' Consistent
with current guidance, establishments now defer a donor who tests
reactive for anti-HBc or anti-HTLV, types I and II, on more than one
occasion, or when further testing on the same donation is positive, or
when a second licensed, cleared, or approved screening test for HBV or
HTLV has been performed on the same donation and is reactive (Refs. 28,
29).
H. Purpose and Scope (Sec. 630.1)
Final Sec. 630.1 describes the purpose and scope of the combined
subparts of part 630 that require blood establishments to perform the
following activities: determine that on the day of donation the donor
is in good health and is eligible to donate blood or blood components;
determine the suitability of the donation for use in transfusion or
further manufacturing; and notify a donor who is deferred from donating
because the donor did not satisfy the eligibility criteria described in
part 630 or because the donor's test results revealed a relevant
transfusion-transmitted infection as described under Sec. 610.40. This
section is consistent with the proposed rule, with one change. Since we
are not defining the term ``you'' in Sec. 630.3, we have finalized
Sec. 630.1(b) to describe the scope as ``Blood establishments that
manufacture blood and blood components, as defined in Sec. 630.3(a)
and (b) of this chapter, must comply with subparts A, B, and C of this
part.'' Accordingly, the requirements in part 630 apply to any
establishment or facility that collects, or performs other
manufacturing steps for, blood or blood components for transfusion,
including components for autologous use, for further manufacturing use,
or for use as a component of a medical device.
I. Medical Supervision (Sec. Sec. 630.5, 640.130)
Final Sec. 630.5(a) requires a responsible physician, as defined
in Sec. 630.3(i), to determine the eligibility of a donor of blood or
blood components, including Source Plasma, in accordance with the
regulations in 21 CFR Chapter I, subchapter F. This section describes
the activities related to the collection of blood and blood components
that the responsible physician may delegate to a physician substitute
or other trained person, taking into account the training and medical
expertise needed to assess whether the donor's health permits the
collection, and to mitigate the risks related to donation. Recognizing
that conditions may change, final Sec. 630.5(a)(1)(i)(C) provides that
the Director, CBER, may authorize the delegation of additional
activities, after determining that delegating the activity would
present no undue medical risk to the donor or to the transfusion
recipient. The requirements in this section are not intended to preempt
State or local laws when those laws require a higher level of medical
oversight for certain blood collection activities This section combines
the existing requirements related to eligibility for donors of Whole
Blood (Sec. 640.3) and Source Plasma (Sec. 640.63) into a single
section.
For the collection of blood and blood components other than Source
Plasma and plasma collected by plasmapheresis, Sec. 630.5(b)
authorizes the responsible physician to delegate the following
activities to a physician substitute or other trained person:
Determining the eligibility of a donor and documenting assessments
related to that determination; collecting blood and blood components;
returning red blood cells to a donor during apheresis procedures; and
obtaining the informed consent of a plateletpheresis donor as described
in Sec. 640.21(g). Under
[[Page 29859]]
Sec. 630.5(b)(2), the responsible physician is not required to be
present at the collection site when any of these activities are
performed, provided that the responsible physician has delegated
oversight of these activities to a trained person who is not only
adequately trained and experienced in the performance of these
activities but also adequately trained and experienced in the
recognition of and response to the known adverse responses associated
with blood collection procedures.
However, under Sec. 630.5(b)(1)(i)(A), the responsible physician
must not delegate the examination and determination that the health of
a donor would not be adversely affected by donating, when the donor's
systolic blood pressure falls outside the range of 90 to 180
millimeters (mm) of mercury, or when the diastolic blood pressure falls
outside the range of 50 to 100 mm of mercury. Additionally, the
responsible physician must not delegate the examination and
determination that the health of a donor would not be adversely
affected by donating Whole Blood or Red Blood Cells more frequently
than specified under Sec. 630.15(a)(1).
Under Sec. 630.5(b)(1)(i)(B), the responsible physician must not
delegate the following determinations: That the health of a donor whose
pulse measurement falls outside the range of 50 to 100 beats per
minute, or is irregular, would not be adversely affected by donating;
that the health of an ineligible autologous donor permits the
collection procedure; and that a dedicated plateletpheresis donor is in
good health. The responsible physician may make the determinations
addressed in Sec. 630.5(b)(1)(i)(B) by telephonic or other offsite
consultation.
Under Sec. 630.5(b)(1)(i)(C), the responsible physician must not
delegate the determination of the health of the donor or the
determination that the blood or blood component collected would present
no undue medical risk to the transfusion recipient, as required for
dedicated donations by an ineligible donor for a specific transfusion
recipient based on documented exceptional medical need. The responsible
physician may make this determination by telephonic or other offsite
consultation. In recognition that conditions may evolve in the future,
we have added Sec. 630.5(b)(1)(v) to permit the responsible physician
to delegate other activities when authorized by the Director, CBER,
based on a determination that delegating the activities would present
no undue medical risk to the donor or to the transfusion recipient. We
anticipate that the Director, CBER, would authorize such delegations
under 21 CFR 640.120, or in response to submissions from individual
establishments, as appropriate. In addition, such authorizations may be
discussed in guidance issued under good guidance practices.
For the collection of Source Plasma and plasma collected by
plasmapheresis, Sec. 630.5(c)(1)(i) authorizes the responsible
physician to delegate to a physician substitute or other trained person
the following activities related to donor eligibility and blood
component collection, provided that the responsible physician or a
physician substitute is on the premises at the collection site: (1)
Determining and documenting donor eligibility, (2) collecting blood and
blood components, (3) returning red blood cells to the donor during
apheresis, (4) other activities authorized by the CBER Director, (5)
the collection of Source Plasma in an approved collection program from
a donor who is otherwise determined to be ineligible, and (6) the
collection of a blood sample for testing required under Sec.
640.65(b)(1)(i). Similar to collections of blood and blood components
subject to delegations under Sec. 630.5(b), Sec. 630.5(c)(1)(i)(A)(1)
through (c)(1)(i)(A)(3) provide that the responsible physician must not
delegate specific responsibilities related to the assessment of donor
blood pressure, donation frequency after red blood cell loss, donor
pulse, and certain plasmapheresis collections from an ineligible donor.
Section 630.5(c)(1)(i)(A)(4) and (c)(1)(i)(A)(5) provide that the
responsible physician must not delegate the responsible physician's
determination related to a donor's false-positive reaction to a
serologic test for syphilis, or the responsible physician's
determination to permit plasmapheresis of a donor with syphilis. In
addition, Sec. 630.5(c)(1)(ii) authorizes the responsible physician,
who may or may not be present when these activities are performed, to
delegate to a trained physician substitute the approval and signature
for a plasmapheresis procedure and review and signature for accumulated
laboratory data, the calculated values of each component, and the
collection records. However, the responsible physician must not
delegate the decision to reinstate a donor in accordance with Sec.
640.65(b)(2)(i). These provisions in Sec. 630.5(c)(1)(ii) were not
expressly included in proposed Sec. 630.5. We have included them here
in order to state more clearly how the new delegation provisions in
Sec. 630.5 affect the existing responsibilities of the responsible
physician.
With respect to donor immunization, consistent with the proposed
rule, Sec. 630.5(c)(2)(i) authorizes the responsible physician to
delegate to a physician substitute or other trained person the
administration of an immunizing agent other than red cells to a donor
in an approved immunization program, provided that the responsible
physician or physician substitute is on the premises. Section
630.5(c)(2)(ii) authorizes the responsible physician to delegate to a
physician substitute the function of donor immunization with red blood
cells, provided that the responsible physician has approved the
procedure and is on the premises when the procedure is performed.
Section 630.5(c)(3) authorizes the responsible physician to delegate to
a physician substitute the administration of the medical history,
physical examination (including examination before immunization), and
informed consent required in Sec. 630.15(b)(1), (b)(2), and (b)(5).
The responsible physician is not required to be present at the
collection site when the physician substitute performs these
activities.
Section 630.5(c)(4) addresses delegations for collections from
infrequent plasma donors, as defined in Sec. 630.3(e). This section
authorizes the responsible physician to delegate to a trained person
the following activities related to collections from infrequent plasma
donors: the activities listed in Sec. 630.15(b)(1)(i) through
(b)(1)(iii) and (b)(1)(v), and the administration of the informed
consent under Sec. 630.15(b)(2). The responsible physician or a
physician substitute is not required to be present at the collection
site provided that the responsible physician has delegated these
activities to a trained person who is also adequately trained and
experienced in the recognition of and response to the known adverse
responses associated with blood collection procedures. However, if
Source Plasma is collected from an infrequent plasma donor and the
donor is otherwise ineligible or is participating in an approved
immunization program, the responsible physician may only delegate
activities as described in Sec. 630.5(c)(1) through (c)(3), as
appropriate to that collection.
Section 630.5(d) requires that, for all collections, establishments
must establish, maintain, and follow standard operating procedures for
obtaining rapid emergency medical services for donors when medically
necessary. In addition, establishments must assure that an individual
(responsible physician, physician substitute, or trained person,
[[Page 29860]]
as defined in Sec. 630.3) who is currently certified in
cardiopulmonary resuscitation is located on the premises whenever the
establishment is performing collections of blood or blood components.
Finally, we have added Sec. 640.130 to new subpart M of 21 CFR
part 640, entitled ``Definitions and Medical Supervision.'' Section
640.130 clarifies that the requirements for medical supervision
established in Sec. 630.5 supplement the regulations in part 640. We
are adding this provision to aid the reader in identifying applicable
requirements for medical supervision related to the collection of blood
and blood components in accordance with part 640.
(Comment 36) One comment agreed that the responsible physician
should direct and control the physician substitutes and trained
personnel, and supported proposed provisions under which the
responsible physician could authorize trained personnel, including
physician substitutes, to determine the donor's eligibility and collect
blood and blood components in the absence of a responsible physician.
(Response) We have finalized the proposed rule to permit delegation
of blood collection activities to trained persons, including physician
substitutes, who are adequately instructed and qualified to perform the
delegated functions. This delegation provision is not intended to
preempt more restrictive requirements under State or local law. We do
not require the responsible physician to be on the premises, except for
red blood cell immunizations, although State or local law may provide
otherwise. We have also clarified the activities that the responsible
physician may not delegate. Delegation is not permitted in these
circumstances because the medical expertise of the responsible
physician is necessary to assess whether the donor's health permits the
collection.
(Comment 37) One comment requested clarification that designated
physician substitutes and trained persons may perform the collection of
platelets, Red Blood Cells and plasma (as distinct from Source Plasma)
and may return red blood cells during an apheresis collection in the
absence of the responsible physician. Another comment criticized a
requirement for the presence of a physician substitute in the
collection of Source Plasma, noting that red blood cells are now
routinely returned by automated equipment during apheresis collections
of plasma, Red Blood Cells, and platelets. The comment stated that,
since modern apheresis devices return red blood cells to the donor
through automated processes, the return of red blood cells does not
pose a heightened risk relative to other procedures, and therefore
there is no need for a responsible physician or physician substitute to
be present during the return of red blood cells to apheresis donors.
The comment suggested that the presence of a physician substitute or
the responsible physician should only be required in the unlikely event
that a Source Plasma establishment was returning red blood cells
manually.
(Response) Section 630.5(b)(1)(iii) and (c)(1)(i)(A) of the final
rule authorize the responsible physician to delegate to a physician
substitute or other trained person the return of red blood cells to the
donor during apheresis. Subject to an exception for certain
plasmapheresis collections, the regulation does not require the
responsible physician to be present at the collection site when red
blood cells are returned to the donor during apheresis, provided that
the responsible physician has delegated oversight of these activities
to a trained person who is also adequately trained and experienced in
the recognition of and response to the known adverse responses
associated with blood collection procedures. However, when this
activity is performed in relation to the collection of plasma by
plasmapheresis (other than a collection from an infrequent plasma
donor), the regulation requires the responsible physician or physician
substitute to be present at the collection site. We have determined
that the presence of the responsible physician or of a physician
substitute under the supervision of the responsible physician is
necessary to help ensure the continued safety of plasmapheresis donors
who are not infrequent donors, as defined in Sec. 630.3(e). This is
because such donors are permitted to donate up to two times every week,
and larger volumes of fluid may be collected at each donation than from
other donors. These factors may increase risks for the donor, and
warrant the on-site presence of a physician substitute or the
responsible physician.
(Comment 38) One comment noted that Sec. 630.5(c) would permit a
collecting establishment to authorize a physician substitute to perform
the functions of a responsible physician in the collection of Source
Plasma, except the responsible physician would be required to be
present for red blood cell immunizations. The comment stated that they
assume that FDA is requiring the presence of the responsible physician
for the red blood cell immunization to assist the recipient of red
blood cells if a life-threatening situation arises during the
immunization process. The comment asserted that this is most likely
based on the fact that potential life-threatening reactions most
commonly occur within 10 to 15 minutes of the start of the transfusion
with as little as 10 milliliters (mL) transfused.
The comment said that they understand the potential risks
associated with red blood cell immunization. However, the comment
stated that having a physician present during the immunization process
does not protect against the single greatest risk to recipients of red
blood cells, which is human error when identifying the blood product
for administration to the recipient of red blood cells. Therefore, in
protecting against this risk, the comment stated that it is imperative
that plasma establishments have processes and procedures in place to
assure that the correct red blood cell product is infused to the
intended recipient. The comment reports that this is currently achieved
by adherence to current good manufacturing practices. The comment
recommended that FDA remove the requirement of having a physician
present during immunization with red blood cells as long as current
good manufacturing practices are followed.
(Response) We agree with the description of the risks of red blood
cell immunizations. We also agree that Source Plasma establishments
must adhere to Current Good Manufacturing Practice for Blood and Blood
Components (21 CFR part 606), including Sec. 606.100(b), which require
establishments to establish, maintain, and follow written standard
operating procedures for all steps in the collection, processing,
compatibility testing, storage, and distribution of blood and blood
components for allogeneic transfusion, and further manufacturing
purposes. However, adherence to current good manufacturing practices
does not replace the medical oversight provided by the responsible
physician, or the clinical expertise that a responsible physician can
provide in the case of an emergency at the establishment. Accordingly,
we require that the responsible physician must be present when a donor
is immunized with red blood cells. Section 630.5(c)(2)(ii) authorizes
the responsible physician to delegate to a physician substitute the
function of donor immunization with red blood cells, provided that the
responsible physician has approved the procedure and is on the premises
at the collection site when the procedure is performed.
[[Page 29861]]
(Comment 39) A comment to proposed Sec. 630.5(e) asserted that
blood collection personnel should be trained in cardiopulmonary
resuscitation and the use of automated external defibrillators, and
should call 911 to transport donors to a medical facility for emergency
care as soon as possible. Another comment noted that the final rule
could require that collection staff be trained in cardiopulmonary
resuscitation.
(Response) Final Sec. 630.5(d) requires blood collection
establishments to establish, maintain, and follow standard operating
procedures for obtaining rapid emergency medical services for donors
when necessary. In addition, blood collection establishments must
assure that an individual (responsible physician, physician substitute,
or trained person) who is currently certified in cardiopulmonary
resuscitation is located on the premises whenever collections of blood
or blood components are performed. We agree that the availability of
such a person on the premises will provide important donor protections
in the event they are needed. We are not including in the codified
language a requirement for a person also to be trained in the use of
automated external defibrillators because such devices are not always
available at collection sites. However, we believe that the presence of
automated external defibrillators may be helpful, and establishments
may choose to provide training on available automated external
defibrillators, in addition to assuring that a person currently
certified in cardiopulmonary resuscitation is located on the premises
during collections. As noted in our response to comment 40, we believe
that establishments will incorporate the use of 911 services into their
procedures for obtaining rapid emergency medical services for donors
when necessary.
(Comment 40) One comment noted that proposed Sec. 630.5(e) would
have required establishments to establish, maintain, and follow
standard operating procedure for providing emergency medical services
for donors within 15 minutes. The comment agreed that SOPs should be
established, maintained, and followed for the provision of emergency
medical services but stated that ensuring a 15 minute response time
would not be feasible in some communities and in any event is beyond
the control of the blood establishment. Other comments also noted that
local emergency medical service response time is community dependent.
Blood centers cannot control how quickly emergency medical services
respond and cannot guarantee a 15 minute response time.
(Response) After considering the comments, we have finalized this
provision without referencing a 15 minute timeframe. We recognize that
in many instances blood collection facilities must rely on the response
time of emergency medical services available through local 911
services. Instead, we are requiring in Sec. 630.5(d) that that
establishments establish, maintain, and follow standard operating
procedures for obtaining rapid emergency medical services for donors
when necessary. In addition, the final rule requires that at least one
person (responsible physician, physician substitute, or trained person)
on the premises during the collection of blood and blood components be
currently certified in cardiopulmonary resuscitation. FDA expects that
procedures established by blood collection establishments for obtaining
rapid emergency medical services will generally result in the provision
of emergency medical services within 15 minutes. However, by not
specifying a 15 minute response time (and instead calling only for a
``rapid'' response), we are recognizing that unanticipated
circumstances that are outside the control of the blood establishment
may delay such care. Establishments should consider the availability of
emergency medical services and local response times, particularly when
determining locations for mobile collections.
(Comment 41) One comment responded that proposed Sec. 630.5(e)
should be reworded to include public emergency medical services. The
comment agreed that the establishment of standard procedures for
providing emergency medical services within 15 minutes, if necessary,
for donors seems appropriate.
(Response) We decline to include the term ``public'' prior to
emergency medical services in Sec. 630.5(d). We interpret emergency
medical services to include an onsite responsible physician or access
to emergency medical services available through 911. If an
establishment determines that emergency medical services accessible
through 911 may not be available rapidly, due to the location of the
collection facility or mobile unit, the establishment should provide
for a responsible physician to be present at the collection site.
J. General Donor Eligibility Requirements (Sec. 630.10)
This section includes requirements to ensure that blood and blood
components are safe, pure and potent. It also includes requirements to
determine that the donor is in good health and the donor's health will
not be adversely affected by the donation. We require the establishment
to provide the donor with certain educational material related to
infectious disease risk so that the donor can self-defer, to check
donor deferral records, to perform a limited physical assessment of the
donor, to assess the donor for risk factors for relevant transfusion-
transmitted infections and other factors that might adversely affect
the donation or the donor's health, to obtain a donor acknowledgement
that is signed or otherwise recorded, to defer ineligible donors, and
to obtain proof of the donor's identity and a postal address where the
donor may be contacted for 8 weeks after donation for purposes of donor
notification under Sec. 630.40.
We received comments on this section from individuals, blood
establishments and trade organizations. We are finalizing this section
largely as proposed, except that we have clarified the language in some
sections and combined or revised other sections. We have combined
proposed Sec. 630.10(e), (f), and (g) covering various aspects of
donor eligibility into one section, Sec. 630.10(e). We have renumbered
proposed Sec. 630.10(h) into final Sec. 630.10(f). Final Sec.
630.10(f)(3) provides a modified standard for donor hemoglobin or
hematocrit. Proposed Sec. 630.10(i) is final Sec. 630.10(g), and we
have clarified proposed Sec. 630.10(i)(2) Donor's written statement of
understanding, now titled ``Donor's acknowledgement'' in Sec.
630.10(g)(2). We also added Sec. 630.10(h) to state more explicitly
what an establishment must do when a donor is ineligible.
1. Section 630.10(a)
Consistent with FDA's long standing requirement that a donor be in
good health at the time of donation to assure that blood, blood
components and blood products manufactured from their donations will be
safe, pure and potent, this section states that an establishment must
not collect blood or blood components before determining that the donor
is eligible to donate. We received no comments on this provision. We
added language to explain that, to be eligible, a donor must be in good
health and free from transfusion-transmitted infections as can be
determined by the processes in this subchapter. The phrase ``as can be
determined by the processes in this subchapter'' clarifies that blood
establishments must assess a donor's eligibility in accordance with
these regulations. Like the proposed rule, this section states that a
donor is ineligible if the donor is not in good health or if the blood
establishment identifies
[[Page 29862]]
factors that may adversely affect the health of the donor or the
safety, purity, or potency of the blood or blood components collected
from the donor.
2. Section 630.10(b)
Section 630.10(b) requires that, before determining eligibility, an
establishment must provide the donor with educational material in an
appropriate format regarding certain relevant transfusion-transmitted
infections when providing that information is necessary to assure the
safety, purity, and potency of blood and blood components, such as for
HIV risk factors. Currently, the only relevant transfusion-transmitted
infection for which FDA has determined that providing such information
is necessary to assure blood safety, purity, and potency is HIV. FDA
first made this recommendation in 1983 (Ref. 30). The donor history
questionnaires and accompanying materials found acceptable by FDA
include blood donor educational material addressing HIV risk behaviors
and signs and symptoms of HIV (Refs. 6, 7, 8). Providing this
educational information in written or electronic format would meet the
requirements of this section. In addition, the provision permits
establishments to provide, in the educational material, information
concerning the risks and hazards of donation. This provision differs
from proposed Sec. 630.10(b) in two significant ways: (1) In response
to comments, we have clarified that blood collection establishments
must provide information concerning certain, and not all, relevant
transfusion-transmitted infections and (2) to provide greater
flexibility and to accommodate existing practices, we have revised this
section to expressly permit establishments to provide, in this
educational material, information regarding the risks and hazards of
the donation procedure to meet the requirements under Sec.
630.10(g)(2)(ii)(E).
(Comment 42) Two comments raised concern that the proposal would
require establishments to provide the donor with too much information
about too many relevant transfusion-transmitted infections. Several
comments suggested that the rule should not require the educational
material to include signs and symptoms of a relevant transfusion-
transmitted infection. Several comments suggested that providing the
donor history questionnaire should be sufficient to meet this
requirement, while several comments suggested that the donor history
questionnaire should not include signs and symptoms of HIV.
(Response) FDA believes that providing educational material to
donors protects the safety of the blood supply and donor health. FDA
believes that self-deferral by at risk donors because of information
provided in the educational materials has helped ensure blood safety
(Refs. 6, 7, 8, 31, 32, 33). Blood establishments have voluntarily
developed donor educational material in response to potential threats
(Refs. 6, 7, 8, 31, 32, 33).
FDA agrees with the comments that educational materials should not
describe all relevant transfusion-transmitted infections. Instead, this
section requires establishments to provide donor information about a
relevant transfusion-transmitted infection when necessary to assure the
safety, purity, and potency of blood and blood components. As noted
previously, currently HIV is the only relevant transfusion-transmitted
infection for which providing such information is necessary. The
longstanding practice of providing educational material about HIV,
including information about signs and symptoms, would continue as a
requirement under this provision.
FDA believes that establishments may choose to include in the donor
educational material information to explain the collection procedure
and the risks and hazards of the procedure, as required under Sec.
630.10(g)(2)(ii)(E). This section expressly permits the incorporation
of that information into the donor educational material, but does not
require it.
3. Section 630.10(c)
Section 630.10(c) requires establishments to determine the donor's
eligibility on the day of donation and prior to collection. Under Sec.
630.10(c)(1), which is applicable to products that cannot be stored for
more than 24 hours, an establishment may determine the donor's
eligibility and collect a sample for testing required under Sec.
610.40 no earlier than 2 calendar days before the day of donation. In
Sec. 630.10(c)(2), the final rule authorizes blood establishments to
clarify a donor's response to a donor history question under Sec.
630.10(e) or (g) in accordance with standard operating procedures and
within 24 hours of the time of collection.
(Comment 43) Several comments stated that for components having a
shelf life of 24 hours, collecting a sample for testing for infectious
diseases one day before donation may not provide enough time to obtain
the results. They requested that FDA allow the donor to be tested 3
days prior to collection of the donation or alternatively allowing the
donation to be released under emergency provisions in Sec. 610.40(g)
or where appropriately labeled as from a donor who has been previously
tested.
(Response) FDA agrees with that there is a need for some
flexibility on the timing for collecting a sample for testing and
making a donor eligibility determination for donors of blood components
that cannot be stored for more than 24 hours. We have decided to
finalize the proposed provision, now Sec. 630.10(c)(1), and provide
that ``when a donor is donating blood components that cannot be stored
for more than 24 hours, you may determine the donor's eligibility and
collect a sample for testing required under Sec. 610.40 of this
chapter, no earlier than 2 calendar days before the day of donation,
provided that your standard operating procedures address these
activities.'' We believe that this 2 calendar day timeframe will be
adequate to accommodate donor testing before collection. We also note
that current Sec. 610.40(g) allows release of untested components in
appropriately documented medical emergency situations.
(Comment 44) FDA received several comments requesting that FDA
permit blood establishments to obtain answers to missing donor
information for 24 hours after the collection occurred.
(Response) FDA realizes that sometimes blood establishments become
aware that there are missing answers to donor history questions, or
they need clarification of answers to certain donor history questions.
In response to comments, and consistent with current FDA policy (Ref.
34), we are adding new Sec. 630.10(c)(2) to the final rule. Section
630.10(c)(2) expressly authorizes establishments to clarify donor
records after collection under these circumstances, ``In the event
that, upon review, you find that a donor's responses to the donor
questions before collection were incomplete, within 24 hours of the
time of collection, you may clarify a donor's response or obtain
omitted information required under paragraph (e) of this section,
provided that your standard operating procedures (required under 21 CFR
606.100) address these activities.'' This applies only to responses to
donor questions, and not to information that establishments are
required to obtain as part of the physical assessment of the donor
addressed in Sec. 630.10(f).
4. Section 630.10(d)
Section 630.10(d) requires a blood establishment to determine the
donor's eligibility before collection by performing four tasks: (1)
Consulting the records of deferred donors maintained under Sec.
606.160(e)(1) and (2). Because it
[[Page 29863]]
may not be feasible to review the cumulative record described in Sec.
606.160(e)(2) prior to collection at all collection sites, the
regulation provides that if pre-collection review is not feasible, the
establishment must consult the cumulative record prior to release of
any blood or blood component prepared from the collection; (2) assuring
that the interval since the donor's last donation is appropriate; (3)
assessing the donor's medical history; and (4) performing a physical
assessment of the donor. We have finalized the description of the last
two steps as proposed, and we have clarified the language used to
describe the second step by omitting unnecessary language.
The first factor has been changed to reference the ``records of
deferred donors maintained under Sec. 606.160(e)(1) and (2) of this
chapter'' instead of the proposed ``list of ineligible donors required
under Sec. 606.160(e)(2) of this chapter'', and to provide flexibility
for consulting the cumulative record before release of blood or blood
components when the record cannot be available at the collection site.
We discuss final Sec. 606.160(e) at comment 25. The review of the
records of deferred donors may be accomplished by making an electronic
query of a centralized database.
(Comment 45) One comment questioned the validity of donor deferral
registries in ensuring the safety of the blood supply. For example, the
comment asserted that requiring collection facilities to consult the
donor deferral registry prior to donation would negatively affect
mobile operations and impact other facilities when computer outages
occur that would have a significant negative impact on blood
availability.
(Response) The requirements in Sec. Sec. 606.160(e) and
630.10(d)(1) will help assure that blood and blood components that are
not suitable for use are not collected or distributed. These provisions
protect donors from making donations that should not be collected,
protect recipients from the release and use of unsuitable donations,
and help establishments to conserve resources used in collecting,
testing, and manufacturing blood and blood components. Moreover, since
Sec. 630.10(d)(1) helps to prevent the collection of unsuitable units,
we believe that it will be feasible for establishments to comply with
these requirements while at the same time maintaining adequate supplies
of suitable blood and blood components. We believe that the
requirements, as finalized, are similar to existing practices within
blood establishments. Moreover, Sec. 630.10(d)(1) of the final rule
now provides additional flexibility so that if unusual circumstances
prevail (for example, at a distant mobile collection, or when an
establishment is having temporary technical difficulties), and pre-
collection review is not feasible because the establishment cannot
consult the cumulative record at the collection site, the establishment
may collect from the donor, but must consult the cumulative record
before release of any blood or blood component prepared from the
collection.
5. Section 630.10(e)
The requirements of proposed Sec. 630.10(e), (f), and (g) are
interrelated. We have combined proposed Sec. 630.10(e), (f), and (g)
into one section, final Sec. 630.10(e). This section requires
establishments to conduct a medical history interview as described in
this section to determine if the donor is in good health, to identify
risk factors closely associated with exposure to, or clinical evidence
of, a relevant transfusion-transmitted infection, and to determine if
there are other conditions that may adversely affect the health of the
donor or the safety, purity, or potency of the blood or blood
components or any product produced from the blood or blood components.
Blood establishments must take a medical history as described in this
section.
Section 630.10(e) also contains specific requirements for
determining that the donor is in good health and free from risk factors
for a relevant transfusion-transmitted infection. This assessment must
include the following factors: (1) Factors that make the donor
ineligible to donate because of an increased risk for, or evidence of,
a relevant transfusion-transmitted infection, including the factors
described in Sec. 630.10(e)(1)(i) through (vi) and (2) other factors
described in Sec. 630.10(e)(2)(i) through (vii) that may make the
donor ineligible, including factors related to donor health or travel
history.
Section 630.10(e) is intended to provide explicitly in our
regulations for our current donor deferral recommendations and blood
establishment practices. We discuss the comments received on that
provision. We received no comments on our proposal in Sec.
630.10(g)(7), under which a donor would be ineligible because she was
pregnant at the time of, or within 6 weeks of, donation, and have
finalized that proposal in Sec. 630.10(e)(2)(v).
(Comment 46) Several organizations requested FDA not to finalize
the provision in proposed Sec. 630.10(e) that would have required an
establishment to determine whether a health care practitioner ever told
the donor not to donate blood.
(Response) We agree. We included this provision, in part, as a
result of the anthrax exposures in 2001, where individuals may have
been advised not to donate. However, prior advice not to donate blood
may be based on a number of factors, including a transient infection,
now cured, or blood loss due to an accident, from which the donor has
long recovered. We have not included this provision in the final rule.
Instead we require establishments to take a medical history, as
described in Sec. 630.10(e). Such a medical history would be focused
on eliciting information related to potential and current risks, either
to the donor, or to the safety of the donated blood product.
(Comment 47) We received comments stating that FDA has recognized
uniform donor history questionnaires and should not add the criteria
for deferral in proposed Sec. 630.10(f).
(Response) FDA believes that use of a current and acceptable donor
history questionnaire, such as the donor history questionnaires and
accompanying materials found acceptable by FDA in guidance (Refs. 6, 7,
8), would meet these requirements. If the need arises, FDA will
describe how to comply with these provisions in guidance documents
issued in accordance with good guidance practices.
(Comment 48) One comment suggested that we abandon the term
``social'' in proposed Sec. 630.10(f)(1), ``social behaviors
associated with relevant transfusion-transmitted infections.''
(Response) We agree and have dropped the term ``social.'' Section
630.10(e)(1)(i) now refers simply to ``behaviors.''
(Comment 49) Other comments stated that FDA should not consider the
behavior of men who have had sex with another man even one time since
1977 to be ``behaviors associated with relevant transfusion-transmitted
infections'' under proposed Sec. 630.10(f)(1).
(Response) This rule does not specify the circumstances under which
FDA would consider men who have sex with another man to be a behavior
associated with relevant transfusion-transmitted infections. Instead,
that is an issue FDA has addressed in previous guidance related to the
issue (Ref. 10). We are currently reviewing this policy. If we
determine that modifications of any behavior-based donor deferral
recommendations are warranted, we will issue new guidance to blood
[[Page 29864]]
establishments in accordance with good guidance practices.
(Comment 50) We received several comments suggesting that FDA
change the following phrase in proposed Sec. 630.10(f)(2), ``Medical
treatments and procedures associated with exposure to relevant
transfusion-transmitted infections.'' The comments stated that this
criterion was too vague and suggested that the donor history
questionnaire would provide a sufficient basis for determining whether
the donor had risk exposures from medical procedures.
(Response) We agree with the comment in part and have made this
criterion, now contained in Sec. 630.10(e)(1)(ii), more specific. FDA
recognizes that many medical procedures present some risk, which cannot
be specifically quantified. Consequently, final Sec. 630.10(e)(1)(ii)
states, ``Receipt of blood or blood components or other medical
treatments and procedures associated with possible exposure to a
relevant transfusion-transmitted infection.'' In any event, we agree
with comments that an acceptable donor history questionnaire, such as
the donor history materials that are currently recognized in FDA
guidances (Refs. 6, 7, 8), may be used to elicit information adequate
to satisfy these provisions.
(Comment 51) One comment asked FDA to clarify how establishments
would gather information related to signs and symptoms of relevant
transfusion-transmitted infections under proposed Sec. 630.10(f)(3).
(Response) In final Sec. 630.10(e)(1)(iii), we require
establishments to assess ``Signs and/or symptoms of a relevant
transfusion-transmitted infection.'' For example, FDA has issued
guidance on signs and symptoms of HIV (Refs. 10, 30). If a donor
exhibits signs or symptoms of HIV, they would be deferred under this
provision. We believe that an establishment would meet this requirement
by determining that the donor is in good health, and using a currently
acceptable donor history questionnaire. FDA has periodically issued new
guidance recommending assessment for signs and symptoms of a new
infectious agent or disease (Refs. 35, 36). FDA will issue guidance in
accordance with good guidance practices in the event that different
information is needed to satisfy the requirements of this section.
(Comment 52) Several comments asked FDA to reconsider the
longstanding requirement for deferral of donors with a ``history of
viral hepatitis.''
(Response) Neither the proposed nor the final rule refers to a
``history of viral hepatitis'' as a factor in determining donor
eligibility. We are finalizing the donor eligibility requirements
without reference to a requirement to defer donors with a history of
viral hepatitis after the age of 11. Instead, under new Sec.
630.3(h)(1)(ii) and (iii), HBV and HCV are relevant transfusion-
transmitted infections. Under Sec. 630.10(e)(1)(iii), an establishment
must defer a donor exhibiting signs and/or symptoms of relevant
transfusion-transmitted infections, including HBV and HCV. Reactive
test results for these relevant transfusion-transmitted infections
would result in donor deferral as described in Sec. 610.41(a).
(Comment 53) One comment requested that that we not finalize the
requirement in proposed Sec. 630.10(f)(4) to determine whether a donor
has been institutionalized in a correctional institution, preferring
that this be addressed in guidance, not regulation. Another comment
recommended that FDA clarify that deferral would be for
institutionalization in a correctional institute for 3 days or more.
(Response) We have finalized a requirement in Sec.
630.10(e)(1)(iv) that establishments determine whether a donor has been
institutionalized in a correctional institution. We have rejected the
suggestion that we leave this deferral to guidance because we concluded
that this deferral is readily described and unlikely to change due to
technological developments. We agree with the second comment and have
further clarified that the deferral applies to donors who were
institutionalized in a correctional institution for 72 consecutive
hours or more in the 12 months before donation.
(Comment 54) We received comments asking us to revise the
definition for ``intimate contact'' provided in proposed Sec.
630.3(e), which was applicable to proposed Sec. 630.10(f)(5), and to
clarify that the deferral for ``intimate contact'' would only apply to
those relevant transfusion-transmitted infections where such
transmission occurs through intimate contact.
(Response) We agree in part with the comment. We have modified the
defined term in Sec. 630.3(f) so that it is now ``intimate contact
with risk for a relevant transfusion-transmitted infection'' and
clarified that this term refers to conduct that could result in the
transfer of potentially infectious body fluids from one person to
another. The provision that is now finalized in Sec. 630.10(e)(1)(v)
incorporates this clarified definition, and requires inquiry concerning
such intimate contact with risk for a relevant transfusion-transmitted
infection, which is defined in Sec. 630.3(f) as having engaged in an
activity that could result in the transfer of potentially infectious
body fluids from one person to another. We have issued guidance when we
believed that deferral for intimate contact with an individual infected
with a relevant transfusion-transmitted infection or exposed to a
relevant transfusion-transmitted infection was appropriate (Refs. 11,
37). FDA will issue a future guidance document as necessary for
deferral of donors because of specific intimate contact with risk for a
relevant transfusion-transmitted infection.
(Comment 55) One comment requested that we state that nonsterile
percutaneous inoculation, as proposed in Sec. 630.10(f)(6), be
considered a basis for deferral only when the inoculation took place
within 4 months of the donation.
(Response) We did not specify in the proposed regulation a
timeframe for this deferral, stating that the blood establishment
should defer the donor if the factor was ``still applicable'' at the
time of donation, and we have not specified a timeframe in the final
rule codifying this factor at Sec. 630.10(e)(1)(vi). FDA's 1992
guidance entitled, ``Revised Recommendations for the Prevention of
Human Immunodeficiency Virus (HIV) Transmission by Blood and Blood
Products,'' recommends a 1 year deferral for nonsterile percutaneous
exposure, and this recommendation is still current (Ref. 10).
(Comment 56) We received several comments asking FDA to modify
proposed Sec. 630.10(g)(1), which identified ``Medical or dental
treatment, or symptoms of a recent or current illness'' as a basis for
ineligibility. These comments asked FDA to delete the reference to
dental treatment.
(Response) We agree with these comments in part. In finalizing
proposed Sec. 630.10(g)(1), we have revised this provision and
separated it into two sections. Section 630.10(e)(2)(i) now requires
establishments to assess donors for symptoms of a recent or current
illness. Section 630.10(e)(2)(ii) now requires establishments to assess
donors for certain medical treatments or medications, such as a major
surgical procedure, that indicates that the donor should not donate. We
have omitted the requirement to defer donors for recent dental
treatment.
(Comment 57) We received several comments asking FDA to delete the
provision in proposed Sec. 630.10(g)(1) through (g)(3) which refer to
ineligibility because of medical treatment, medication, or major
surgical procedure.
[[Page 29865]]
One comment suggested that the deferral be limited to the criteria and
medications enumerated in current FDA guidance documents. Several
comments asked FDA to identify major medical procedures.
(Response) We have finalized Sec. 630.10(e)(2)(ii) to require
blood establishments to assess donors for certain medical treatments or
medications, such as a major surgical procedure, that indicate that the
donor should not donate. This provision is intended to protect the
health of the donor and ensure the safety and purity of the blood
product. We note that we have issued guidance on donor deferral
criteria for certain medications (Ref. 38). We believe that
establishments can meet the requirements of this section by using
current donor history questionnaire materials recognized as acceptable
by FDA, or other approved donor history questionnaire. If our
recommendations for deferral for medical procedures or specific
medications change, we would issue guidance in accordance with good
guidance practices.
(Comment 58) We received several comments asking FDA not to
finalize proposed Sec. 630.10(g)(4), under which a donor would be
ineligible on the basis of travel to, or residence in, an area endemic
for a transfusion-transmitted infection. The comments criticized the
provision as vague and more appropriately dealt with in FDA guidance
documents.
(Response) In finalizing this provision in Sec. 630.10(e)(2)(iii),
we have provided additional clarity by stating that a donor would be
ineligible on the basis of such travel or residence only when such
screening is necessary to assure the safety, purity, and potency of
blood and blood components due to the risks presented by donor travel
and the risk of transmission of that transfusion-transmitted infection
by such donors. For example, in the future we may determine that
screening donors under this provision for the Chickungunya virus, a
transfusion-transmitted infection that is transmitted by mosquitoes, is
necessary to assure the safety, purity, and potency of blood and blood
components. If so, we would address deferral of donors with a travel
history to an area endemic for Chickungunya in accordance with good
guidance practices.
(Comment 59) Several comments suggested that we delete the
provision in proposed Sec. 630.10(g)(6), which would have required a
determination of ineligibility due to exposure or possible exposure to
a released disease or disease agent relating to a transfusion-
transmitted infection, if it was known or suspected that such a release
has occurred. The comments suggested that this provision was vague and
better addressed in guidance when an event occurs.
(Response) In Sec. 630.10(e)(2)(iv), we have finalized this
provision as proposed. This factor only becomes relevant when a disease
or disease agent for a transfusion-transmitted infection has been
released. We expect this to apply in rare circumstances, such as after
a serious accident or bioterrorism attack involving the release of such
agents. FDA intends to issue guidance, as practicable, when a released
disease or disease agent is identified and is of a nature or type that
donor deferral would be warranted. We note that we previously issued
guidance on the deferral of donors with possible exposure to anthrax
due to a possible bioterrorism event (Ref. 39).
(Comment 60) We received several comments on proposed Sec.
630.10(g)(8), which would have required blood establishments to
determine to be ineligible donors who gave answers to medical history
questions that appeared unreliable due to the apparent influence of
drugs or alcohol, or due to another reason affecting the reliability of
the donor's answers. The comments agreed with the deferral, but stated
that blood establishment procedures were adequate to address this
issue.
(Response) We combined donor suitability requirements from existing
regulations for Whole Blood donations (Sec. 640.3) and Source Plasma
donations (Sec. 640.63) in the final rule. Source Plasma regulations
have had a longstanding requirement (Sec. 640.63(d)) that ``any donor
who, in the opinion of the interviewer, appears to be under the
influence of any drug, alcohol, or for any reason does not appear to be
providing reliable answers to medical history questions, shall not be
considered a suitable donor.'' Until now, there has not been a
corresponding provision in the requirements for Whole Blood donors,
even though a donor who does not provide reliable answers presents
similar risks in that venue. We are finalizing this requirement for all
donations in Sec. 630.10(e)(2)(vi).
In the preamble to the proposed rule we gave, as an example of an
unreliable answer, a donor who states that he or she is donating in
order to be tested for infectious agents. This is because of our
concern that the donor may be aware of some additional, undisclosed,
risk factor that leads him or her to seek information on their
infection status by presenting at a blood donation center. Such
undisclosed risk factors endanger blood safety, particularly when the
donor is in the ``window period'' when the donor is infected and
infectious, but the infection cannot yet be detected by donor screening
tests. We did not receive comments on this example. We have decided to
expressly require the deferral of a donor who states they are seeking
testing for a relevant transfusion-transmitted infection. We expect
that blood establishments may then refer the donors to public health
testing clinics and other venues providing testing.
(Comment 61) We received comments requesting that we not finalize
the proposed requirement to determine a donor to be ineligible due to
receipt of a xenotransplantation product, or intimate contact with such
a recipient (proposed Sec. 630.10(g)(5)).
(Response) In final Sec. 630.10(e)(2)(vii), we require
establishments to assess the eligibility of a donor on the basis of
receipt of a xenotransplantation product. We finalized this provision
to protect the health of the donor who received the xenotransplantation
product and to address the risk of transmission of animal infectious
agents by blood and blood products collected from such a donor. In
2002, we discussed those risks in a draft guidance entitled ``Guidance
for Industry: Precautionary Measures to Reduce the Possible Risk of
Transmission of Zoonoses by Blood and Blood Products from
Xenotransplantation Product Recipients and Their Intimate Contacts''
(Ref. 37). We have not finalized the proposed requirement to require
screening for intimate contact with a xenotransplantation recipient.
If, in the future, we determine that donation by an individual who has
had intimate contact with a recipient of a xenotransplantation product
may affect that donor's health, or the safety, purity, or potency of
the blood or blood component, or product produced from the blood or
blood component collected from that donor, we will issue guidance to
address these risks.
6. Section 630.10(f)
As we described earlier, we combined proposed Sec. 630.10(e)
through (g) into Sec. 630.10(e) in the final rule. We have finalized
proposed Sec. 630.10(h) as final Sec. 630.10(f).
The physical assessment criteria set forth in Sec. 630.10(f)(1)
through(6) in this final rule requires establishments to determine that
a donor is in good health which helps to assure that blood and blood
components collected are safe, pure, and potent. This section requires
establishments to determine on the day of donation and prior to
collection of blood or blood components that the
[[Page 29866]]
donor is in good health, indicated in part by a normal temperature, a
blood pressure within acceptable limits, an acceptable hemoglobin or
hematocrit level, a regular pulse, and a minimum weight requirement.
Blood establishments are also required to perform an examination of the
donor's phlebotomy site and the donor's arms and forearms.
a. Temperature (Sec. 630.10(f)(1)).
(Comment 62) We received no comments objecting to the requirement
for measuring a donor's temperature. We received one comment asking
whether we would specify a subnormal temperature.
(Response) We are finalizing the proposed requirement to determine
that the donor's oral body temperature does not exceed 37.5 [deg]C
(99.5[emsp14][deg]F), or the equivalent if measured at another body
site, since an elevated temperature indicates that the donor is not in
good health and may be a symptom of infection or other adverse
condition. On the other hand, a temperature that is a few degrees lower
than 37.5 [deg]C (99.5[emsp14][deg]F), is not necessarily indicative of
poor health. We decline to specify a subnormal temperature at this
time. Instead, we leave assessment of an apparently healthy donor who
presents for donation with an unusually low temperature for blood
establishments to address in their standard operating procedures.
b. Blood Pressure (Sec. 630.10(f)(2)).
(Comment 63) Several comments recommended that FDA should not
finalize a requirement for determining the donor's blood pressure,
while others recommended not specifying limits for systolic and/or
diastolic blood pressure measurements, or addressing such bounds only
in guidance. One comment stated that a baseline blood pressure for all
donors at each donation is needed in the event of a reaction.
(Response) Current Sec. 640.3(b)(2) requires that donors be in
good health, as demonstrated by systolic and diastolic blood pressure
within normal limits, unless the examining physician is satisfied that
an individual with blood pressure outside these limits is an otherwise
qualified donor. In the preamble to the proposed rule we had solicited
comments requesting supporting scientific data regarding the necessity,
or lack of necessity of requiring specific upper and lower blood
pressure limits for a donor (72 FR 63416 at 63426 and 63427). We did
not receive significant data. In November 2009, we asked the Blood
Products Advisory Committee whether available data support the utility
of obtaining pre-donation blood pressure measurements as predictors of
risk of an adverse response to donation, and the majority responded
that data did not establish pre-donation blood pressure as a predictor
of risk of an adverse response. However, even though the vote did not
support blood pressure measurement as a predictor of risk, many members
of the committee stated that blood pressure measurement should be
retained as part of the donor assessment. The committee members noted
that studies examining adverse events and blood pressure have been
restricted to donors with currently acceptable blood pressure levels.
Several committee members were concerned that it was not safe for
donors with blood pressures above 180 mm of mercury to donate. They
noted the lack of data on the safety of blood donations in hypertensive
donors and the potential for severe adverse events in such donors.
Other committee members noted that low blood pressure could be
predictive of adverse events in young female donors who have low blood
volume.
We are finalizing a requirement to measure the donor's blood
pressure before donation. If a donor's systolic blood pressure is
outside the range of 90 to 180 mm of mercury, or if the donor's
diastolic blood pressure is outside the range of 50 to 100 mm of
mercury, establishments may permit the donor to donate only when the
responsible physician has examined the donor and determined that the
health of the donor would not be adversely affected by donating. Note
that under Sec. 630.5(b)(1)(i)(A) and (c)(1)(i)(A)(1), the responsible
physician is not authorized to delegate this examination and
determination of the health of the donor, and must personally perform
this examination and determination. Final Sec. 630.10(f)(2) is
consistent with the proposed rule and largely consistent with the
current requirement in Sec. 640.3(b)(2), and will assure that donors
who present with either unusually high, or unusually low, blood
pressure will be examined by the responsible physician before they are
permitted to donate. We are establishing these criteria in the
regulation, rather than providing a flexible standard, because we have
determined that establishing clear criteria will be more protective of
donor health. We note that, under the limits provided in Sec.
630.10(f)(2), donors with blood pressure readings above 140/90 would be
eligible to donate, even though such donors may be hypertensive (Ref.
40). However, experience to date indicates that donors with blood
pressures in the range provided in this rule may safely donate (Refs.
41, 42).
(Comment 64) In response to our request for comments on the
accuracy of blood pressure measurements, one comment stated that ``Many
factors can influence blood pressure along with pulse such as stress,
exercise, and caffeine intake. In addition, interobserver differences
are found with measurements that rely on sphygmomanometers and
stethoscopes. Therefore, a general preference for automated devices is
found not only among donor centers but also among clinics, hospitals,
and for use at home. These devices are commercially available and
approved for sale. We recommend that FDA acknowledge the acceptance of
automated devices in either the preamble to the final rule or in
guidance. FDA also notes that an isolated measurement of blood pressure
may not reliably assess acceptability for donation.''
(Response) We are not requiring that a specific type of device to
be used to measure blood pressure. Establishments may use manual or
automated devices as long as such use is consistent with the applicable
standards or current good manufacturing practices, and their own
standard operating procedures.
(Comment 65) The comment recommended that FDA provide the
following, or similar, guidance: ``Firms should have a procedure for
re-measuring the vital signs if there is reason to believe stress or
other factors have affected the initial measurement.''
(Response) We are not issuing guidance on this issue at this time.
We recognize that stress and other factors may affect initial
measurements of the donor's blood pressure and pulse, required under
Sec. 630.10(f)(2) and (f)(4). In accordance with Sec. 606.100(b)(2),
establishments must have standard operating procedures for taking a
donor's blood pressure and pulse before collection. However, these
requirements do not prevent a blood collection establishment from
providing in those standard operating procedures for taking and relying
upon a second measurement of blood pressure if there is reason to
believe stress or another factor affected the initial measurement and
taking a second measurement is consistent with medical practice.
c. Hemoglobin or hematocrit determination (Sec. 630.10(f)(3)).
We proposed to require that a donor's hemoglobin level or
hematocrit value be determined using a sample of blood obtained by
fingerstick, venipuncture or by a method that provides equivalent
results. Blood obtained from the earlobe is not acceptable. We received
no
[[Page 29867]]
comments on this provision and are finalizing this provision as
proposed. This section was proposed as Sec. 630.10(h)(3)(i); we now
finalize it as the first paragraph of Sec. 630.10(f)(3). We further
proposed to retain the existing requirement for autologous donations
that a donor's hemoglobin level be no less than 11 grams of hemoglobin
per deciliter of blood or a hematocrit value of 33 percent. We received
no comments on this provision and are finalizing this provision as
proposed. In addition, for allogeneic donations, we proposed to retain
existing requirements that a donor's hemoglobin level be no less than
12.5 grams of hemoglobin per deciliter of blood or a hematocrit value
of no less than 38 percent. We also solicited comments (72 FR 63416 at
63427) on:
Changing the minimum acceptable hemoglobin level to 12.0
grams per deciliter of blood or hematocrit of 36 percent for female
allogeneic donors, or whether a decision to collect from donors with
such levels should be left to the discretion of the medical director of
the collecting establishment on a case-by-case basis;
The possibility of adverse effects caused by the
collection of blood and blood components from female allogeneic donors
with a minimum level of 12.0 grams of hemoglobin per deciliter of blood
or a hematocrit value of 36 percent;
The possibility of adverse effects caused by the
collection of blood and blood components from allogeneic donors with a
minimum level of 12.5 grams of hemoglobin per deciliter of blood or a
hematocrit value of 38 percent;
Establishing a more stringent interdonation interval; and
The use of copper sulfate solution based methods as an
appropriate method to determine acceptable hemoglobin levels.
Since the proposed rule was published, FDA has brought up issues
related to blood donation, hemoglobin levels, and iron depletion in
donors for discussion at two Blood Products Advisory Committee meetings
on September 10, 2008 and July 27, 2010 (Refs. 43, 44). In addition,
the Department of Health and Human Services, Public Health Service,
Advisory Committee on Blood Safety and Availability discussed iron
depletion and donor informed consent at its December 17, 2008 meeting
(Ref. 45). In co-sponsorship with the Department of Health and Human
Services, National Heart, Lung and Blood Institute, AABB, America's
Blood Centers and Plasma Protein Therapeutics Association, FDA held a
workshop entitled ``Public Workshop: Hemoglobin Standards and
Maintaining Adequate Iron Stores in Blood Donors'' on November 8-9,
2011 (November 2011 Workshop) (Ref. 46).
At the July 2010 Blood Products Advisory Committee meeting,
following the discussion of hemoglobin qualification standards and iron
depletion in donors, the committee voted unanimously (10 yes votes, 0
no votes, 1 abstention) in support of raising the hemoglobin level for
men, but did not support a change in the hemoglobin level for women (10
no votes and 1 abstention) (Ref. 44). The shortcomings of relying
solely on hemoglobin measurement and the need to study measures to
mitigate iron deficiency in blood donors were discussed at both
meetings of the Blood Products Advisory Committee (Refs. 43, 44) and at
the November 2011 Workshop (Ref. 46). After reviewing those discussions
and the data presented at those meetings, we have decided to promulgate
different standards for male and female donors, but not to alter the
current 8 week interval between donations of Whole Blood and single
donations of apheresis Red Blood Cells. Recognizing that research in
this area continues and that data may be developed to support a change
in donor hemoglobin standards, we have provided for greater flexibility
in donor hemoglobin standards.
Section 630.10(f)(3)(i) now requires that allogeneic donors must
have a hemoglobin level or hematocrit value that is adequate to assure
donor safety. In addition, we establish minimum standards. The minimum
standard established for female allogeneic donors in Sec.
630.10(f)(3)(i)(A) is consistent with the current standard: A
hemoglobin level that is equal to or greater than 12.5 grams per
deciliter of blood, or a hematocrit value that is equal to or greater
than 38 percent. However, we recognize that a lower hemoglobin/
hematocrit level is also within the normal range for female donors.
Since hemoglobin levels are influenced by the male hormone
testosterone, female donors typically have lower hemoglobin levels than
male donors. The fact that a female donor's hemoglobin/hematocrit level
is lower than that of a male of similar age does not necessarily mean
that the female donor has low iron stores, which the body uses to
replace hemoglobin lost to blood donation (Refs. 47, 48). For this
reason, in the preamble to the proposed rule we specifically requested
comment on whether to permit collections from female allogeneic donors
with a hemoglobin level of 12.0 grams per deciliter of blood or a
hematocrit value of 36 percent. We are not establishing that minimum
level at this time. However, Sec. 630.10(f)(3)(i)(A) provides that an
establishment may collect blood from female allogeneic donors who have
a hemoglobin between 12.0 and 12.5 grams per deciliter of blood, or
hematocrit value between 36 and 38 percent, provided that the
establishment takes additional steps to assure that the lower value is
adequate with respect to donor safety, in accordance with a procedure
that has been found acceptable for this purpose by FDA. FDA has not yet
recognized any such procedures, and awaits the development of data
related to these issues. Conceivably, these steps might include a pre-
donation measure of iron stores by means of a ferritin test, or iron
replacement therapy and monitoring of iron stores. We have determined
that standard collections from a donor with a hemoglobin level as low
as 12.0 grams per deciliter of blood or hematocrit value of 36 percent
would meet minimum potency levels based on calculated hemoglobin
content.
Section 630.10(f)(3)(i)(B) of the final rule establishes a minimum
standard for male allogeneic donors of 13.0 grams of hemoglobin per
deciliter of blood, or a hematocrit value that is equal to or greater
than 39 percent. This standard aligns more closely with the low range
of normal levels for men, and is higher than the current regulation's
minimum standard of 12.5 grams of hemoglobin per deciliter of blood, or
a hematocrit value that is equal to or greater than 38 percent (Ref.
48). We requested comment in the preamble to the proposed rule on the
possibility of adverse effects on male donors with a minimum hemoglobin
level of 12.5 grams per deciliter of blood or a hematocrit value of 38
percent. We solicited these comments, in part, because of our concern
about possible adverse effects of collecting blood from male donors
with below normal hemoglobin or hematocrit levels, and reports about
iron depletion resulting from blood donation (Refs. 46, 49, 50). Males
with below normal hemoglobin or hematocrit levels may have a higher
incidence of iron deficiency due to frequent blood donations or
undiagnosed conditions such as gastrointestinal bleeding due to colon
cancer. Since the proposed rule published, the results of a study
sponsored by the Department of Health and Human Services, National
Heart, Lung and Blood Institute, the Retrovirus Epidemiology Donor
Study-II (REDS-II)
[[Page 29868]]
Donor Iron Status Evaluation Study (REDS-II-RISE study) on hemoglobin
levels in donors have become available (Refs. 49, 50). The results of
the REDS-II-RISE study amplified existing concern about frequent
donation and iron depletion. In this rule, we are establishing higher
minimum hemoglobin/hematocrit levels for male donors after reviewing
that study and considering the comments submitted.
(Comment 66) We received numerous comments asking FDA not to make
changes in acceptable hemoglobin and hematocrit levels for male and
female donors until the REDS-II-RISE study on hemoglobin levels in
donors was completed.
(Response) We are finalizing this rule after reviewing the results
of the REDS-II-RISE study. Preliminary results of the REDS-II-RISE
study were presented at the July 2010 Blood Products Advisory Committee
meeting. At the conclusion of that discussion, the advisory committee
voted unanimously that the available scientific evidence supported
raising the minimum hemoglobin/hematocrit levels for male donors. The
committee did not support lowering minimum standards for female donors
(Ref. 44). The REDS-II-RISE study published on October 10 and 24, 2011,
and the results were discussed at a November 2011 Workshop (Ref. 46).
Results from the REDS-II-RISE study were published in an article
entitled, ``Iron deficiency in blood donors: The REDS-II Donor Iron
Status Evaluation (RISE) Study,'' (Ref. 50). The authors reported a
high prevalence of iron depletion in frequent blood donors. As
recommended by the comments, FDA has considered the results of the
REDS-II-RISE study in determining appropriate hemoglobin standards for
this rule. We agree that the study provides important new information
on hemoglobin levels in donors, and supports increasing the minimum
hemoglobin/hematocrit requirements for male donors. We recognize that
this is an important donor safety issue, and we will continue to review
the scientific data as we consider these issues in the future.
(Comment 67) We received one comment supporting lowering the
hemoglobin level for women and one opposing lowering the hemoglobin
level for women. The comment supporting a lower minimum hemoglobin
level stated that a hemoglobin level of 12.0 grams per deciliter of
blood was normal for women, and allowing such donors to donate would
improve blood availability. The comment opposing lowering the minimum
hemoglobin level stated that this practice would make more women
susceptible to anemia and iron deficiency.
(Response) For female allogeneic donors, the current minimum
hemoglobin/hematocrit levels remain the default minimum levels under
this rule. In the event that an establishment takes additional steps
that are adequate to assure donor safety an establishment may collect
from female donors with normal, but lower, hemoglobin levels, between
12.0 and 12.5 grams per deciliter of blood, or a hematocrit value
between 36 and 38 percent, provided the establishment has taken
additional steps to assure that this alternative standard is adequate
to ensure that the health of the donor will not be adversely affected
due to the donation, in accordance with a procedure that has been found
acceptable for this purpose by FDA. We have not yet found such a
procedure adequate for this purpose. However, we recognize that, in the
future, new data may support revised hemoglobin/hematocrit standards
for female allogeneic donors, particularly if it becomes possible to
measure other values, including iron stores, before donation. In
determining or recognizing an alternative measure, FDA intends to
consider other evidence related to donor health, including iron stores.
Until then, establishments must follow the current standard for female
allogeneic donors: A hemoglobin level of 12.5 grams per deciliter of
blood or a hematocrit value of 38 percent.
(Comment 68) One comment stated that changing the hemoglobin level
could affect cleared devices as some are cleared based on a specified
hemoglobin/hematocrit lower limit.
(Response) We recognize that some operator's manuals for apheresis
devices describe the minimum hemoglobin level of 12.5 grams per
deciliter of blood, or a hematocrit value of 38 percent, and that these
references would need to be updated to reflect the new minimum standard
for male donors. In addition, related changes to apheresis device
software may be needed.
d. Pulse (Sec. 630.10(f)(4)).
Current regulations require that a donor of Source Plasma have a
normal pulse, but do not specify a related requirement for donors of
Whole Blood or other blood components. We proposed in Sec.
630.10(h)(4) to require that all donors have a regular pulse that
measures between 50 and 100 beats per minute. A donor with an irregular
pulse or measurements outside these limits would be permitted to donate
only when the responsible physician has examined the donor and
determines and documents that the health of the donor would not be
adversely affected by donating. We have finalized this provision in
Sec. 630.10(f)(4) with one change. The final rule provides that a
donor with an irregular pulse or measurements outside these limits may
be permitted to donate only when the responsible physician determines
and documents that the health of the donor would not be adversely
affected by donating. This determination may be made by the responsible
physician on the basis of an assessment of the donor's information (for
example, the responsible physician may conclude that the donor's low
pulse rate is due to regular marathon running). This provision thus
does not require that the responsible physician personally examine the
donor. Note that under final Sec. 630.5(b)(1)(i)(B) and
(c)(1)(i)(A)(2), the responsible physician cannot delegate this
determination that the donor's health would not be adversely affected
by donating.
(Comment 69) Several comments opposed adding a requirement for
determining that the donor has a regular pulse between 50 and 100 beats
per minute. One comment indicated that the physician should examine the
donor for any irregularity in their pulse, not just a pulse outside the
proposed limits.
(Response) To assure that donors are in good health and will not be
adversely affected by donating, we are finalizing the requirement to
measure the donor's pulse and assess eligibility based on pulse rate
and regularity. In November 2009, FDA asked the Blood Products Advisory
Committee if available data support the utility of obtaining pre-
donation pulse measurements as predictors of risk of adverse response
to donation. The majority of the committee agreed (10 yes votes, 8 no
votes) that pulse measurement was a predictor of risk of adverse
response to donation. In particular, high pulse rates may be associated
with higher rates of vasovagal reactions. We also agree with the
comment that an irregular pulse can indicate that a donor is not in
good health (Ref. 51). Therefore, final Sec. 630.10(f)(4) requires
that the donor's pulse must be regular and between 50 and 100 beats per
minute--no less than 50 beats per minute, and no more than 100 beats
per minute. A donor with an irregular pulse or measurements outside
these limits is ineligible unless the responsible physician determines
and documents that the health of the donor would not be adversely
affected by donating.
(Comment 70) One comment asserted that a phone consultation between
the blood collection center and the responsible physician should be
sufficient to determine whether a donor
[[Page 29869]]
with an irregular pulse can donate, rather than the proposed
requirement that responsible physician actually ``examine'' the donor.
For example, the comment stated that their blood collection center
routinely permits the responsible physician on-call to give phone
authorization for donors with pulse rates between 40 and 50 beats per
minute to donate, when it is ascertained by the donor's history that
the donor is an athlete.
(Response) We agree with the comment. A donor with an irregular
pulse or measurements outside the limits provided in final Sec.
630.10(f)(4) may be permitted to donate when the responsible physician
has determined that the health of the donor would not be adversely
affected by donating. We have not finalized a requirement that the
responsible physician must examine the donor, and we provide that in
appropriate circumstances the responsible physician may make a
determination of whether a donor's health would be adversely affected
by donating blood or blood components. Such a determination may be
reached by a phone consultation between the establishment and the
responsible physician, though under Sec. 630.5(b)(1)(i)(B) and
(c)(1)(i)(A)(2), the responsible physician cannot delegate the
determination that the donor's health would not be adversely affected
by donating.
e. Weight (Sec. 630.10(f)(5)).
We proposed in Sec. 630.10(h)(5) that a donor weigh a minimum of
50 kilograms (110 pounds) and not have any unexplained loss of greater
than 10 percent of body weight within the past 6 months. We are
finalizing the requirement that donors weigh at least 110 pounds, but
have not finalized the requirement related to unexplained weight loss.
(Comments 71) Several comments suggested deleting the requirement
to assess the donor's weight because most blood establishments do not
currently weigh donors. Several comments said there was no
justification for the 110 pounds lower weight limit and that deferrals
based on the overall health of the donor were better addressed through
the donor history questionnaire.
(Response) Section 630.10(f)(5) does not require blood
establishments to weigh Whole Blood donors. Blood establishments may
make this determination by asking a donor whether the donor weighs at
least 110 pounds.
f. Skin examination (Sec. 630.10(f)(6)).
In proposed Sec. 630.10(h)(6) we proposed requirements that: (1)
The donor's phlebotomy site be free of evidence of infection,
inflammation, lesions, and pitted skin and (2) the donor's arms and
forearms be free of punctures and scars indicative of injected drugs of
abuse. We have finalized these provisions, except that we have deleted
the reference to ``pitted skin''.
(Comment 72) One comment recommended that FDA not include the term
``pitted skin'' from the final rule. The comment stated frequent
plasmapheresis donors would be expected to have pitted areas of their
skin due to the needle punctures for their donations as frequently as
twice per week. The comments asserted that a close examination for
pitted skin could lead to deferral of committed donors.
(Response) We agree with the comment that frequent donors often
have pitted areas of their skin due to needle punctures. Therefore, we
do not include the term pitted skin in Sec. 630.10(f)(6) of the final
rule, and require only that the donor's arms must be free of infection,
inflammation, and lesions. We note that pitted skin may be more
difficult to decontaminate, which may affect the choice of the
phlebotomy site.
7. Section 630.10(g)
a. Proof of identity and postal address (Sec. 630.10(g)(1)).
We proposed in Sec. 630.10(i)(1) that collection establishments
obtain, before donation, proof of the donor's identity and a mailing
address where the donor may be contacted for 8 weeks following
donation. Establishments are currently required to maintain a record of
this address in the donor record as required under Sec.
606.160(b)(1)(x) (redesignated in this rule as Sec.
606.160(b)(1)(ix)). Establishments may use this information to contact
the donor to communicate regarding test results for evidence of
infection, as required under Sec. 630.40. We are finalizing this
provision as proposed, except that the final rule specifies that the
donor's mailing address must be a postal address.
(Comment 73) One comment suggested that the donor's name and last
four digits of their Social Security Number (United States) or Social
Insurance Number (Canada), with proof of an address, would be adequate
proof of a donor's identification. Another comment stated that it is
not always possible to obtain photographic identification, stating that
members of certain groups are reluctant to have their photographs
taken. The comment stated that FDA should allow for other means of
identifying the donor.
(Response) We have finalized the rule to require that blood
establishments obtain proof of identity of the donor prior to donation.
However, we have not specified the means of establishing proof. We
believe that photographic identification, a valid driver's license,
validated biometric means, or other means can be useful in establishing
the donor's identity. Establishments must include procedures for
establishing donor identity in their standard operating procedures
under Sec. 606.100(b). We also note that, while this provision
establishes a requirement for Whole Blood donors, Sec. 640.65(b)(3)
has long required Source Plasma establishment to have a donor
identification system in place. For Source Plasma establishments, Sec.
630.10(g)(1) does not add new requirements.
(Comment 74) We received several comments objecting to the
requirement to obtain an address where the donor may be contacted for 8
weeks after donation. One comment stated that this provision would have
an impact on blood collection on college campuses due to the movement
of college students to other addresses for the summer. One comment
referenced information from the United States Postal Service,
indicating that most individuals who move do leave a forwarding
address. The comment suggested that donors can be contacted through
this mechanism. The comment further suggested that newer communication
technologies such as email and cell phones can be used for notification
purposes when necessary.
(Response) We have finalized the rule to require that blood
establishments obtain a postal address where the donor may be contacted
for 8 weeks after donation. This provision supports effective
communication on issues that may be important to the donor and his or
her contacts. We recognize that, when the donors are found ineligible
prior to collection, they are deferred and notified of the reasons for
their deferral at the blood center. However, communication with the
donor becomes necessary after donation due to reactive or positive test
results obtained on the donation. We believe that most establishments
invite the donor back to the donor center to inform the donor of
reactive or positive infectious disease test results on the donation.
We do not believe that the provision improperly burdens blood
establishments because of college students and other mobile
populations. Student donors would provide the postal address where they
expect to be in residence if they plan to leave school during the 8
weeks
[[Page 29870]]
following donation. We recognize that other means of contact, such as
email or telephone, may permit more rapid communication. Establishments
may also request an email address or telephone number, although the
rule does not require establishments to collect this information. If
the donor has been successfully contacted by other means, then we do
not require that contact be made using the postal service.
b. Donor acknowledgement (Sec. 630.10(g)(2)).
In proposed Sec. 630.10(i)(2), we proposed to require
establishments to provide the donor with a written statement of
understanding to be read and signed by the donor. The establishment
would be required to use procedures to assure that the donor
understands the material provided in the statement, which must not
include language that would waive any of the donor's legal rights and
must address seven elements: (1) The donor statement that he or she has
reviewed the educational material required by Sec. 630.10(b); (2) the
donor's agreement not to donate if the donation could put the blood
supply at risk; (3) testing of the donor's blood; (4) additional
testing of the donor's blood if initial tests are reactive; (5) the
consequences if the donation is determined not to be suitable, or if
the donor is ineligible; (6) the risks and hazards of the specific
donation procedure or of immunization, if applicable; and (7) the
donor's opportunity to ask questions and withdraw consent at any time.
We have modified the provision after considering comments received
to the proposed rule and the recommendations made from the Blood
Products Advisory Committee at the April 28-29, 2011, meeting (Ref.
52). For clarity, we now call this ``Donor's acknowledgement,'' instead
of the proposed ``Donor's written statement of understanding.'' The
statement does not have to be in a written form only, although it must
provide for a signature or other documented acknowledgement.
In proposed Sec. 630.10(i)(2)(iv), we proposed to require that the
donor be informed that a blood sample will be tested for specified
relevant transfusion-transmitted infections and that the further
testing might be required for reactive donations. Although we are
finalizing the requirement that the donor be informed of infectious
disease testing, following the recommendation of the Blood Products
Advisory Committee at the April 2011 meeting (Ref. 52), we are not
finalizing a requirement that the donor acknowledge that infectious
disease testing may include additional testing of reactive samples
(proposed Sec. 630.10(i)(2)(iv)). We are not including this detailed
requirement in the final rule, and are finalizing 6 out of the 7
proposed requirements.
We have also clarified the requirement that the donor be informed
of the risks and hazards of the donation procedure. We now require in
Sec. 630.10(g)(2)(ii)(E) that the donor acknowledgement include
acknowledgment that the donor has been provided and reviewed
information regarding the risks and hazards of the specific donation
procedure that the donor will undergo. This is required for every
donation of blood and blood components, including Source Plasma and
other donations by apheresis. We are finalizing this section with the
additional modifications discussed in our responses to comments.
(Comment 75) One comment questioned the use of the term
``understanding'' as used in ``written statement of understanding'' in
proposed Sec. 630.10(i)(2).
(Response) We have revised the provision to require that the donor
acknowledge that the donor has read the material provided. Accordingly,
we now designate this as ``Donor's acknowledgement''.
(Comment 76) We were also asked how this section relates to other
sections of the existing Source Plasma regulations on informed consent.
(Response) For collections of plasma and platelets for apheresis,
Sec. Sec. 630.15(b) and 640.21(g) require establishments to engage the
donor at least annually in an informed consent dialogue. See discussion
in comments 86 and 117. The requirement to obtain a donor
acknowledgement applies to every collection of blood and blood
components, including apheresis collections of plasma and platelets.
The donor's acknowledgement must be obtained at each donation.
(Comment 77) Several comments objected to a requirement that the
donor ``sign'' a statement and urged FDA to allow an electronic
signature.
(Response) We agree that this requirement can be satisfied by an
electronic signature. Final Sec. 630.10(g)(2)(i) requires that the
donor's acknowledgement be provided by signature or other documented
acknowledgement.
8. Section 630.10(h)
We have added Sec. 630.10(h) to make explicit a requirement in the
proposed regulation. Section 630.10(h) provides that a blood
establishment must not collect from a donor found, before collection,
to be ineligible, unless an exception exists. In addition, we
incorporated existing requirements to defer donors found to be
ineligible and to notify the donors of their deferral as required in
Sec. 630.40(a).
K. Donor Eligibility Requirements Specific to Whole Blood, Red Blood
Cells and Plasma Collected by Apheresis (Sec. 630.15)
Section 630.15(a) establishes donor eligibility requirements for
the collection of Whole Blood and Red Blood Cells collected by
apheresis, and Sec. 630.15(b) establishes donor eligibility
requirements for collections of Source Plasma and plasma collected by
plasmapheresis. These requirements are in addition to those in Sec.
630.10.
For donors of Whole Blood and Red Blood Cells collected by
apheresis, this rule requires that donation frequency be consistent
with protecting the donor's health, describes minimum intervals between
donations, and addresses donations by donors undergoing therapeutic
phlebotomy. We have added references to Red Blood Cells collected by
apheresis to the heading and at several points in this section to
clarify the applicability of Sec. 630.15(a) to Red Blood Cells
collected by apheresis.
For donors of Source Plasma and plasma collected by plasmapheresis,
the rule requires the responsible physician, subject to Sec. 630.5(c),
to conduct an appropriate medical history and physical examination of
the donor. Additionally, blood establishments are required to weigh the
donor before each plasmapheresis procedure and to assess the donor's
total protein level prior to each donation. This provision includes a
requirement in Sec. 630.15(b)(1)(ii) to defer a plasmapheresis donor
found to have a medical condition that would place the donor at risk
from plasmapheresis, and to defer a donor because of red blood cell
loss as described in the rule. This section also contains informed
consent requirements for donors of Source Plasma and plasma collected
by plasmapheresis. These provisions complement other requirements for
the collection of plasma by plasmapheresis in part 640 and part 630,
including restrictions on frequency of collection as specified in
Sec. Sec. 640.32 and 640.65. In addition Sec. 630.15(b)(1) cross-
references certain exceptions provided for plasmapheresis collections
from infrequent plasma donors in Sec. 630.25.
1. Section 630.15(a)
Consistent with the proposed rule, final Sec. 630.15(a)(1)
requires that for a
[[Page 29871]]
collection resulting in a single unit of Whole Blood or Red Blood Cells
collected by apheresis, the donation frequency must be no more than
once in 8 weeks. For an apheresis collection resulting in two units of
Red Blood Cells, the donor must not donate more than once in 16 weeks.
These limitations on donation frequency reflect long standing donation
interval practices established to protect the donor from potential
health risks associated with frequent donations of Whole Blood or Red
Blood Cells. The purpose of these provisions is to protect the health
of the donor and allow time for red blood cell recovery. In Sec.
630.15(a)(1)(ii), we provide two exceptions to the donation interval:
(1) The donation is for autologous use as prescribed by the donor's
physician and the responsible physician determines and documents that
the donation may proceed or (2) the donation is a dedicated donation
based on the intended recipient's documented exceptional medical need
and the responsible physician determines and documents that the health
of the donor would not be adversely affected by donating. In the final
rule, we added the term ``exceptional'' to clarify that this exception
to donation frequency should apply only in those rare situations where
the recipient's need for a component from a donor with particular
characteristics is exceptional. For example, it may be appropriate to
rely on this exception in the event that a recipient needs a blood
component that is negative for a rare blood cell antigen. Under this
exceptional medical need provision, the responsible physician must
examine the donor and determine and document that the health of the
donor would not be adversely affected by donating. Under Sec.
630.5(b)(1)(i), the responsible physician is not authorized to delegate
the examination of the donor or the determination that the health of
the donor would not be adversely affected by donating.
For clarity, the requirements regarding therapeutic phlebotomy have
been consolidated in the final rule in Sec. 630.15(a)(2).
(Comment 78) One comment stated that the applicability of proposed
Sec. 630.15 to Red Blood Cells collected by apheresis was unclear. The
comment stated that ``double unit collection programs,'' often have
additional and different donor eligibility requirements, as described
in proposed Sec. 630.15(a)(1).
(Response) Final Sec. 630.15(a) now more expressly includes Red
Blood Cells collected by apheresis. Final Sec. 630.15(a)(1)
establishes minimum time intervals between collections of Whole Blood,
and single and double units of Red Blood Cells by apheresis. These time
intervals are consistent with existing regulations and guidance. This
addition makes explicit what was less directly stated in the proposed
rule. Proposed Sec. 630.15(a)(1) referred to ``double unit collection
programs,'' which are double Red Blood Cell collections by apheresis.
Moreover, proposed Sec. 640.12 required establishments to determine
the eligibility of donors of Red Blood Cells in accordance with
Sec. Sec. 630.10 and 630.15.
(Comment 79) One comment stated that FDA should not specify 8 and
16 week donation intervals. Instead, the comment recommended that a
blood establishment determine donation frequency without reference to a
specific donation interval, taking into account the donor history, the
results of a limited physical examination, the participation of a
medical director or his or her designee, and the blood center's
procedures. Another comment recommended that a physician be allowed to
authorize more frequent collection by certifying that the prospective
donor has recovered from the prior donation without evidence of
residual effects or to allow the physician to simply certify that the
prospective donor meets his/her requirements for a repeat donation on
the day of the examination.
(Response) FDA regulations have long specified a minimum interval
of 8 weeks between Whole Blood donations, unless a physician examines
the donor and certifies the donor to be in good health. FDA is
finalizing minimum donation intervals in this rule to protect the
health of donors of Whole Blood and Red Blood Cells collected by
apheresis because too frequent donation may adversely affect a donor's
health (Refs. 47, 48). In the final rule at Sec. 630.15(a)(1), we are
retaining a minimum requirement for an 8 week interval between the
donation of a unit of Whole Blood or donation of a single unit of Red
Blood Cells by apheresis, and requiring a 16 week interval after a
double collection of Red Blood Cells. A 16 week interval following a
double collection of Red Blood Cells is recommended in current FDA
guidance (Ref. 53). Blood establishments are free to establish longer
donation intervals.
We have provided a limited exception to these donation intervals to
allow for more frequent collections for: (1) An autologous donation as
prescribed by the donor's physician only when the donor has been
examined by the responsible physician who determines and documents that
the donation may proceed and (2) a dedicated donation based on the
intended recipient's documented exceptional medical need, only when the
responsible physician examines the donor and determines and documents
that the health of the donor would not be adversely affected by
donating.
(Comment 80) Several comments requested that we clarify in the
final rule that donors with hereditary hemochromatosis can donate more
frequently than the 8 week interval set forth in proposed Sec.
630.15(a)(1) and also to clarify that more frequent donations from such
donors may be collected more frequently without an exception or
alternative under Sec. 640.120.
(Response) Final Sec. 630.15(a)(2) states clearly that a donation
may be collected from a donor more frequently than once in 8 weeks for
collections resulting in a single unit of Whole Blood or Red Blood
Cells, or 16 weeks for apheresis collections resulting in a double
collection of Red Blood Cells, when the donor is determined to be
eligible under Sec. 630.10 and the collection is a physician-ordered
therapeutic phlebotomy of a donor, including a donor with hereditary
hemochromatosis. Establishments do not need an exception or alternative
under Sec. 640.120 to make a collection under this provision if the
requirements set forth in Sec. 630.15(a)(2) are met.
(Comment 81) One comment recommended that the term ``iron
overload'' should be substituted for the term ``hereditary
hemochromatosis'' in the provision providing an exception to the
requirement to label a collection with the disease state of a donor
undergoing therapeutic phlebotomy.
(Response) We decline to substitute the term ``iron overload'' for
the term ``hereditary hemochromatosis'' in final Sec. 630.15(a)(2).
The term, ``iron overload'' describes imprecisely the donors for whom
establishments would perform phlebotomies without charge. However, we
agree with the comment that this provision may, at some time in the
future, appropriately be applied to collections from donors whose
therapeutic phlebotomy is necessitated by a disease or condition other
than hereditary hemochromatosis. Accordingly, final Sec. 630.15(a)(2)
provides that no labeling for the disease or condition is required if:
(i) The donor meets all eligibility criteria; (ii) the donor undergoes
a therapeutic phlebotomy as prescribed by a licensed health care
provider treating the donor for (A) hereditary hemochromatosis; or (B)
another disease or condition, when the health of a donor with that
disease or condition will not be adversely
[[Page 29872]]
affected by donating, the donor's disease or condition will not
adversely affect the safety, purity, and potency of the blood and blood
components collected, or any products manufactured from them, and the
collection is in accordance with a procedure that has been found
acceptable for this purpose by FDA; and (iii) the establishment
performs without charge therapeutic phlebotomies for all individuals
with that disease or condition. Labeling to identify the disease state
or condition that necessitated the therapeutic phlebotomy is still
required when these criteria are not met.
(Comment 82) Another comment suggested that the final rule should
not require a physical examination by a responsible physician at the
time of donation for individuals presenting a prescription for
therapeutic phlebotomy for medical reasons. The comment observed that
the 2001 guidance document entitled, ``Guidance for Industry: Variances
for Blood Collection from Individuals with Hereditary
Hemochromatosis,'' (Ref. 54) did not provide for such a physical
examination for exceptions or alternatives granted in accordance with
that guidance document.
(Response) We agree with this suggestion. The final rule does not
require that an individual undergoing a prescribed therapeutic
phlebotomy to promote the donor's health be examined by a responsible
physician at the time of donation. The physical assessment required for
all donors under Sec. 630.10(f) still applies, however.
(Comment 83) One comment supported the proposal that disease
labeling would not be required for blood and blood components donated
by an individual with hereditary hemochromatosis if the donor meets all
eligibility criteria and the collecting establishment performs
therapeutic phlebotomies without charge for all individuals with
hereditary hemochromatosis, including those who need therapeutic
phlebotomy but do not wish or are not eligible to donate. However, the
comment recommended that the final rule authorize blood establishments
to accept grants and gifts from third parties, including partial
insurance coverage, related to the costs of phlebotomy.
(Response) The final rule provides that blood establishments do not
have to label donations from a donor with hereditary hemochromatosis
with the donor's disease state if the donor is eligible and the
establishment does not charge anyone with hereditary hemochromatosis
(or another disease or condition, if the conditions in the regulation
are met) for therapeutic phlebotomy. This provision is intended to
remove the incentive for an individual with hereditary hemochromatosis
to provide untruthful answers to donor eligibility questions for a
blood donation in order to receive the benefit of a phlebotomy without
charge. If a blood establishment charged a fee for an ineligible donor
to undergo a therapeutic phlebotomy, but not for an eligible donor with
hereditary hemochromatosis, the ineligible hereditary hemochromatosis
donor would have an incentive to deny risk conditions that might
preclude cost-free donation (Ref. 55). This policy is in part based on
recommendations of the Advisory Committee on Blood Safety and
Availability (Ref. 56). We decline to modify this provision to address
the acceptance of grants, gifts, or insurance payments. We note that we
did not propose such a provision, and we believe that a reference to
grants, gifts, or insurance payments could confuse patients seeking a
therapeutic phlebotomy.
(Comment 84) One comment suggested that hospitals that transfuse
suitable blood and blood components labeled with the donor's iron
overload disease state should include a statement to that effect in
their informed consent for transfusion.
(Response) This rule does not address the content of hospital
discussions related to informed consent for transfusion. Final Sec.
630.15(a)(2) authorizes blood establishments to collect blood and blood
components only from donors, including donors with hereditary
hemochromatosis, determined to be eligible. Blood from hereditary
hemochromatosis donors has been used for transfusion in other countries
without reports of adverse events in recipients (Refs. 57, 58, 59).
1. Section 630.15(b)
We revised proposed Sec. 630.15(b)(1), formerly entitled
``Physical examination and informed consent,'' by dividing it into two
sections. This clarifies that separate requirements apply for the
medical history and physical examination (final Sec. 630.15(b)(1)) and
for obtaining informed consent (final Sec. 630.15(b)(2)). As a result,
proposed Sec. 630.15(b)(2) through (b)(7) are finalized as Sec.
630.15(b)(3) through (b)(8).
a. Medical history and physical examination (Sec. 630.15(b)(1)).
This section, titled ``Physical examination and informed consent''
in the proposed rule, is now titled ``Medical history and physical
examination.'' Informed consent requirements are now addressed in Sec.
630.15(b)(2). The new heading more accurately describes the assessment
required under this section. As proposed, we would have required the
responsible physician to examine the donor for medical conditions that
would place the donor at risk during plasmapheresis. We intended for
this physical examination to include conducting an appropriate medical
history and physical examination to identify medical conditions that
may place the donor at risk from plasmapheresis.
(Comment 85) One comment stated that FDA should not require a
responsible physician to examine the donor before the initial donation
and at least annually thereafter. The comment asserted that
plasmapheresis collection has been in place for years without risk to
donors. The comment also stated that an annual and initial exam is
unnecessary for infrequent plasma donors and donors not participating
in immunization programs.
(Response) Examination by a qualified licensed physician is already
required under current Sec. 640.63(b) for all Source Plasma donors,
and we believe that the requirement to conduct a medical history and
physical examination before the first donation, and at least annually
thereafter, contributes to the safety record of these collections. We
have modified this requirement by authorizing the responsible physician
in Sec. 630.5(c)(3) to delegate this activity to a physician
substitute, as defined in Sec. 630.3(g). During the annual physical,
donors may be examined for a variety of conditions, such as heart
disease, seizures, trouble breathing, allergies, recent medical
operations, or medications, in order to ensure that donating will not
adversely affect the health of the donor. Such evaluations would
include a physical examination and medical history which might identify
medications or underlying medical conditions that would lead to donor
deferral. Because frequent donation by plasmapheresis of plasma for
transfusion raises similar donor safety concerns, this requirement now
applies to collections from frequent plasmapheresis donors, and not
only to Source Plasma donors.
However, we agree with the comment that an annual and initial
examination is unnecessary for an infrequent plasma donor, as defined
in Sec. 630.3(e). Final Sec. 630.25 provides certain exceptions from
donor eligibility requirements for infrequent plasma donors, including
the requirement for an enhanced medical history and physical
examination under Sec. 630.15. These donors remain subject to
[[Page 29873]]
the requirements for medical history and physical assessment under
Sec. 630.10.
b. What requirements apply to obtaining informed consent? (Sec.
630.15(b)(2)).
(Comment 86) Several comments stated that for plasmapheresis
donors, the distinction between the written statement of understanding
and informed consent should be clarified.
(Response) We have clarified that the written statement of
understanding, renamed and revised as the donor's acknowledgement in
final Sec. 630.10(g)(2), applies to the collection of all blood and
blood components, including Source Plasma and plasmapheresis
collections. Informed consent for Source Plasma donation has long been
required under current Sec. 640.61, and this rule continues those
requirements for Source Plasma and plasmapheresis collections. In
recognition that the donation of Source Plasma and plasma by
plasmapheresis may present additional and potentially greater risks to
the donors, Sec. 630.15(b)(2) requires the responsible physician to
obtain the informed consent of such a donor on the first day of
donation or no more than 1 week before the first donation. Section
630.5 addresses the authority of the responsible physician to delegate
this task. The responsible physician must explain the risks and hazards
of the procedure to the donor. The explanation must be made in such a
manner that the donor may ask questions of the responsible physician.
The explanation must also give the donor a clear opportunity to refuse
the procedure. This informed consent process involves a dialogue
between the donor and the responsible physician. The establishment must
obtain informed consent from these donors at least once every year. If
a donor does not return for 6 months, the establishment must obtain
informed consent again. If new risks and hazards are identified, or if
the donor is enrolled in a new program such as an immunization or
special collection program, then a new informed consent, addressing the
specific risks and hazards of that program, must be obtained. The
informed consent requirements in Sec. 630.15(b)(2) are in addition to
the donor acknowledgement, which under Sec. 630.10(g)(2), must be
obtained from the donor at each donation.
c. Weight (Sec. 630.15(b)(3)).
Section 630.15(b)(2) of the proposed rule would have required that
establishments determine a donor's weight at each donation of plasma by
plasmapheresis. We received several comments regarding this provision,
which we address in this rule, and are finalizing this provision in
Sec. 630.15(b)(3) as proposed.
(Comment 87) Two comments asserted that weighing a donor at each
donation is not useful. One comment further stated that donors are not
weighed prior to plateletpheresis procedures, and there is no evidence
that asking the donor to state their weight, as opposed to weighing
donors, has been unsafe. The comment further asserted that it would not
make sense to require a donor to be weighed prior to a co-collection of
plasma and platelets by apheresis as donors are currently not weighed
prior to triple plateletpheresis procedures, and there have been no
adverse events.
(Response) We are finalizing this provision as proposed, and
require establishments to weigh a donor before collecting plasma by
plasmapheresis. A current weight measurement permits the collecting
establishment to calculate accurately the plasma volumes to be
collected based on a weight specific nomogram. The need for accurate
measurement applies to all collections by plasmapheresis, whether
Source Plasma, or frequent or infrequent plasmapheresis collection. We
have not included a requirement to weigh plateletpheresis donors. The
instructions for use for the apheresis devices used for such
collections vary concerning whether they require the user to weigh the
donor. Instead, establishments would address donor weight in their
standard operating procedures for plateletpheresis collection in a
manner that is consistent with the instructions for use (operator's
manual) for the apheresis devices used by the establishment to collect
platelets.
When there is a co-collection including plasma by apheresis, this
provision requires the establishment to weigh the donor because the
collection of plasma by apheresis will be based on the donor's weight.
In addition, the instruction for use, including the operator's manual
of the device used to collect platelets by apheresis, may include an
instruction to determine the donor's weight for co-collections with
plasma.
(Comment 88) One comment also recommended that in addition to
weighing donors at Source Plasma establishments, the donor's height be
taken once a year. The comment suggested that conversion of the
measurement of height and weight to lean body mass should be the basis
for the quantity of plasma removed.
(Response) Measuring the donor's height combined with measuring a
donor's weight may be useful in identifying and using a more accurate
nomogram to determine the maximum quantity of plasma that should be
collected from the donor by plasmapheresis. However, we believe donors
are able to accurately report their height, which is less likely to
fluctuate over time than their weight. Therefore, Sec. 630.15(b)(3)
requires establishments to weigh each donor prior to each donation,
while permitting reliance on a donor's self-reported height when needed
to determine an accurate nomogram for the maximum quantity of plasma
that should be collected. We note that under current Sec. 606.65(e)
establishments must follow the device instructions for use and
operators manual of the apheresis collection device.
d. Total protein level (Sec. 630.15(b)(4)).
We are finalizing the requirement for collection establishments to
test the donor's blood sample for total plasma protein, and that the
donor have a value of no less than 6.0 grams per deciliter and no more
than 9.0 grams per deciliter. Consistent with current Sec.
640.63(c)(5) and proposed Sec. 630.15(b)(4), this section requires
establishments to continue the practice of assessing protein levels
before each plasmapheresis procedure. In addition, we are maintaining
the existing requirement in current Sec. 640.65(b)(1)(i), which
requires establishments to assess a Source Plasma donor's total protein
levels, and to perform a plasma or serum protein electrophoresis or
quantitative immuno-diffusion test or an equivalent test to determine
immunoglobulin composition of the plasma or serum, on the day of the
first medical examination or plasmapheresis, and at least every 4
months thereafter. Final Sec. 640.65(b)(2)(i) requires the responsible
physician to review the accumulated laboratory data, including any
tracings of the plasma or serum protein electrophoresis pattern, the
calculated values of the protein composition of each component, and the
collection records within 14 calendar days after the sample is drawn to
determine whether or not the donor should be deferred from further
donation. Comments on Sec. 640.65(b)(2)(i) are discussed at comment
118.
(Comment 89) Several comments questioned the validity of the
proposal to require 9.0 grams protein per deciliter value for the upper
limit for total plasma protein. One comment stated the requirement for
total protein should specify that the donor's total plasma or serum
protein must have a value of no less than 6.0 grams per deciliter and
that the acceptable upper limit may be established based on applicable
[[Page 29874]]
statistical analysis of test results on their donors.
(Response) After further consideration, we are finalizing these
limits largely as proposed. We consider the lower limit, no less than
6.0 grams protein per deciliter, and the total upper limit of 9.0 grams
protein per deciliter in a plasma or serum sample, as appropriate
measurement parameters to ensure the donor's health. We have determined
that the reference ranges for testing protein in serum and plasma are
comparable (Ref. 60); the final rule now applies these lower and upper
limits whether testing is performed on either a plasma or serum sample.
Although the comments questioned the value of an upper limit, we
consider an upper limit to be necessary to ensure donor health, because
high protein levels can be associated with adverse health conditions,
such as plasma cell dyscrasias (Ref. 61).
(Comment 90) Another comment suggested FDA should consider a
flexible regulation to allow for the development of an acceptable
alternative to the current procedures.
(Response) We have not identified a need to provide for a variable
standard in this rule. An establishment that proposes to use a
different standard may submit a request for an exception or alternative
under Sec. 640.120.
e. Examination before immunization (Sec. 630.15(b)(5)).
We have finalized Sec. 630.15(b)(5) to be consistent with proposed
Sec. 630.15(b)(4), but we have revised the language for clarity. This
section requires the responsible physician, subject to Sec. 630.5, to
conduct an appropriate medical history and physical examination of the
donor no more than 1 week before the first immunization injection of a
donor for the production of high-titer antibody plasma. This requires
that the responsible physician conducts an appropriate medical history
and physical examination, as described in Sec. 630.15(b)(1), before
the first immunization. It further provides an opportunity to obtain an
informed consent specific for participation in an immunization program,
as required in Sec. 630.15(b)(2)(iv) (Ref. 62). However, it is not
necessary to repeat the medical history and physical examination
required in Sec. 630.15(b)(1) if the immunized donor's plasma is
collected within 3 weeks of the first immunization injection. Under
Sec. 630.15(b)(5)(ii), establishments are not required to re-examine a
donor before immunizing the donor for the production of high-titer
antibody plasma if the donor is currently participating in a
plasmapheresis collection program and is eligible under Sec. 630.10.
f. Deferral of donors due to red blood cell loss (Sec.
630.15(b)(6)).
For the safety of the donor, we are requiring establishments to
defer donors from donating Source Plasma and plasma collected by
plasmapheresis following red blood cell loss due to a donation of Whole
Blood or Red Blood Cells collected by apheresis. Establishments must
also ensure that the cumulative red blood cell loss resulting from
previous donations does not adversely affect the health of the donor.
Under final Sec. 630.15(b)(6)(i), establishments must defer a
donor from donating plasma by plasmapheresis for 8 weeks following a
donation of Whole Blood or a single unit of Red Blood Cells by
apheresis. However, establishments may collect Plasma by plasmapheresis
48 hours after a donation of Whole Blood or a single unit of Red Blood
Cells, provided the extracorporeal volume of the apheresis collection
device is less than 100 mL (Sec. 630.15(b)(6)(i)). We authorize
collection under these circumstances because the risk of red blood cell
loss in the donor is lower. The limited volume of the extracorporeal
circuit limits the donor's potential red blood cell loss in routine
apheresis collection. In addition, under Sec. 630.15(b)(6)(ii), plasma
donors must be deferred for 16 weeks if the donor donates two units of
Red Blood Cells during a single apheresis procedure. Final Sec.
630.15(b)(6)(iii) requires deferral for 8 weeks or more if the
cumulative red blood cell loss in any 8 week period could adversely
affect donor health.
We have not finalized the provisions in the proposed rule that
would have required deferral after red blood cell loss of equal to or
greater than 200 mL (proposed Sec. 630.15(b)(5)(i) and (b)(5)(iii)).
We recognize that it is difficult to measure the amount of blood lost
in order to determine whether the volume is equal to or greater than
200 mL. Instead, we are finalizing the requirement in Sec.
630.15(b)(6)(iii) to defer the donor if the donor's cumulative red
blood cell loss in any 8 week period could adversely affect donor
health. We have addressed deferral due to red blood cell loss in
guidance (Ref. 63) and intend to issue future guidance on the impact of
the cumulative red blood cell loss following frequent apheresis
procedures.
(Comment 91) One comment noted that FDA's guidance, ``Guidance for
Industry and FDA Review Staff: Collection of Platelets by Automated
Methods,'' which published in December 2007 during the comment period
for the proposed rule, contained recommendations for 16 week deferral
of platelet donors who experienced losses of red blood cells of 300 mL
or more. The comment recommended that 16 week deferrals for larger red
blood cell loss should be included for plasma donors in this final
rule.
(Response) We agree with this comment about the relevance of FDA's
recommendations in ``Guidance for Industry and FDA Review Staff:
Collection of Platelets by Automated Methods,'' hereafter, referred to
as the ``2007 Guidance'' (Ref. 64). Because the risks associated with
red blood cell loss are comparable for donors of plasma and platelets
by apheresis, Sec. 630.15(b)(6)(iii) requires establishments to defer
for 16 weeks plasma donors who donate two units of Red Blood Cells
during a single apheresis procedure.
(Comment 92) Another comment stated that specific deferral periods
are unnecessarily restrictive, and that there should be a provision
similar to that in the proposed rule at Sec. 640.21(e), to the effect
that collection of plasma by apheresis should be permitted following a
donation of Whole Blood or other red cell loss, if the extracorporeal
red blood cell volume for the apheresis device is less than or equal to
100 mL. The comment noted that most of the plasma collected by
apheresis from volunteer blood donors is plasma collected concurrently
with apheresis platelets. The comment stated that since FDA recognizes
that plateletpheresis collection is safe in this circumstance, it does
not make sense to have more restrictive criteria for the collection of
plasma by apheresis during plateletpheresis, as the red blood cell loss
would be the same for these procedures.
(Response) We recognize that a co-collection of Plasma and
Platelets may occur and we agree that the risks associated with red
blood cell loss for collections of Source Plasma and Plasma by
apheresis are similar to those for collections of Platelets by
apheresis. The requirements for deferral of Plasma donors due to red
blood cell loss following Whole Blood or Red Blood Cell donation or
inadvertent red blood cell loss are addressed in this section.
Separately, we are finalizing a corresponding provision for the
deferral of Platelet donors due to Whole Blood or Red Blood Cell
donation or red blood cell loss in Sec. 640.21. We intend for the
deferrals for red blood cell loss to be the same for all collections of
Plasma and Platelets by apheresis, including co-collections, because we
consider the
[[Page 29875]]
risks of red blood cell loss to be the same.
In the final rule, we require the deferral of plasmapheresis donors
following the donation of Whole Blood and Red Blood Cells, and because
of cumulative red blood cell loss over time. Consistent with the final
requirements for Platelets in Sec. 640.21, Sec. 630.15(b)(6)(i)
permits the collection of Source Plasma and Plasma by plasmapheresis 2
days after a donation of Whole Blood or a single unit of Red Blood
Cells, provided the extracorporeal volume of the apheresis collection
device is less than 100 mL.
g. Exceptions to deferral due to red blood cell loss (Sec.
630.15(b)(7)).
Final Sec. 630.15(b)(7) provides an exception to deferral due to
red blood cell loss for certain Source Plasma donors. While the
introductory paragraph of proposed Sec. 630.15(b)(6) referred to
participation in a plasmapheresis program instead of to Source Plasma
collections, we finalized this exception using the more explicit term
``Source Plasma.'' In proposed Sec. 630.15(b)(6)(i), the responsible
physician would have been required to conduct an examination and
``certify'' the donor's good health; final Sec. 630.15(b)(7)(i)
requires that the responsible physician examine the donor at the time
of the current donation and determine and document that the donor is in
good health and the donor's health permits the plasmapheresis. Under
Sec. 630.5(c)(1)(i)(A), the responsible physician is not authorized to
delegate this examination and determination. In proposed Sec.
630.15(b)(6)(ii), this exception would apply when the ``donor possesses
an antibody that is transitory, of a highly unusual or infrequent
specificity, or of an unusually high titer.'' In final Sec.
630.15(b)(7)(ii), the exception is reserved for donors whose plasma
possesses a property such as an antibody, antigen, or protein
deficiency, that is transitory, of a highly unusual or infrequent
specificity, or of an unusually high titer. This reference to the
donor's plasma, instead of the narrower reference to an ``antibody'' in
the plasma is repeated in final Sec. 630.15(b)(7)(iii), which requires
the establishment to document the special characteristics of the
donor's plasma and the need for plasmapheresis of that donor. We
altered this provision to refer more generally to the unusual
characteristics of the plasma, rather than to a specific antibody,
because we recognized that this exception should be available under
appropriate circumstances where the donor's plasma has other unusual
characteristics, such as a rare antigen. As additional protection
against additional red blood cell loss in a collection under this
provision, final Sec. 630.15(b)(7)(iv) provides that the
extracorporeal volume of the apheresis device used to collect plasma
under this provision must be less than 100 mL. We note that donors who
donate subject to this exception must be advised of the risks and
hazards related to this donation under Sec. Sec. 630.10(g)(2) and
630.15(b)(2), or under Sec. 630.15(b)(2)(iv), if the donor is newly
enrolled in the program.
(Comment 93) One comment asserted that the statement in the
proposed rule at Sec. 630.15(b)(6)(ii), ``the donor possesses an
antibody that is transitory. . .'' requires modification. The comment
stated that the usual antibody characterized this way would be anti-Jka
or -Jkb. The comment continued that it would be difficult to determine
whether the plasma was collected from someone who has an antibody that
is transitory before it is collected. The comment recommended the
language be changed to state, ``donor's plasma contains an antibody. .
.''
(Response) We are retaining the word ``transitory'' in final Sec.
630.15(b)(7), although it now refers to a transitory property in the
donor's plasma, rather than specifically to a transitory antibody. This
provision is meant to apply to collections of plasma from individuals
with specific transitory properties. These provisions apply only when
an establishment knows that the donor's plasma has a particular
property that is transitory.
h. Malaria (Sec. 630.15(b)(8)).
Consistent with proposed Sec. 630.15(b)(7), final Sec.
630.15(b)(8) does not require Source Plasma donors to be free from risk
of malaria (for example, based on residence in or travel history to a
malaria endemic area). We do not require establishments to screen
Source Plasma donors for malaria risk factors because Source Plasma
undergoes further manufacturing steps to effectively remove or
inactivate pathogens such as the malaria parasite, and licensed plasma
derivatives manufactured from Source Plasma have not transmitted
malaria.
(Comment 94) Several comments agreed with our proposal to not
require freedom from malaria risk for Source Plasma donors.
(Response) We are finalizing this provision as proposed.
(Comment 95) In response to our request for comments with
supporting data concerning whether this provision should be expanded to
donors of plasma for transfusion (72 FR 63416 at 63429), one comment
supported not requiring an assessment of malaria risk, but did not
provide supporting data. The comment stated that there is very low
residual red blood cell contamination in a plasmapheresis product, and
that the thawing process renders the malaria parasite non-viable. The
comment also cited the lack of historical malaria transmission from
Fresh Frozen Plasma.
(Response) The malaria parasite resides in red blood cells, and we
recognize most red blood cells are removed from plasma collected by
apheresis. There are limited data on the viability of malaria parasites
in plasma and the residual red blood cells contained in plasma.
However, plasma intended for transfusion, unlike Source Plasma used to
manufacture plasma derivatives, does not undergo further manufacturing
steps to remove or inactivate pathogens. Absent data demonstrating that
the risk of transfusion-transmitted malaria is eliminated with plasma
products intended for transfusions as well as a licensed test for
malaria, we require that all donors, except Source Plasma donors, be
assessed for risk of malaria.
(Comment 96) Two comments responded to our request for comments
concerning whether Source Plasma donors should be screened for other
parasitic diseases. The comments recommended that Source Plasma donors
not be screened for other parasitic diseases, since, due to the nature
of Source Plasma donation and the manufacturing process, these have no
impact on product quality or safety. One comment urged FDA to
distinguish between plasma collected for transfusion and plasma
collected for further manufacture, and consider the intended final use
of the products. The comment recommended that donors should not be
screened for any pathogen that can be removed by filtration.
(Response) We are not including in this final rule a specific
exemption for assessing Source Plasma donors for risk of all parasitic
diseases; nor are we eliminating donor screening for pathogens that can
potentially be removed by filtration or other manufacturing methods.
Insufficient data were submitted in support of these proposals. We
intend to address recommendations for donor screening and testing for
specific new diseases identified as relevant transfusion-transmitted
infections on a case by case basis. We recently chose not to recommend
screening or testing of Source Plasma donors for Chagas disease,
another parasitic infection (Ref. 24). We intend to continue such
[[Page 29876]]
individual assessments and issue appropriate recommendations in the
future.
L. Exceptions for Certain Ineligible Donors (Sec. 630.20)
Section 630.20 permits, under certain circumstances, the collection
of blood and blood components from individuals who do not meet one or
more of the eligibility requirements under Sec. Sec. 630.10 or 630.15,
or are deferred under Sec. 610.41. In finalizing this provision, we
made several changes. In the first sentence, we make clear a
requirement that was implicit in the proposed rule: That collection
authorized under this provision may proceed only after the
establishment performs the required donor assessments and determines a
donor to be ineligible under any provision of Sec. Sec. 630.10(e) and
(f) or 630.15(a). We have not included the reference to donors deferred
under Sec. 610.41 because of a reactive screening test for a relevant
transfusion-transmitted infection in final Sec. 630.20. We determined
that the provision was unnecessary to include here because Sec. Sec.
610.40(h)(2)(i) and 610.41(a)(5) already authorize autologous
collections from reactive donors, and Sec. Sec. 610.40(h)(2)(ii) and
610.41(a)(2) and (3) authorize plasmapheresis collections under a
special collection program. For a collection from a reactive donor
outside these provisions, a blood establishment would first file a
request under Sec. 640.120. We expect that such requests would occur
only in extraordinary medical circumstances. We also reorganized the
section and clarified the responsible physician's role and
responsibilities for all collections authorized under Sec. 630.20.
Final Sec. 630.20(a) permits establishments to collect from
certain ineligible donors donating only for autologous use, as
prescribed by the donor's physician. Autologous donors have long been
permitted to donate blood for their own use even though they do not
meet eligibility criteria, including a reactive result on a donor
screening test. This section provides additional protections for an
ineligible, autologous donor who may not be in good health: The donor
must have a hemoglobin level no less than 11.0 grams of hemoglobin per
deciliter of blood or a hematocrit value no less than 33 percent, and
the responsible physician must determine and document before the
collection that the health of the donor permits the collection. Under
Sec. 630.5(b)(1)(ii), the responsible physician must not delegate the
determination of the donor's health. Note that Sec. 630.20(c)(1) of
the proposed rule stated that this exception would be available when
``[t]he donation is for autologous use . . . and is not for allogeneic
transfusion or for further manufacturing use.'' Final Sec. 630.20(a)
defines the scope of this exception in fewer words that are intended to
have the same meaning, ``The donation is for autologous use only''
(emphasis added).
Also consistent with the proposed rule, final Sec. 630.20(b)
permits the collection of plasma from donors participating in an
approved Source Plasma program to collect plasma for further
manufacturing use into in vitro products for which there are no
alternative sources. One example of such products is plasma collected
from donors with relevant transfusion-transmitted infection(s) or other
diseases; the plasma may be used to develop positive controls for
infectious disease test kits. The collection must take place under the
medical oversight specified in the approved plasmapheresis program, and
for each collection the donor must meet the criteria in Sec.
630.10(f)(1) through (6) and the responsible physician must determine
and document that the donor's health permits the collection procedure.
Under Sec. 630.5(c)(1)(i)(A)(2), the responsible physician must not
delegate the determination that the donor's health permits the
collection procedure.
Final Sec. 630.20(c) provides an exception when the donation is
restricted for use solely by a specific transfusion recipient based on
documented exceptional medical need, and the responsible physician
determines and documents that the donor's health permits the collection
procedure, and that the donation presents no undue risk to the
transfusion recipient. This is similar to proposed Sec. 630.20(c)(3),
but we have clarified that this applies to the collection of blood
components for transfusion (not further manufacturing use), and that
the medical need of the transfusion recipient must be exceptional.
Consistent with final Sec. 630.15(a)(1)(ii)(B), we added the term
``exceptional'' to clarify that this exception to donor eligibility
should apply only in those rare situations where the recipient's need
for a component from a donor with particular characteristics is
exceptional.
(Comment 97) Two comments recommended that the language throughout
this section refer to ``responsible physician or physician substitute''
instead of to ``responsible physician.''
(Response) We decline to add the extra words requested here.
Section 630.5 addresses the activities which the responsible physician
may delegate.
(Comment 98) Two comments asserted that it was unnecessary and
burdensome to require the responsible physician to examine and certify
the good health of an autologous donor before allowing a collection
under this exception. The comments noted that autologous donors are
under the care of their personal physicians, and these collections take
place pursuant to prescription or physician's order. Autologous donors
may wish to donate at facilities geographically distant from the
facility where the blood establishment's responsible physician is
located. The comments stated that the rule should therefore not require
examination by the responsible physician. Some comments also criticized
the proposed requirements that the responsible physician examine the
donor and certify in writing that the donor's health permits the
collection procedure for special collection programs and directed
donations.
(Response) We have revised proposed Sec. 630.20. For collections
under these exceptions, the final rule requires that the responsible
physician determine and document that the donor's health permits the
collection procedure, and additionally for directed donations under
Sec. 630.20(c), that the donation presents no undue medical risk to
the transfusion recipient. We note that this determination will be made
after the applicable donor eligibility assessments required under Sec.
630.10 and Sec. 630.15 are performed. The responsible physician can
make these determinations based on information developed during the
donor eligibility assessments, rather than during an additional
examination of the donor, and, consistent with Sec. 630.5(b)(1)(i)(B)
through (b)(1)(i)(C) and (c)(1)(i)(A)(2) through (c)(1)(i)(A)(3), can
make this determination from another geographic location. The
responsible physician's determination must be documented. In accordance
with Sec. 606.100, blood establishments must have written standard
operating procedures for collections under these provisions.
We also note that establishments must have prior written approval
from the Director, CBER for special collections under Sec. 630.20(b).
FDA will review donor selection criteria for these programs, as well as
the provision for medical oversight of collections, and must approve
the procedures before such collections may proceed. In some
circumstances, FDA may require additional donor protections to be in
place. For example, FDA may determine that collections from donors with
[[Page 29877]]
clotting factor deficiencies may proceed only if the responsible
physician examines the donor before each donation and is present to
oversee the collection. These terms would be addressed in FDA's review
and approval of the special collection program. In additional, final
Sec. 630.20(b) requires that ineligible donors who are permitted to
donate under this section must meet the criteria in Sec. 630.10(f)(1)
through (6).
For collections under Sec. 630.20(c), the responsible physician is
not authorized to delegate the determination that the donor's health
permits the collection procedure, or that the donation presents no
undue medical risk to the transfusion recipient. Because the collection
and transfusion of blood and blood components from such collections may
present risks to both the donor and the transfusion recipient, we have
determined that these determinations must be made by the responsible
physician, who may make these determinations from an offsite location.
(Comment 99) One comment emphasized the importance of directed
platelet donations, and urged FDA to rely on the blood establishment to
determine whether to collect platelets from a donor with a hematocrit
value of 37 percent (just below the value of 38 percent referenced in
current regulations) when the collection is intended for a specific
recipient based on documented medical need.
(Response) We agree that dedicated platelet donations are
important. Final Sec. 630.20(c) would permit dedicated donations based
on documented exceptional medical need, provided that the responsible
physician determines and documents that the donor's health permits the
collection procedure, and that the donation presents no undue medical
risk to the transfusion recipient.
M. Exceptions From Certain Donor Eligibility Requirements for
Infrequent Plasma Donors (Sec. 630.25)
We are finalizing this provision largely as proposed. For greater
clarity, we have included a definition of ``infrequent plasma donor''
in new Sec. 630.3(e), and we use that defined term in this section. An
infrequent plasma donor is a donor who has not donated plasma by
plasmapheresis or a co-collection of plasma with another blood
component in the preceding 4 weeks, and who has not donated more than
12.0 liters of plasma (14.4 liters of plasma for donors weighing more
than 175 pounds) in the past year. Final Sec. 630.25 provides
exceptions for collections from infrequent plasma donors who are not
participating in an immunization program. This reflects our
determination that, for these collections, it is not necessary for
establishments to assess infrequent plasma donors using the medical
history and physical examination required in Sec. 630.15(b)(1); to
perform the test for total protein required to be performed prior to
collection under Sec. 630.15(b)(4) and periodically under Sec.
640.65(b)(1)(i); or to perform a plasma or serum protein
electrophoresis or quantitative immuno-diffusion test or an equivalent
test to determine immunoglobulin composition of the plasma or serum, as
required under Sec. 640.65(b)(1)(i). Further, it is not necessary for
the responsible physician to review the laboratory data as required in
Sec. 640.65(b)(2)(i).
We have added the term ``medical history'' in the first sentence of
final Sec. 630.25(a), to make clear that this provision may provide an
exception to the requirements in Sec. 630.15(b)(1) to conduct both the
medical history and physical examination required for Source Plasma or
frequent plasma collection. However, blood establishments are still
required to perform the medical history and physical assessment
required under Sec. 630.10. In addition, as discussed in response to
comment 102, we have directly addressed the applicability of this
exception to donors who previously donated a co-collection of plasma
and another blood component by apheresis.
(Comment 100) One comment stated that the donor eligibility
requirements for frequent plasma donors are unnecessary for infrequent
donors.
(Response) Our regulations have long provided additional donor
eligibility requirements for Source Plasma donors (see current Sec.
640.63) to address potential risks associated with frequent
plasmapheresis donation, and this rule incorporates those long-standing
provisions. However, we agree that infrequent plasma donors are not
exposed to the same risks as frequent donors. In final Sec. 630.25, we
provide exceptions from certain donor eligibility requirements for
infrequent plasma donors.
(Comment 101) One comment recommended that the exceptions in Sec.
630.25 should be applicable to donors who donate plasma more frequently
than once in 4 weeks if the donor's physician determines the donor to
be in good health.
(Response) We decline to accept this comment. The conduct of a
medical history and physical exam, the pre-collection review of total
protein levels, and the periodic review of protein composition and
other laboratory data as required by Sec. Sec. 630.15(b)(1), (b)(4),
and 640.65(b) are necessary to protect the health of plasma donors who
are not infrequent plasma donors, as defined in Sec. 630.3(e) (Refs.
65, 66).
(Comment 102) One comment requested clarification concerning
whether the exceptions proposed in Sec. 630.25 should be available
when a donor made a recent platelet donation by apheresis. Another
comment stated that this provision would unnecessarily restrict
infrequent plasma collections after red blood cell loss. The comment
noted that proposed Sec. 630.25 did not address the applicability of
this exception after recent donation of platelets by apheresis. The
comment noted that most of the plasma collected by apheresis from
volunteer blood donors is plasma collected at the same time as
apheresis platelets. The comment stated that the criteria for the
collection of plasma at the same time as collection of platelets by
apheresis should be similar.
(Response) Final Sec. 630.25 provides exceptions for infrequent
plasma donors, as defined in Sec. 630.3(e), who are not participating
in an immunization program. In response to the comment, we have not
included in final Sec. 630.25 the references to red blood cell loss
due to apheresis and Whole Blood collections, which we included in
proposed Sec. 630.25(a). Instead, final Sec. 630.25 provides for more
narrow exceptions to the provisions that relate to the risks of
frequent plasmapheresis. We address the deferral of plasma donors for
red blood cell loss in Sec. 630.15(b)(6) and (7), and the deferral of
platelet donors for red blood cell loss in Sec. 640.21(f).
We agree with the comment that the effects of a recent co-
collection of plasma with platelets or another blood component by
apheresis should be considered in determining whether the exceptions in
Sec. 630.25 are available. Accordingly, Sec. 630.25 applies only to
infrequent plasma donors, and Sec. 630.3(e) excludes from the
definition of infrequent plasma donor a donor who has donated a co-
collection of plasma with another blood component by apheresis in the
preceding 4 weeks. This reflects our determination that, like donations
of plasma by plasmapheresis, co-collections of plasma and platelets or
another blood component by apheresis during the previous 4 weeks should
not be subject to these exceptions. In this way, FDA provides
protection to donors from the risks associated with frequent donation
of plasma by apheresis (Ref. 64).
[[Page 29878]]
N. Donation Suitability Requirements (Sec. 630.30)
We have finalized requirements in Sec. 630.30(a) to define when a
donation is suitable, and in Sec. 630.30(b) to state what an
establishment must do when a donation is not suitable.
Under final Sec. 630.30(a)(1) through (4), a donation is suitable
when: (1) The establishment determines that the donor is not currently
deferred from donation as determined by review of the records of
deferred donors described in Sec. 606.160(e); (2) the results in
accordance with Sec. Sec. 630.10 through 630.25 indicate that the
donor is in good health and procedures were followed to ensure that the
donation would not adversely affect the health of the donor; (3) the
results in accordance with Sec. 630.10(e) indicate that the donor is
free from risk factors for, or evidence of, relevant transfusion-
transmitted infections and other factors that make the donor ineligible
to donate; (4) the donor's blood has been tested in accordance with
Sec. 610.40 and, unless an exception applies, is negative or
nonreactive; and (5) the donation meets other requirements in
subchapter F. The final rule now specifies in Sec. 630.30(a)(1) that
an establishment must determine that the donor is not currently
deferred from donation by reviewing the donor records described in
Sec. 606.160(e). Final Sec. 630.30(a)(2) clarifies that the
determination of the donor's good health must also include a finding
that procedures were followed to ensure that the donation would not
adversely affect the health of the donor.
Proposed Sec. 630.30(a)(5) would have required an establishment to
determine as part of its review of the suitability of platelet
components that ``you have taken adequate steps to assure that the
donation is tested for bacterial contamination and found negative.''
After further consideration we have determined that this provision,
which concerns a current good manufacturing practice, should be
codified in part 606, which is titled ``Current Good Manufacturing
Practice for Blood and Blood Components.'' Accordingly, we discuss
comments to proposed Sec. 630.30(a)(5) at comments 13 through 24
(discussing final Sec. 606.145). Consistent with proposed Sec.
630.30(a)(6), Sec. 630.30(a)(5) in the final rule states that a
donation is suitable when the donation meets other requirements in
subchapter F.
We have made several changes from the proposal in finalizing Sec.
630.30(b), titled ``What must you do when the donation is not
suitable?'' Final Sec. 630.30(b)(1) now provides ``You must not
release the donation for transfusion or further manufacturing use
unless it is an autologous donation, or an exception is provided in
this chapter.'' This provision is revised to state more explicitly a
clear consequence of finding that a donation is not suitable.
Final Sec. 630.30(b)(2), consistent with the proposed rule,
requires a blood establishment to defer the donor of an unsuitable
donation. However, although the proposed rule would have required
deferral of all donors of platelets found to be bacterially
contaminated, Sec. 630.30(b)(2) of the final rule requires deferral
only when the establishment determines in accordance with new Sec.
606.145 that the bacterial contamination is likely to be associated
with a bacterial infection that is endogenous to the bloodstream of the
donor. We made this change in response to comments, which are discussed
at comment 103. In addition, we discuss the requirement to determine
whether contaminating bacteria are likely to be associated with a
bacterial infection that is endogenous to the bloodstream of the donor
at comment 103.
We are not finalizing the provision (proposed Sec. 630.30(b)(3))
that would have required establishments to enter information about
deferred donors into the cumulative record of deferred donors. As
discussed at comments 25 through 28, we are finalizing the requirements
related to the cumulative record of deferred donors more narrowly and
new Sec. 606.160(e)(2), not this section, specifies the information
required to be included in that record.
Consistent with the proposed rule, we require establishments to
notify deferred donors in accordance with final Sec. 630.40. However,
although we reiterated the reasons for deferral and notification in the
language of proposed Sec. 630.30(b)(4), in final Sec. 630.30(b)(4) we
are taking the simpler approach of cross-referencing the donor
notification requirements in Sec. 630.40. This is not a substantive
change.
(Comment 103) Several comments opposed a broad requirement to defer
and notify donors when their platelet component is identified as
bacterially contaminated. Some comments observed that the presence of
bacteria on a donor's skin is expected and typically is not an
indication of illness in the donor. Most instances of bacterial
contamination of platelets occur due to the limitations of collection
facility practices, which may permit the introduction of skin flora or
other contaminants into the collection. On the other hand, in some
instances, the presence of certain bacterial contaminants in a platelet
component could indicate an underlying bacteremia, and potentially a
serious illness in the donor. One comment also asserted that donor
deferral based on a bacterial culture positive result may be
appropriate if: (1) The positive culture is an indication of an
underlying donor pathology that may be cause for deferral (for example,
a donor who cultured positive for Streptococcus bovis who later was
found to have colonic pathology) or (2) the positive culture may
indicate a higher risk of future contaminated collections.
One comment would support notification only when a local
investigation completely ruled out collection facility practices as the
source of contamination. Another comment asserted that while
identification of the bacterial contaminant is likely to be performed
to aid the medical director in evaluating the potential risk to
transfusion recipient or donor, the extent of this identification may
be limited to ``coagulase negative Staphylococcus'' or ``Bacillus
species, not anthracis.'' The comment went on to state that further
identification of the species of the bacterial contaminant should not
be required.
(Response) We agree that most instances of bacterial contamination
of platelets occur because of limitations to aseptic methods of
collection. If we were to require deferral and notification of all
donors who donated platelets that subsequently tested positive for
bacterial contamination, we would unnecessarily alarm many fully
qualified donors. We further agree with the comments noting that a
subset of the findings of contamination are linked to bacteria-
associated illness in the donor, such as a colonic malignancy which may
be signaled by the presence of Streptococcus bovis in the donated
platelets (Ref. 19). Accordingly, we have narrowed the proposal related
to donor deferral and notification. Under Sec. 630.30(b)(3), a
collection establishment must defer the donor of bacterially
contaminated platelets when the contaminating organism is identified in
accordance with Sec. 606.145 as likely to be associated with a
bacterial infection that is endogenous to the bloodstream of the donor.
This reference to endogenous infection is intended to refer to bacteria
that originate from the bloodstream of an asymptomatic donor, and not
to bacteria that are typically found on the surface of the skin.
This rule does not require donor deferral when the presence of
bacteria is due to contamination with the skin flora, or other
contamination at the collection site. We have similarly limited donor
notifications related to
[[Page 29879]]
platelet contamination. Final Sec. 630.30(b)(4) requires
establishments to notify donors in accordance with Sec. 630.40. As
noted at comment 107, Sec. 630.40(a) now requires an establishment to
make reasonable attempts to notify any donor whose donated platelets
have been determined under Sec. 606.145(d) to be contaminated with an
organism that is identified as likely to be associated with a bacterial
infection that is endogenous to the bloodstream of the donor.
(Comment 104) Several comments stated that they consider the
decision whether to defer and notify the donor to fall within the
purview of the collection facility's medical director. They stated that
regulation is not required in this area. Another comment stated that
blood establishments already have a defined policy for how to
investigate situations where a blood component contains a contaminant
in the unit that might suggest the presence of a systemic infection in
the donor, and that the donor should be notified and then investigated,
counseled and/or treated as appropriate by a knowledgeable physician.
The comment asserted that AABB has in place a logical and medically
sound approach to these issues and that current procedures set forth by
the industry organization and establishments are sufficient.
(Response) We recognize that numerous blood establishments already
defer and notify donors in accordance with the policies embodied in
this regulation. However, others do not, and donors at those facilities
may not receive information that is important to their health. In order
to protect these donors, we are requiring donor deferral and
notification when the responsible physician for the collection
establishment determines that the contaminating organism is likely to
be associated with bacterial infection that is endogenous to the
bloodstream of the donor.
(Comment 105) Another comment recommended that FDA not finalize
these donor deferral and notification provisions. The comment urged FDA
to instead provide separate guidance after FDA approves a bacterial
release test. The comment asserted that guidance was needed to address
the deferral period and the reason for deferral.
(Response) Since the proposed rule was published, the tools for
bacterial testing of platelets have improved and notification practices
have evolved. FDA has cleared several devices for quality control
testing of platelets, including two culture-based systems and two non-
culture-based rapid tests. One test has also been cleared as a safety
measure following testing with an early culture. In the United States,
culture of apheresis platelets by collection centers is virtually
universal. Approximately 65 percent of Whole Blood-derived platelets
are pooled early in storage (pre-storage pooling) at the collection
center and are all cultured; the remaining 35 percent are pooled just
prior to transfusion by the transfusion service and are typically
tested with a rapid test (information obtained at the AABB July 2012
workshop) (Ref. 20). In addition, AABB published industry standards
requiring follow-up of positive samples to identify the organism (Ref.
17). A practice of notifying donors after finding endogenous bacteria
with clinical consequences, such as Streptococcus bovis, has been
reported by the American Red Cross, among others (Refs. 18, 19). These
circumstances support even more strongly the donor deferral and
notification provisions we proposed. Accordingly, we decline the
comments' request that we delay finalizing these provisions. We will
issue additional guidance as appropriate.
(Comment 106) Another comment stated that a lookback procedure with
respect to all cases of bacterial contamination would not be
appropriate; rather, reasonable medical judgment should be applied in
these instances.
(Response) We are not requiring a lookback procedure in this rule.
O. Requalification of Previously Deferred Donors (Sec. 630.35)
We received no comments on proposed Sec. 630.35. On our own
initiative, we have restructured this provision to more clearly
identify situations where a prior deferral will not prevent future
donations by an eligible donor. This section continues to provide that
a previously deferred donor may donate again if that donor meets donor
eligibility criteria at the time of the current collection, and if the
collecting establishment determines that the basis for the previous
deferral is no longer applicable.
In final Sec. 630.35(a), we make clear that the basis for a
previous deferral is no longer applicable if the deferral was for a
defined period of time and that time period has passed, or if the
deferral was otherwise temporary, such as those deferrals based on
eligibility criteria described in final Sec. 630.10(f)(1) through (5)
or Sec. 630.15(b)(4). These sections require deferral for individual
donor conditions that may change over time: temperature, blood
pressure, hemoglobin or hematocrit, pulse, weight, and for
plasmapheresis donors, total protein levels.
Final Sec. 630.35(b) makes clear that when the basis for the
deferral is no longer applicable, donors who were deferred for reasons
other than under Sec. 610.41(a) may be found to be eligible to donate
under a requalification method or process found acceptable for such
purpose by FDA. For example, donors who were deferred under Sec.
630.10(e)(1)(vi) for tattooing involving nonsterile percutaneous skin
inoculation could be requalified after 12 months if they meet all other
donor eligibility criteria (Ref. 67). FDA intends to recognize
additional methods and processes in guidance documents issued in
accordance with good guidance practices. In addition, to respond to
individual requests or a public health need, FDA may also authorize
alternative procedures related to donor requalification under Sec.
640.120. We note that reentry of donors deferred under Sec. 610.41(a)
is already addressed in current Sec. 610.41(b), which remains in
effect.
P. Requirements for Notifying Deferred Donors (Sec. 630.40)
We have finalized Sec. 630.40(a) consistently with the proposed
rule, in which we proposed to move the existing donor notification
provision from Sec. Sec. 630.6 to 630.40, and to add a requirement for
notifying donors whose platelet component has tested positive for a
bacterial contamination that is likely due to an infection endogenous
to the bloodstream of the donor. In addition, the proposed and final
rules incorporate updated references to notification after deferral due
to ineligibility under new Sec. Sec. 630.10 and 630.15. While existing
Sec. 630.6(a) requires notification of a donor determined not to be
suitable based on suitability criteria under Sec. 640.3 or Sec.
640.63, those provisions are being replaced by the donor eligibility
criteria in Sec. Sec. 630.10 and 630.15. Throughout final Sec.
630.40, we also made conforming changes to certain terminology to be
consistent with terms used elsewhere in this final rule.
(Comment 107) Several comments, discussed at comments 104 through
106, raised concerns about deferral and notification of donors whose
platelet component has tested positive for bacterial contamination that
is likely due to an infection endogenous to the bloodstream of the
donor. A few comments stated that it would be difficult to notify
donors whose platelets indicate evidence of bacterial infection in the
donor because FDA has
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not issued guidance regarding how to identify such situations.
(Response) As noted at Comment 20, we now require in Sec.
606.145(d) that the responsible physician for the collection
establishment determine whether the contaminating organism is likely to
be associated with a bacterial infection that is endogenous to the
bloodstream of the donor. Donor deferral and notification are required
only after the responsible physician has made this determination, based
on medical judgment, in accordance with the blood collection
establishment's SOP.
Q. Platelets: Eligibility of Donors (Sec. 640.21)
In this final rule, we have revised requirements for collection of
Platelets based on comments. We published the proposed rule in November
2007 and subsequently in December 2007 issued the 2007 Guidance (Ref.
64), as we discussed in comment 91. Many of the comments criticized
provisions of the proposed rule, while supporting recommendations made
in the 2007 Guidance. We have finalized this section to be more
consistent with our recommendations in the 2007 Guidance document.
Consistent with proposed Sec. 640.21(a)(1), final Sec. 640.21(a)
requires establishments to determine the eligibility of platelet donors
in accordance with Sec. Sec. 630.10 and 630.15, except as expressly
modified in Sec. 640.21. We received no comments on this provision and
are finalizing it as proposed.
Proposed Sec. 640.21(b) stated that a donor must not serve as the
source of Platelets for transfusion if the donor has recently ingested
a drug that adversely affects platelet function. We have finalized this
provision in two sections. Final Sec. 640.21(b) states that a
plateletpheresis donor must not serve as the source of Platelets for
transfusion if the donor has recently ingested a drug that adversely
affects platelet function. This is because a donor of platelets
collected by plateletpheresis will typically be the sole source of
platelets provided in a therapeutic transfusion, and the effects of any
drugs on platelet function will not be mitigated by pooling the
affected platelets with platelets from other donors who have not taken
the drug. Final Sec. 640.21(c) states that a Whole Blood donor must
not serve as the source of Platelets for transfusion if the donor has
recently ingested a drug that adversely affects platelet function,
unless the platelet unit is labeled to identify the ingested drug. We
made this change because we recognize that establishments frequently
pool multiple units of Whole Blood platelets in order to mitigate the
effects of a single unit collected from a donor who ingested a drug
that adversely affects platelet function.
In final Sec. 640.21(d), we require establishments to assess and
monitor the donor's platelet count. Establishments: (1) Must take
adequate and appropriate steps to assure that the donor's platelet
count is at least 150,000 platelets/[micro]L before plateletpheresis
begins. If an establishment does not have records of a donor's platelet
count from prior donations and is not able to assess the donor's
platelet count either prior to or immediately following the initiation
of the collection procedure, the establishment must not collect 9.0 x
10\11\ or more platelets in that donation; (2) must defer from platelet
donation a donor whose pre-donation platelet count is less than 150,000
platelets/[micro]L until a subsequent pre-donation platelet count
indicates that the donor's platelet count is at least 150,000
platelets/[micro]L; and (3) must take appropriate steps to assure that
the donor's intended post-donation platelet count will be no less than
100,000 platelets/[micro]L. We revised these provisions in response to
comments that proposed Sec. 640.21(c) was too prescriptive.
Final Sec. 640.21(e) addresses frequency of plateletpheresis
collection in a manner that is largely consistent with the proposed
rule. Consistent with proposed Sec. 640.21(c)(4)(i), final Sec.
640.21(e)(1) provides that a donor may donate no more than a total of
24 plateletpheresis collections during a 12-month rolling period.
Proposed Sec. 640.21(c)(4)(ii) authorized no more than 2 single
component collections of platelets by plateletpheresis within a 7
calendar day period, with a minimum of 2 calendar days between
procedures, and proposed Sec. 640.21(c)(4)(iii) would have authorized
no more than one double or triple component collection procedure within
a 7 calendar day period. However, the proposed rule did not provide
numerical values to distinguish among single, double, and triple
collections. Final Sec. 640.21 provides one value, 6 x 10\11\
platelets, to identify collections that warrant a longer deferral
period between donations. Final Sec. 640.21(e)(2) provides that when
an establishment collects fewer than 6 x 10\11\ platelets, the
establishment must wait at least 2 days before any subsequent
plateletpheresis collection. The establishment must not attempt to
collect more than 2 collections within a 7 day period. Final Sec.
640.21(e)(3) provides that when an establishment collects 6 x 10\11\ or
more platelets, the establishment must wait at least 7 days before any
subsequent plateletpheresis collection (proposed Sec.
640.21(c)(4)(iii)).
Consistent with proposed Sec. 640.21(d), final Sec. 640.21(e)(4)
provides an exception to these limits. For a period not to exceed 30
days, a donor may serve as a dedicated plateletpheresis donor for a
single recipient as often as is medically necessary, provided that the
donor is in good health, as determined and documented by the
responsible physician, and the donor's platelet count is at least
150,000 platelets/[micro]L, as measured at the conclusion of the
previous donation or before initiating plateletpheresis for the current
donation. Current Sec. 610.40(c)(1) addresses the frequency of donor
testing for such dedicated plateletpheresis donors.
Final Sec. 640.21(f) addresses the deferral of plateletpheresis
donors due to red blood cell loss in a manner that is generally
consistent with proposed Sec. 640.21(e). Proposed Sec. 640.21(e)
referred to deferral ``for a period of 8 weeks after donating a unit of
Whole Blood or after losing a volume of whole blood equal to or greater
than 450 mL, or red blood cells equal to or greater than 200 mL,
cumulatively over an 8 week period; or . . . for a period of 16 weeks
after donating a double Red Blood Cells unit collection.'' Final Sec.
640.21(f)(1) finalizes a requirement to defer a donor from donating
plateletpheresis or a co-collection of platelets and plasma by
apheresis for 8 weeks following donation of a unit of Whole Blood or a
single unit of Red Blood Cells by apheresis. Consistent with proposed
Sec. 640.21(e), and in recognition that certain apheresis collection
devices limit potential losses of red blood cells and whole blood, the
rule provides an exception to this 8 week deferral, this section
permits such apheresis collections 2 calendar days after a donation of
Whole Blood or a single unit of Red Blood Cells, provided that the
extracorporeal volume of the device is less than 100 mL. While proposed
Sec. 640.21(e) did not reference the collection of Platelets with
Plasma in this exception, we are responding to comments by addressing
that collection in final Sec. 640.21(f)(1). Final Sec. 640.21(f)(2)
finalizes a 16 week deferral after a donation of a double Red Blood
Cells collection. We have not finalized the proposed requirement to
defer a donor based on cumulative loss of whole blood or red blood
cells over an 8 week period, because it may be difficult for the
establishment to assess cumulative blood loss. Instead, final Sec.
640.21(f)(3) requires an establishment to defer a donor for 8 weeks or
more if
[[Page 29881]]
the cumulative red blood cell loss in any 8 week period could adversely
affect donor health.
Proposed Sec. 640.21(a)(2) would have required blood collection
establishments to include a statement that the ``long-term effects of
frequent apheresis are unknown'' in the platelet donor's statement of
understanding (finalized as the donor acknowledgement in Sec.
630.10(g)(2)). Instead of finalizing that provision, we have
incorporated the informed consent requirements found in current Sec.
640.21(c), into final Sec. 640.21(g). As with Source Plasma donation,
the responsible physician must obtain the informed consent of a
plateletpheresis donor on the first day of donation, and at subsequent
intervals no longer than 1 year. Informed consent for plateletpheresis
would involve a dialogue between the plateletpheresis donor and the
responsible physician. The responsible physician must explain the risks
and hazards of the procedure to the donor; that explanation must be
made in such a manner that the donor may give consent, but also has a
clear opportunity to refuse the procedure. Authorization to delegate
this task to a trained person is addressed in Sec. 630.5(b)(1)(iv).
This requirement is different from and is in addition to the
requirement in Sec. 630.10(g) to obtain a donor's acknowledgement at
every donation.
(Comment 108) One comment suggested that we use the term ``platelet
apheresis'' throughout this provision.
(Response) We use the term ``plateletpheresis'' in this rule to
describe the process of using automated methods to collect Platelets
while returning other blood components to the donor. The use of this
term is consistent with our current regulations and the 2007 Guidance.
(Comment 109) Two comments stated that proposed Sec. 640.21(b)
should be finalized consistently with the recommendations on deferring
donors of apheresis platelets who have ingested drugs that inhibit
platelet function.
(Response) The recommendations for deferring plateletpheresis
donors for ingesting platelet-inhibiting drugs that are contained in
the 2007 Guidance are consistent with this final rule (Ref. 64).
(Comment 110) One comment stated that donors of Whole Blood-derived
platelets should not be deferred for ingesting platelet-inhibiting
drugs. The comment stated that a Whole Blood-derived platelet component
collected from a donor who has ingested platelet inhibitory drugs would
not be given as a single unit dose, and platelet-inhibiting effects of
the ingested drugs would be very limited.
(Response) Final Sec. 640.21(b) states that a plateletpheresis
donor must not serve as a source of platelets for transfusion if the
donor has recently ingested drugs that adversely affect platelet
function. Final Sec. 640.21(c) now states that a Whole Blood donor
must not serve as the source of Platelets for transfusion if the donor
has recently ingested a drug that adversely affects platelet function
unless the labeling of the unit identifies the ingested drug that
adversely affects platelet function. This information will enable the
transfusion service to make an informed decision when selecting a
single unit of Whole Blood platelets for a small dose transfusion (for
example, to a neonate), and will provide useful information to
collection establishments and transfusion services when selecting units
to pool for a standard dose for the transfusion of platelets. We are
not prescribing a specific method for labeling these units. Currently
available methods include providing the information on the unit label,
as a sticker placed on the unit, or in labeling such as a tie-tag
attached to the unit.
(Comment 111) Several comments observed that the proposal in Sec.
640.21(c)(1) applicable to frequent platelet collections, which would
require a platelet count before commencing a collection by apheresis,
is not consistent with the 2007 Guidance, which recommended that
historic averages or default counts may be used in lieu of an actual
platelet count. The comments supported those alternatives to a
requirement to obtain an actual platelet count, which might not be
available at mobile collection sites. Other comments suggested that the
regulation should permit reliance on platelet counts taken at other
times, including an average of the donor's last three venous platelet
counts, the donor's last post-donation platelet count, the platelet
count obtained from a pre-collection venous blood sample from the
donor's previous donations, the average pre-platelet counts for local
donor populations, and the default count for the collection equipment
being used. One comment noted that first time donors at mobile
collection sites would not have a record of previous platelet counts,
but should still be permitted to donate.
(Response) Although we recommend that blood establishments obtain a
pre-donation sample from a donor for a platelet count when feasible, we
agree that under some conditions it may not be possible to measure a
donor's platelet count before commencing the collection of platelets by
apheresis. We have revised the final rule accordingly. Final Sec.
640.21(d) requires the collecting establishment to assess and monitor
the donor's platelet count for all collections of Platelets by
plateletpheresis. However, we do not require an actual measurement of
the donor's platelet count before initiating an apheresis collection of
Platelets, unless the establishment suspects that the donor's platelet
count is less than 150,000 platelets/[mu]L. Instead, Sec. 640.21(d)(1)
requires establishments to take adequate and appropriate steps to
assure that the donor's platelet count is at least 150,000 platelets/
[mu]L before initiating plateletpheresis collection. We believe that
the recommendations in the 2007 guidance (Ref. 64), which address the
use of historic values or the default machine setting when an actual
platelet count cannot be obtained in advance of a donation, would
currently satisfy the requirement in Sec. 640.21(d)(1) to take such
adequate and appropriate steps. If an establishment does not have
records of a donor's platelet count from prior donations and is not
able to assess the donor's platelet count either prior to or
immediately following the initiation of the collection procedure, the
establishment may collect platelets by plateletpheresis, but must not
collect 9.0 x 10\11\ or more platelets from that platelet donor. Final
Sec. 640.21(d)(2) requires establishments to defer a donor whose pre-
donation platelet count is less than 150,000 platelets/[mu]L until a
subsequent pre-donation count indicates that the donor's platelet count
is at least 150,000 platelets/[mu]L. This provision requires an actual
measurement of the donor's platelet count before initiating another
collection of platelets.
(Comment 112) One comment asked whether the proposal that the post-
donation count be no less that 100,000 platelets/[mu]L would require
blood centers to perform a post-donation platelet count. The comment
stated that performing a post-donation count is burdensome. Another
comment said that post-collection counts should never be required. The
comment stated that apheresis collection device settings can be
validated to reliably avoid post-collection counts below 100,000
platelets/[mu]L.
(Response) Final Sec. 640.21(d)(3) requires a collecting
establishment to take appropriate steps to assure that the donor's
intended post-donation platelet count will be no less than 100,000
platelets/[mu]L. We expect that establishments will implement this
requirement by validating the settings on their apheresis collection
devices to
[[Page 29882]]
avoid post-collection counts below 100,000 platelets/[mu]L.
(Comment 113) One comment suggested that FDA specify that in the
event the donor's post-donation platelet count is less than 100,000
platelets/[mu]L, the donation should be reviewed by the Medical
Director, who, based on the donor's history, may deem the donor to be
eligible for future donations.
(Response) Because Sec. 640.21(d)(3) requires establishments to
take appropriate steps to assure that a platelet donor's intended post-
donation platelet count will be no less than 100,000 platelets/[mu]L,
we believe that this situation will occur rarely. If the donor returns
to donate platelets, Sec. 640.21(d) would require the establishment to
assess and monitor the donor's platelet count, and, under Sec.
640.21(d)(1), would require the establishment to take adequate and
appropriate steps to assure that the donor's platelet count is at least
150,000 platelets/[mu]L before initiating plateletpheresis collection.
A donor whose pre-donation count is less than 150,000 platelets/[mu]L
must be deferred under Sec. 640.21(d)(2).
(Comment 114) Several comments suggested that limitations on
frequency of plateletpheresis collections should not be finalized. They
criticized as unnecessary the limitations to 24 collections in a 1 year
period and the requirement for a 2 day interval between each
collection. Some comments stated that there is no evidence to support a
requirement for a 7 day donation interval following the donation of a
double or triple component. One comment asserted that other protections
(such as following instructions for use on apheresis collection
devices) are adequate to protect the donor.
(Response) We have finalized these requirements in Sec. 640.21(e).
Some studies have demonstrated a higher incidence of iron deficiency in
frequent plateletpheresis donors. In a United Kingdom study of serum
ferritin levels of frequent plateletpheresis donors, there was a direct
correlation between plateletpheresis donation frequency and iron
depletion. The authors suggested that the iron depletion in these
donors is due to blood loss that can occur with each plateletpheresis
donation (Ref. 68). In addition, frequency of donation may affect the
donor's ability to replace platelets adequately (Ref. 69). For this
reason, in order to protect the health of the donor, we have finalized
limits on the frequency of platelet donation in Sec. 640.21(e). We
agree that collection of more than a single replacement dose of
platelets is generally safe. However, the specified interdonation
intervals are prescribed to assure that plateletpheresis donors have
time to recover their platelet counts between collections.
We also note that Sec. 640.21(e)(4) provides an exception that may
be available when a donor serves as a dedicated plateletpheresis donor
for a single recipient. Under this exception a healthy donor may donate
more frequently during a 30 day period, in order to provide platelets
for a recipient in need of multiple transfusions of platelets.
(Comment 115) One comment noted that the proposed deferrals of
plasma donors for red blood cell loss contained in proposed Sec.
630.15(b)(5) were different from the deferrals for platelet donors for
red blood cell loss in proposed Sec. 640.21(e).
(Response) We have harmonized the deferrals for red blood cell loss
in final Sec. 640.21(f) based on comments regarding co-collection of
Platelets and Plasma by apheresis, discussed at comment 92.
(Comment 116) One comment recommended that a Whole Blood donor
should have to wait 8 weeks before donating by plateletpheresis, unless
the instrument used is designed to collect less than 100 mL of red
blood cells, regardless of the donor's hematocrit, when the donor is
not fully re-infused. The comment stated that there is a potential for
plateletpheresis donors to lose more than 100 mL of red blood cells
based on the type of machine used and the donor's hematocrit, and
identified one apheresis device with an extracorporeal blood volume
greater than 200 mL.
(Response) Final Sec. 640.21(f)(1) allows an establishment to
collect either platelets by apheresis or platelets with Plasma by
apheresis 48 hours after a donation of Whole Blood or Red Blood Cells,
only if the extracorporeal volume of the apheresis collection device is
less than 100 mL. An establishment could not collect platelets by
apheresis using the device with an extracorporeal volume greater than
200 mL identified by the comment under this provision.
(Comment 117) Two comments criticized proposed Sec. 640.21(a)(2),
which would have required the statement of understanding to include a
statement that the long-term effects of frequent apheresis are unknown.
One comment suggested that there is adequate published literature that
would indicate that the effects of long-term frequent apheresis are
known. Another similar comment asserted that no long-term adverse
effects have been reported with frequent apheresis, and it is not
necessary to include a statement with information provided to the
donor.
(Response) Final Sec. 640.21(g) requires the responsible physician
to explain the risks and hazards of the procedure to the donor as part
of the informed consent process. In addition, Sec. 630.10(g)(2)(ii)(E)
requires that, at every donation, the donor acknowledge that the donor
has been provided and reviewed information regarding the risks and
hazards of the specific donation procedure. These regulations do not
require that the donor be informed that the long term effects of
frequent apheresis are unknown; we recognize that, as knowledge
improves, such a statement may no longer be accurate. However, even
though the current literature does not answer all questions concerning
the long term consequences of frequent plateletpheresis (Ref. 70), the
informed consent must address long term risks and hazards associated
with frequent apheresis, such as iron depletion (Refs. 71, 72). The
donor's informed consent is required before the first plateletpheresis
donation, and at least yearly thereafter.
R. Source Plasma: Plasmapheresis (Sec. 640.65(b))
We have finalized these sections largely as proposed. Final Sec.
640.65(b)(1)(i) and (b)(2)(i) now reference Sec. 630.25, incorporating
those exceptions related to collections from infrequent plasma donors.
This reflects our determination, as described in the section addressing
Sec. 630.25, certain provisions are not necessary for these
collections. Final Sec. 640.65(b)(2)(i) also requires that
plasmapheresis donors be tested every 4 months to assure that they have
a total protein of no less than 6.0 grams per deciliter, and no more
than 9.0 grams per deciliter in a plasma sample or a serum sample. We
received comments on this protein standard, which is also incorporated
in Sec. 630.15(b)(4). We discuss those comments at comment 89. Final
Sec. 640.65(b)(2)(i) further requires the responsible physician to
review the accumulated laboratory data, including any tracings of the
plasma or serum protein electrophoresis pattern, the calculated values
of the protein composition of each component, and the collection
records to determine if the donor should be deferred from further
donation. This section further requires that if the review is not
completed within 14 calendar days after the sample is drawn, the
collection establishment must defer the donor pending the review. This
will assure that establishments do not take additional collections from
an ineligible
[[Page 29883]]
donor in the event that this review is delayed.
(Comment 118) A few comments to proposed Sec. 640.65(b)(2)(i)
recommended that the review time for determining whether a donor would
be deferred from further donation should remain at 21 days, not 14 days
as proposed. The comment stated that the current 21 day allowance is
needed to ensure adequate time for testing, return of test results to
the laboratory and medical review. The comment stated that FDA should
note that Canadian health authorities recently changed their
requirement to 21 days.
(Response) We decline to provide a 21 day timeframe for review.
This change from 21 days to 14 days reflects changes on how samples are
submitted for testing, and how test results are transmitted. These
changes permit faster receipt and review of test results. As we noted
in the proposed rule, current Sec. 640.65(b)(2)(i) requires this
review to take place within 21 days; we are reducing the time period to
14 calendar days because results are typically transmitted and recorded
electronically, permitting faster access. Requiring medical review of
these laboratory test results within 14 days is one of the important
protections this rule provides to Source Plasma donors.
S. Source Plasma: General Requirements (Sec. 640.69)
We have finalized two sections as final Sec. 640.69(e) and (f).
These provisions incorporate industry practices known as the Qualified
Donor Standard and Inventory Hold. Final Sec. 640.69(e) provides that
establishments must ensure that Source Plasma donated by paid donors is
not used for further manufacturing into injectable products until the
donor has a record of being found eligible to donate in accordance with
Sec. 630.10, and a record of negative test results on all tests
required under Sec. 610.40(a), on at least two occasions in the past 6
months. Because the regulation requires the establishment to determine
a paid donor to be eligible on at least two occasions, but does not
require that a unit be collected at the time of the initial eligibility
determination, the regulation permits establishments that prefer to
establish a donor's qualification by screening the donor and collecting
a blood sample, but not a full donation, for testing in accordance with
Sec. 610.40(a).
We have finalized the inventory hold provision proposed in Sec.
640.69(f) to require establishments to hold Source Plasma donated by
paid donors in quarantine for a minimum of 60 days before it is
released for further manufacturing use to make an injectable product.
In addition, we now state explicitly the conditions that would prevent
an establishment from distributing Source Plasma from quarantine. Under
final Sec. 640.69(f), an establishment must not distribute quarantined
donations if the donor is subsequently deferred under Sec. 610.41
because of a reactive screening test for evidence of infection due to a
relevant transfusion-transmitted infection, or if the establishment
subsequently determines the donor to be ineligible under Sec. 630.10
due to risk factors closely associated with exposure to, or clinical
evidence of, infection due to a relevant transfusion-transmitted
infection. Since Source Plasma would be placed in quarantine under this
section after the donation has been determined to be suitable under
Sec. 630.30, this section describes the information, typically
obtained in connection with a subsequent Source Plasma donation by the
donor, which would disallow the distribution from quarantine of that
donor's prior donations. We added this language so that establishments
would understand that, under this section, post-donation information
would prevent the distribution of quarantined donations if that
information consisted of a reactive screening test on a subsequent
donation or a subsequent donor deferral due to risk factors associated
with relevant transfusion-transmitted infection. Other donor
information would not prevent distribution of previously quarantined
units, even if it led to deferral of the donor from current
collections. For example, information related to a donor's health on
the day of a future donation (see, for example, Sec. 630.10(f)(1)
through (f)(6)) would not affect the distribution from quarantine of
previously collected units.
(Comment 119) Two comments noted that proposed Sec. 640.69(e) and
(f) would codify existing, voluntary practices used in Source Plasma
establishments. The comments urged FDA not to mandate voluntary
industry standards. The comments noted that the Qualified Donor
Standard and Inventory Hold were developed before nucleic acid testing
was available to identify HIV as well as certain other relevant
transfusion-transmitted infections, and that the use of nucleic acid
testing significantly improves the identification of recent infections
in the donor. According to the comments, incorporating these industry
standards in regulation could inhibit the development of new practices
based on new technology, and otherwise limit flexibility in the future.
(Response) As we explained in the proposed rule, these provisions
are intended to provide additional mitigations of the risk of
infectious disease transmission presented by collections from paid
Source Plasma donors. Since the 1970s, it has been documented that paid
Source Plasma donors are at higher risk than volunteer blood donors for
certain relevant transfusion-transmitted infections (Ref. 73). In a
1998 report, the General Accounting Office (GAO) compared the incidence
rates (positives per 100,000 person years) between paid and volunteer
plasma donors, reporting ``we found that the incidence rates for HIV,
HBV, and HCV were much higher for paid donors. HIV incidence rates were
19 times higher among paid donors (61.8 versus 3.3 for volunteer
donors), while HBV and HCV rates were 31 times (245.5 versus 8.0) and 4
times higher (63.5 versus 14.9), respectively.'' The GAO concluded,
``there is a consistent pattern of higher marker rates among paid
donors than among volunteer donors.'' The GAO further recognized the
Qualified Donor Standard and Inventory Hold help to mitigate the risks
of infection from plasma pools used for manufacturing plasma derivative
products. Accordingly, in consideration of the additional risks
presented by the paid Source Plasma donors, both industry and the GAO
have recognized the importance of these practices in increasing the
safety of products manufactured from Source Plasma. Although donor
testing has improved with the advent of nucleic acid testing, Source
Plasma collectors have continued to incorporate the Qualified Donor
Standard and Inventory Hold into their quality standards, as reflected,
for example, by the Plasma Protein Therapeutics Association, Quality
Standards of Excellence, Assurance and Leadership (QSEAL) Certification
Program (Ref. 74).
We solicited comments and supporting data in the proposed rule on
whether other requirements would achieve the same results as these
practices. We did not receive responsive comments and data. FDA
appreciates that, in the future, new standards and practices may
develop, which could replace the Qualified Donor Standard and Inventory
Hold. However, such alternatives have not yet been identified. If
appropriate alternative standards become available in the future, FDA
could allow the use of those appropriate alternative standards as
alternative procedures under Sec. 640.120,
[[Page 29884]]
as well as revise this regulation when warranted.
(Comment 120) One comment asked that the wording in Sec. 640.69(e)
be revised to state that Source Plasma may be released once a donor has
two sets of negative/non-reactive/not implicated viral marker test
results. The comment further asserted that it should not be a
requirement that the samples sent for testing be drawn at the same time
the donor donates Source Plasma.
(Response) Under the final rule, an establishment may draw samples
for testing under Sec. 610.40(a) without collecting Source Plasma at
the same time.
(Comment 121) One comment questioned the requirements in Sec.
640.69(f), asserting that a proposal to require Source Plasma
collectors to store the plasma at the collection center during the 60-
day Inventory Hold would be unduly burdensome. The comment noted that
the voluntary industry standard for the 60-day hold gives the
manufacturer the flexibility to determine the most appropriate place
for storage. Moreover, the comment stated that a requirement to use
interim ``quarantine'' labeling on individual Source Plasma collections
would add cost. The comment also stated that the term ``Quarantine''
should not be used because it implies that the plasma being placed in
the 60-day hold is violative, when the product is simply held in
inventory as part of the standard routine process.
(Response) The language of the proposed rule would not have
required that Source Plasma be stored at the collection site, nor did
it require establishments to label individual collections of Source
Plasma as ``Quarantined.'' Rather the proposed rule simply required
that the product be ``held in quarantine.'' The final rule requires
that Source Plasma be held for a minimum of 60 days and prohibits
distribution of certain units ``after placing a donation in
quarantine.'' Final Sec. 640.69(f) does not specify where an
establishment must store the product. The establishment is not required
to store the product at the collection site, and an establishment may
store the product at an appropriate off site facility during the 60-day
Inventory Hold. Nor does this provision require individual labeling of
units. Instead, it simply requires that the establishment be able to
identify any units that may not be distributed because of post-donation
information received during the 60-day hold, and to identify when the
60-day hold has expired for a unit. We believe that establishments can
meet these requirements by employing a variety of methods, including
physical segregation, labeling (units, cases, or other packing units),
or by electronic means (such as by computerized inventory). Finally, we
disagree that the use of the term ``quarantine'' in this context
suggests that the product subject to the Inventory Hold is violative.
Rather, the term merely implies that the establishment is restricted
from distributing the quarantined product while it is subject to the
Inventory Hold.
(Comment 122) One comment objected to the use of ``paid'' to
describe donors of Source Plasma subject to this provision. The comment
asserted that paid Source Plasma donors are compensated for the time it
takes to fulfill their commitment to donate. The comment stated that
donating blood and plasma should be encouraged and that it is often
necessary to reward donors for their donation.
(Response) We have finalized the rule incorporating the term ``paid
donor.'' This usage is consistent with current Sec.
606.121(c)(8)(v)(A), which is applicable to transfusable blood and
blood components. That section defines a paid donor as a person who
receives monetary payment for a blood donation.
T. Source Plasma: Records (Sec. 640.72)
In proposed Sec. 640.72(a)(2) through (a)(4), we proposed several
changes to current Sec. 640.72 in order to conform to changes in this
rule. We have finalized this section largely as proposed.
(Comment 123) One comment asked FDA to authorize establishments
under Sec. 640.72(a)(3) to maintain as an electronic record the
records of the plasma donor's informed consent to participate in the
plasmapheresis program, and where applicable, to participate as an
immunized donor. This informed consent is required under Sec.
630.15(b)(2). The comment stated that informed consent requirements
should be consistent with proposed Sec. 630.10(i)(2), which allows for
a ``signature or acceptable substitute for a signature to indicate that
understanding''.
(Response) We note that the donor acknowledgement, which the
establishment is required under final Sec. 630.10(g)(2) to obtain at
each donation, requires a signature or other documented
acknowledgement. The donor acknowledgement record is required to be
maintained in accordance with Sec. 606.160(a). For informed consent,
obtained at the intervals specified in Sec. 630.15(b)(2), final Sec.
640.72(a)(3) now requires establishments to maintain the original or a
clear copy or other durable record which may be electronic, of the
donor's consent for participation in the plasmapheresis program or
immunization.
(Comment 124) Several comments questioned the reference in proposed
Sec. 640.72(a)(4) to documentation by the responsible physician that
the donor is in good health under Sec. Sec. 630.10 and 630.15 on the
day of examination. The comments stated that trained persons would be
capable of making assessments under Sec. Sec. 630.10 and 630.15.
(Response) We agree with the comment that reference to Sec. Sec.
630.10 and 630.15 in proposed Sec. 640.72(a)(4) was misplaced.
Instead, under final Sec. 640.72(a)(4) we require that records of the
medical history and physical examination of the donor, conducted in
accordance with Sec. 630.15(b)(1) and, where applicable, Sec.
630.15(b)(5), must address the eligibility of the donor as a
plasmapheresis donor and, if applicable, an immunized donor. Delegation
of this examination and determination is addressed in Sec.
630.5(c)(3).
U. Source Plasma: Reporting of Donor Reactions (Sec. 640.73)
We are not finalizing Sec. 640.73 in this rule. Instead, FDA
intends to finalize this section when FDA finalizes the proposed rule,
``Safety Reporting Requirements for Human Drug and Biologicals'' (68 FR
12406, March 14, 2003) (Ref. 75). We will address in that final rule
the comments received on proposed Sec. 640.73 in this docket. By doing
so, we intend to consolidate the safety and reporting requirements of
all human drugs and biologicals under this chapter into one
comprehensive regulation.
V. Alternative Procedures (Sec. 640.120)
We are finalizing proposed Sec. 640.120 which separates and
revises current Sec. 640.120(a) into proposed Sec. 640.120(a) and
(b), and revises and redesignates current Sec. 640.120(b) as Sec.
640.120(c). Under proposed Sec. 640.120(a), a blood establishment
could request that the Director, CBER, approve a proposed exception or
alternative to any requirement in Title 21 of the CFR, Chapter I,
subchapter C (21 CFR parts 200 through 299; these include drug
regulations, such as current good manufacturing practice regulations,
that are applicable to blood products) and F (21 CFR parts 600 through
680), regarding blood, blood components, or blood products. Current
Sec. 640.120(a) authorizes exceptions or alternatives to regulations
in subchapter F but omits reference to subchapter C; proposed Sec.
640.120(a) addressed this omission. Under proposed Sec. 640.120(a)(1),
an establishment could request an
[[Page 29885]]
exception or alternative in writing, or, if there are difficult
circumstances and submission of a written request is not feasible, as
an oral request under proposed Sec. 640.120(a)(2). We also proposed in
Sec. 640.120(b) to permit the CBER Director to issue an exception or
alternative to these regulations in the event of a public health
emergency which impacts blood and blood product establishments or blood
availability. We proposed to redesignate current Sec. 640.120(b) as
Sec. 640.120(c), and to revise it to state that FDA would publish
alternative procedures and exceptions periodically on the CBER Web site
rather than in the Federal Register, as our current regulations
provide.
We are finalizing this provision largely as proposed, while making
some clarifying changes. In final Sec. 640.120(a), we no longer refer
to our approval of an exception or alternative procedure. Instead, we
refer to issuing an exception or alternative. This is consistent with
the use of the term ``issue'' in proposed Sec. 640.120(b).
In Sec. 640.120(b), we proposed that the Director be authorized
``in a public health emergency'' to issue exceptions or alternatives if
``necessary to assure that blood, blood components, or blood products
will be available in a specified location to respond to an
unanticipated immediate need for blood, blood components or blood
products.'' Final Sec. 640.120(b) authorizes the Director ``to respond
to a public health need'' by issuing a notice of exception or
alternative if an exception or alternative is ``necessary to assure
that blood, blood components, or blood products will be available in a
specified location or locations to address an urgent and immediate need
for blood, blood components, or blood products or to provide for
appropriate donor screening and testing.'' We made these two changes to
emphasize that this authority will be available to address urgent and
immediate needs for blood, blood components, and blood products. The
use of this provision is not contingent on whether that need could have
been anticipated. In addition, we made explicit the Director's
authority to issue exceptions or alternatives to provide for
appropriate donor screening and testing. In recent years, we have
confronted shortages and near-shortages of important donor tests. These
situations have caused us to recognize the importance of being able to
protect donors and recipients by permitting the use of alternative, but
adequate, testing algorithms.
(Comment 125) FDA received two comments on proposed Sec. 640.120.
Both comments concerned Sec. 640.120(b), relating to alternative
procedures during a public health emergency. The comments urged FDA to
be more specific about which regulatory provisions in subchapters C and
F of Title 21 of the CFR would potentially be the subject of exceptions
or alternative procedures during a public health emergency. One comment
further indicated that blood establishments would be better able to
prepare facilities and train staff if CBER provided more specific
information about exceptions and alternative procedures which may be
used during a public health emergency.
(Response) The Agency does not agree that potential variances
should be listed within the regulation. Whether or not an exception or
alternative is appropriate will depend on the specific situation. The
scope, duration, and nature of a specific situation, how it impacts
blood establishments, and the extent to which blood and blood products
continue to be available, will determine whether a particular provision
in subchapter F of title 21 of the CFR would be an appropriate subject
for an exception or alternative procedure to address the public health
need. Current Sec. 610.40(g) authorizes release or shipment of blood
or blood components prior to testing in appropriately documented
medical emergency situations. Moreover, CBER has posted on its Web site
a document entitled ``Exceptions and Alternative Procedures Approved
Under 21 CFR 640.120'' (Ref. 76), which provides examples of exceptions
and alternatives permitted under current Sec. 640.120(a). Blood
establishments may find this information to be useful for emergency
planning purposes. In addition, FDA intends to continue to work with
stakeholders on how to assure the continued availability of safe, pure,
and potent blood and blood products during emergencies and other
situations that may warrant a variance under this section.
W. Reagent Red Blood Cells (Sec. Sec. 660.31, 660.32)
We are not finalizing proposed Sec. 660.31, which proposed that
donors of peripheral blood for Reagent Red Blood Cells, used as
diagnostic substances for laboratory tests, must meet all the criteria
for donor eligibility under Sec. Sec. 630.10 and 630.15, and we are
deleting current Sec. 660.31. We are also deleting Sec. 660.32, which
addressed the collection of blood for Reagent Red Blood Cells from
donors of peripheral blood. We are taking this action because blood
collection establishments in the United States are fully subject to the
requirements for donor eligibility, testing, and donation suitability
discussed at length in this rulemaking, and these requirements are
duplicative for such collections. Moreover, Reagent Red Blood Cells are
licensed products subject to licensing standards to assure that the
product is safe, pure, and potent. FDA assures that all licensed
Reagent Red Blood Cells meet standards for safety, purity, and potency.
(Comment 126) One comment asked FDA not to reference in Sec.
660.31 the criteria for donor eligibility in Sec. Sec. 630.10 and
630.15. The comment stated that Reagent Red Blood Cells are not used
for transfusion and are further processed for reagent use only; it is
not necessary for donors of these products to meet the criteria in
Sec. Sec. 630.10 and 630.15.
(Response) We do not agree that donor eligibility provisions should
not apply to donors of Red Blood Cells to be manufactured into Reagent
Red Blood Cells. Blood collection establishments in the United States
must comply with Sec. Sec. 630.10 and 630.15, and we will require
manufacturers of licensed Reagent Red Blood Cells to comply with
applicable standards. However, we are deleting Sec. Sec. 660.31 and
660.32 from the final rule as duplicative.
X. Quality System Regulation: Scope (Sec. 820.1)
We did not receive any comments on this section and we are
finalizing the section as proposed.
Y. Technical Amendments
As has been noted elsewhere in this document, we are making a
number of technical changes. These include changes in terminology in
certain provisions as follows:
We are removing the terms ``communicable disease agent'',
``communicable disease agents'', and ``communicable disease agent(s)''
wherever they appear and adding in their place ``relevant transfusion-
transmitted infection'', ``relevant transfusion-transmitted
infections'', and ``relevant transfusion-transmitted infection(s)'' to
be consistent with the new definition of ``relevant transfusion-
transmitted infection'' in Sec. 630.3(h). These changes occur
throughout 21 CFR part 610 subpart E, as well as in the following
provisions: Sec. Sec. 606.121(c)(11), (c)(12), and (i)(5), 606.122(e),
630.40(b)(3), (d)(1), (d)(1)(i), (d)(1)(iii), 640.5(f), and 640.67;
We are removing the terms ``qualified licensed
physician'', ``licensed physician'', and ``physician on the premises''
and adding in their place ``responsible physician'' to be consistent
with the new definition of
[[Page 29886]]
``responsible physician'' in Sec. 630.3(i). These changes occur in the
following provisions: Sec. Sec. 606.110(a), 640.65(b)(1)(i),
(b)(1)(ii), (b)(2)(i), (b)(2)(iii), and (b)(2)(iv), 640.66, and
640.71(b)(1);
We are removing the terms ``suitable'' or ``suitability''
and adding in their place ``eligible'' or ``eligibility'' to be
consistent with the new definition of ``eligibility of a donor'' in
Sec. 630.3(d). These changes occur in the following provisions:
Sec. Sec. 606.40(a)(1), 606.100(b)(1), 606.121(i)(5),
606.160(b)(1)(x), 610.40(h)(2)(iv)(A), 610.41(a)(3), (a)(4), and (b),
630.40(a), (b), (b)(1), and (c), 640.12, 640.31, and 640.51;
We also are removing ``supplemental test'' and
``supplemental (additional, more specific) test'', or similar wording,
and adding in their place ``further testing'' to be consistent with the
further testing requirements in Sec. 610.40(e). These changes occur in
the following provisions: Sec. Sec. 610.40(e)(2), 610.46(a)(2),
(a)(3), (a)(4), (b)(2), and (b)(3), 610.47(a)(2), (a)(3), (a)(4),
(b)(2), and (b)(3), 630.40(a), (b)(3), and (d)(1)(iii);
We are removing the term ``certified in writing'' and
adding in its place ``determined and documented'' to be consistent with
the requirement to determine and document in Sec. 640.21(e)(4). This
change occurs in Sec. 606.110(a); and
We are removing the reference to ``Health Care Financing
Administration'' and replacing the reference with this Federal Agency's
current name, ``Centers for Medicare and Medicaid Services'' in Sec.
610.40(f).
As part of this final rule, we also are removing certain provisions
from the CFR because the provisions are superseded or replaced by
provisions in the final rule. These include: Sec. Sec. 610.40(c)(2)
and (i), 640.3, 640.27, 640.61, 640.62, and 640.63. For the same
reasons, we are removing and reserving Sec. Sec. 640.4(a), 640.5(a),
and 640.64(a). With these changes, we need to make conforming changes
when these removed provisions are referenced elsewhere in the CFR.
Sec. 610.40(i): The final rule removes from the CFR
610.40(i), which addresses syphilis testing, because syphilis testing
is now addressed in Sec. 610.40(a). Accordingly, as part of this final
rule, we are removing references to Sec. 610.40(i) that appear in:
Sec. Sec. 610.40(d), (g), and (h)(1), 610.41(a) and (a)(5), and
610.42(a). In removing the reference to Sec. 610.40(i) from Sec. Sec.
610.40(d), 610.41(a) and (a)(5), and 610.42(a), we are also removing
the text ``or by a serological test for syphilis'', which modifies the
reference to Sec. 610.40(i). In removing the reference to Sec.
610.40(i) in Sec. 610.40(h)(2)(vi), we are adding in its place a
reference to Sec. 610.40(a), and, because of the changes to Sec.
640.5, we are removing the related reference to performing syphilis
testing under Sec. 640.5. In Sec. 610.40(h)(2)(vii), we are removing
the reference to Sec. 610.40(i), and replacing it with references to
Sec. Sec. 640.65(a)(2)(ii) and(b)(1)(i), which address syphilis
testing for Source Plasma donors. We are also removing Sec.
640.65(b)(2), and replacing it with the more precise citation to Sec.
640.65(b)(2)(ii) through (b)(2)(iv).
Sec. 640.3: The final rule removes from the CFR 640.3,
which addresses suitability requirements for Whole Blood donors. This
subject is now addressed in part 630. Accordingly, as part of this
final rule, we are removing the reference to Sec. 640.3 that appears
in Sec. 606.121(i)(5) and adding in its place a reference to Sec.
630.10. We are removing the reference to Sec. 640.3 that appears in
Sec. 640.4(e) and adding in its place a reference to Sec. 630.10. We
are removing the references to Sec. 640.3 that appear in Sec. Sec.
640.12, 640.31(a) and 640.51(a), and substituting references to
Sec. Sec. 630.10 and 630.15. We are removing the reference to Sec.
640.3 as part of our changes to newly designated Sec. 630.40(a), and
adding in its place the reference to Sec. Sec. 630.10 and 630.15.
Sec. 640.62: The final rule removes from the CFR 640.62,
which addresses medical supervision in Source Plasma situations. This
subject is now addressed in part 630. Accordingly, as part of this
final rule, we are removing references to Sec. 640.62 that appear in
Sec. Sec. 640.22(c), 640.32(b), and 640.52(b). To clarify that Sec.
630.5 applies to medical supervision for the collection of Source
Plasma and other collections addressed in part 640, we have added Sec.
640.130 in new subpart M. This section states that the requirements for
medical supervision established in Sec. 630.5 supplement the
regulations in part 640.
Sec. 640.63: The final rule removes from the CFR 640.63,
which addresses suitability requirements for Source Plasma donors. This
subject is now addressed in part 630. Accordingly, as part of this
final rule, we are removing the reference to Sec. 640.63 that appears
in Sec. 606.110(b) and adding in its place a reference to Sec. Sec.
630.10 and 630.15. We also are removing the reference to Sec. 640.63
as part of our revisions to newly designated Sec. 630.40(a), and
adding in its place a reference to Sec. Sec. 630.10 and 630.15. As
part of our changes to Sec. Sec. 640.31(b) and 640.51(b), we also are
removing references to Sec. 640.63 and adding in their place a
references to Sec. Sec. 630.10 and 630.15. Similarly, as part of our
revisions to Sec. 640.72, we are removing the reference to Sec.
640.63 in Sec. 640.72(a)(2) and adding in its place a reference to
Sec. Sec. 630.10 and 630.15. We also are removing the reference to
Sec. 640.63(b)(3) in Sec. 640.72(a)(4) and adding in its place
references to Sec. 630.15(b)(1) and (b)(5), among other changes.
III. Legal Authority
FDA is issuing this rule under the authority of sections 351 and
361 of the Public Health Service Act (PHS Act) (42 U.S.C. 262 and 264),
and certain provisions of the FD&C Act (21 U.S.C. 201 et seq.).
The establishment of these criteria for determining the eligibility
of a donor of blood and blood components and the suitability of blood
and blood components for transfusion or for further manufacturing is
intended to assure that donations are safe, pure, and potent including
preventing unsafe units of blood or blood components that may transmit
a relevant transfusion-transmitted infection from entering the blood
supply, while safeguarding the health of donors.
FDA has been delegated authority under section 361 of the PHS Act
to make and enforce regulations necessary to prevent the introduction,
transmission, or spread of communicable disease from foreign countries
into the States or possessions, or from one State or possession into
any other State or possession. Intrastate transactions affecting
communicable disease transmission may also be regulated under section
361 of the PHS Act (Independent Turtle Farmers of Louisiana, Inc. v.
United States, 703 F.Supp.2d 604, 620-21 (W.D. La. 2010); Louisiana v.
Mathews, 427 F. Supp. 174, 176 (E.D. La. 1977)).
It is important to recognize that, in the past, blood transfusion
and manufacturing of blood derivatives presented significant risks of
transmission of communicable diseases such as HBV and HIV. Risks of
transmission of infectious diseases still remain from emerging
infectious agents. As FDA has previously noted, section 361 of the PHS
Act, ``is designated to eliminate the introduction of communicable
disease, such as hepatitis, from one state to another. Of necessity,
therefore, this authority must be exercised upon the disease causing
substance within the state where it is collected, manufactured, or
otherwise found. Thus, the Commissioner of Food and Drugs may
promulgate current good manufacturing practice regulations for
[[Page 29887]]
intrastate blood banking, pursuant to the [PHS Act], as hepatitis is a
communicable disease. Without proper controls, it is likely to spread
on an interstate basis.'' (39 FR 18614, May 28, 1974). These statements
are equally true today, where the spectrum of diseases transmitted by
blood has increased to include, for example, HIV agents that cause
AIDS, and HCV, an additional cause of hepatitis as well as emerging
infectious agents. We understand communicable diseases to include those
transmitted by viruses, bacteria, fungi, parasites, and transmissible
spongiform encephalopathy agents. Preventing the spread of communicable
disease is the important purpose underlying the comprehensive
regulations for blood establishments now in place, which this final
rule modifies and modernizes.
Under section 361 of the PHS Act, FDA is authorized to enforce the
regulations it issues to prevent the introduction, transmission, or
spread of communicable disease interstate through such means as
inspection, disinfection, sanitation, destruction of animals or
articles found to be so infected or contaminated as to be sources of
dangerous infection in human beings, and other measures that may be
necessary. In addition, under section 368(a) of the PHS Act, any person
who violates a regulation prescribed under section 361 of the PHS Act
may be punished by imprisonment for up to 1 year. Individuals may also
be punished for violating such a regulation by a fine of up to $100,000
if death has not resulted from the violation or up to $250,000 if death
has resulted. For organizational defendants, fines range up to $200,000
and $500,000. Individuals and organizations also face possible
alternative fines based on the amount of gain or loss (18 U.S.C. 3559
and 3571(b) through (d)). Federal District Courts also have
jurisdiction to enjoin individuals and organizations from violating
regulations implementing section 361 of the PHS Act. (See Califano v.
Yamasaki, 442 U.S. 682, 704-05 (1979); United States v. Beatrice Foods
Co., 493 F.2d 1259, 1271-72 (8th Cir. 1974), cert. denied, 420 U.S. 961
(1975).)
Blood and blood components introduced or delivered for introduction
into interstate commerce are subject to section 351 of the PHS Act,
which requires that such products be licensed (42 U.S.C. 262). Section
351 of the PHS Act further authorizes FDA, by delegation, to establish
requirements for such biologics licenses (42 U.S.C. 262(a)(2)(A)). In
addition to its authority under section 361 of the PHS Act, FDA relies
on this authority when the final regulations are applied to products
subject to biologics license. To obtain a license, applicants must show
that the biological product is safe, pure, and potent and that the
manufacturing establishment meets all applicable standards designed to
assure the continued safety, purity, and potency of the blood and blood
components. FDA license revocation regulations provide for the
initiation of revocation proceedings if, among other reasons, the
establishment or the product fails to conform to the standards in the
license application or in the regulations designed to ensure the
continued safety, purity, or potency of the product (Sec. 601.5).
Violations of section 351 are punishable by a 1-year term of
imprisonment, a fine as described in the preceding paragraph, or both
(42 U.S.C. 262(f), 18 U.S.C. 3571). Blood and blood components are also
drugs or devices, as those terms are defined in sections 201(g)(1) and
(h) of the FD&C Act (21 U.S.C. 321(g)(1) and (h); see United States v.
Calise, 217 F. Supp. 705, 708-09 (S.D.N.Y. 1962)); 42 U.S.C. 262(j)
(``The Federal Food, Drug, and Cosmetic Act (21 U.S.C. 301 et seq.)
applies to a biological product subject to regulation under this
section, except that a product for which a license has been approved .
. . shall not be required to have an approved [new drug] application .
. . .''). Since blood and blood components are drugs or devices
generally subject to the FD&C Act, in issuing these regulations, FDA
relies on the FD&C Act's grant of authority to issue regulations for
the efficient enforcement of the FD&C Act (21 U.S.C. 371(a)). The FD&C
Act requires blood establishments to comply with the FD&C Act's current
good manufacturing practice provisions and related regulatory scheme.
Under section 501 of the FD&C Act (21 U.S.C. 351), drugs, including
blood and blood components, are deemed ``adulterated'' if the methods
used in their manufacturing, processing, packing, or holding do not
conform with current good manufacturing practice (21 U.S.C.
351(a)(2)(B)). Devices are deemed ``adulterated'' if the methods used
in, or the facilities or controls used for, their manufacture, packing,
storage, or installation are not in conformity with current good
manufacturing practice requirements established by FDA in regulations
(21 U.S.C. 351(h) and 360j(f)(1)). The provisions of this rule are
critical aspects of current good manufacturing practice. The regulation
requires collection establishments to assure that donors of blood and
blood components meet the essential criteria for eligibility, and that
blood and blood components are suitable for transfusion or further
manufacturing. Blood and blood components not manufactured in
accordance with current good manufacturing practice, including the
provisions of this rule, and other provisions in the CFR, would be
considered adulterated under 21 U.S.C. 351(a)(2)(B) or 21 U.S.C. 351(h)
and 360j(f)(1), and collection establishments and blood and blood
components would be subject to the FD&C Act's enforcement provisions
for violations of the FD&C Act. These include seizure of violative
products (21 U.S.C. 332), injunction against ongoing and future
violations, and criminal penalties (21 U.S.C. 333 and 18 U.S.C. 3571).
The FD&C Act punishes both misdemeanor and felony violations of the
FD&C Act. Misdemeanor violations are punishable by a term of
imprisonment of up to 1 year, a fine as described previously, or both.
(21 U.S.C. 333(a)(1), 18 U.S.C. 3571). Individuals convicted of felony
violations may be sentenced to a term of imprisonment of up to 3 years,
a fine of up to $250,000, or both. Organizations convicted of felony
violations may be sentenced to a fine of up to $500,000. Individuals
and organizations also face possible alternative fines based on the
amount of gain or loss (18 U.S.C. 3571(b) through (d)).
IV. Analysis of Impacts
FDA has examined the impacts of the final rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612) and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct 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 Agency believes that this final rule is not a significant
regulatory action as defined by Executive Order 12866.
The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because the costs associated with this rule are
expected to be minimal, the Agency certifies that this rule will not
have a significant economic impact on a substantial number of small
entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that Agencies prepare a written statement, which includes an
[[Page 29888]]
assessment of anticipated costs and benefits, before proposing ``any
rule that includes any Federal mandate that may result in the
expenditure by State, local, and tribal governments, in the aggregate,
or by the private sector, of $100,000,000 or more (adjusted annually
for inflation) in any one year.'' The current threshold after
adjustment for inflation is $141 million, using the most current (2013)
Implicit Price Deflator for the Gross Domestic Product. FDA does not
expect this final rule to result in a 1-year expenditure that would
meet or exceed this amount.
This rule sets forth requirements for donor eligibility and
donation suitability to ensure the safety, purity, and potency of the
blood and blood components used for transfusion or for further
manufacture. Costs estimated in this analysis include costs related to
the SOPs and bacterial testing requirements for blood collection
establishments and transfusion services. The total upfront costs are
$16,042,628, and include costs related to the review, modification, and
creation of standard operation procedures. The mean annual costs of
$892,233 include costs related to the bacterial testing and speciation
of platelets. We anticipate that this final rule will preserve the
safety, purity, and potency of blood and blood components by preventing
unsafe units of blood or blood components from entering the blood
supply, and by providing recipients with increased protection against
communicable disease transmission. The requirements set forth in this
rule will also help to decrease the number of blood transfusion related
fatalities that are associated with the bacterial contamination of
platelets. The annual value of additional fatalities averted related by
testing of Whole Blood-derived platelets is estimated to be
approximately $27 million to $90 million and the annual value of
averted nonfatal sepsis infections is estimated to be $3.19 million to
$4.91 million.
The full discussion of economic impacts is available in Docket No.
FDA-2006-N-0040 (formerly Docket No. 2006N-0221) and at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm (Ref. 77).
V. Environmental Impact
FDA has determined under 21 CFR 25.30(h) that this action is of a
type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
VI. Federalism
FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the final
rule does not contain policies that have substantial direct effect 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, FDA has concluded that the
final rule does not contain policies that have federalism implications
as defined in the Executive Order and, consequently, a federalism
summary impact statement is not required.
VII. The Paperwork Reduction Act of 1995
This final rule contains information collection provisions that are
subject to review by the Office of Management and Budget (OMB) under
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The title,
description, and respondent description of the information collection
provisions are shown in the following paragraphs with an estimate of
the annual reporting, recordkeeping, and disclosure burdens. 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: Requirements for Blood and Blood Components Intended for
Transfusion or for Further Manufacturing Use.
Description: FDA is amending the regulations applicable to blood
and blood components, including Source Plasma, to make donor
eligibility and testing requirements more consistent with current
practices in the blood industry, to more closely align the regulations
with current FDA recommendations, and to provide flexibility to
accommodate advancing technology. The following information collection
provisions are for recordkeeping, and third party disclosure.
In this final rule, under Sec. 606.100(b), FDA requires
establishments to establish, maintain, and follow written SOPs for all
steps in the collection, processing, compatibility testing, storage,
and distribution of blood and blood components for allogeneic
transfusion, autologous transfusion, and further manufacturing
purposes. Under this provision, FDA also clarifies that establishments
must establish, maintain, and follow written SOPs for all steps in the
investigation of product deviations related to Sec. 606.171; and for
all steps in recordkeeping related to current good manufacturing
practice and other applicable requirements and standards. FDA has
separated the requirements for procedures for donor deferral and donor
notification, previously provided under Sec. 606.100(b)(20), into the
requirement for procedures for donor deferral under Sec.
606.100(b)(20) and the procedures for donor notification under Sec.
606.100(b)(21). In addition, under Sec. 606.100(b)(22), blood
collection establishments and transfusion services must have procedures
to control the risk of bacterial contamination of platelets, including
all steps required under Sec. 606.145.
FDA continues to require, under Sec. 606.160(b)(1)(i), collection
establishments to maintain donor records that include donor selection,
including medical interview and examination and where applicable,
informed consent. The regulations in this final rule that pertain to
the requirements to maintain donor records under Sec.
606.160(b)(1)(i), are as follows:
Sec. 606.110(a)(2) allows for the use of plateletpheresis
and leukapheresis procedures provided that the procedure is performed
under the supervision of a responsible physician who is aware of the
health status of the donor, and the physician has determined and
documented that the donor's health permits plateletpheresis or
leukapheresis.
Sec. 630.5(b)(1)(i) allows the responsible physician to
delegate to a physician substitute or other trained person the activity
of determining the eligibility of a donor and documenting assessments
related to that determination (with certain specified exceptions).
Sec. 630.10(f)(2) allows a donor with blood pressure
measurements outside of the established limits to donate only when the
responsible physician determines and documents that the health of the
donor would not be adversely affected by donating.
Sec. 630.10(f)(4) allows a donor with an irregular pulse
or measurements outside of the established limits to donate only when
the responsible physician determines and documents that the health of
the donor would not be adversely affected by donating.
Sec. 630.10(g)(2)(i) requires that prior to each
donation, collection establishments must provide information to the
donor addressing the elements specified in Sec. 630.10(g)(2)(ii)(A)
through (g)(2)(ii)(E) and obtain the donor's
[[Page 29889]]
acknowledgement that the donor has reviewed the information.
Sec. 630.15(a)(1)(ii)(A) requires that when a donation is
for autologous use, the responsible physician must determine and
document that the donation may proceed.
Sec. 630.15(b)(2) requires that: (1) The responsible
physician must obtain the informed consent of a plasma donor on the
first day of donation or no more than 1 week before the first donation,
and at subsequent intervals of no longer than 1 year; (2) the
responsible physician must obtain the informed consent of a plasma
donor who does not return within 6 months of the last donation; (3) the
responsible physician must explain the risks and hazards of the
procedure to the donor; (4) if a donor is enrolled in a new program,
such as an immunization or special collection program, the responsible
physician must again obtain an informed consent specific for that
program.
Sec. 630.15(b)(7)(i) requires that the responsible
physician determines and documents that the donor is in good health and
the donor's health permits the plasmapheresis.
Sec. 630.15(b)(7)(iii) requires that special
characteristics of the donor's plasma and the need for plasmapheresis
of the donor under Sec. 630.20(b) are documented at the establishment.
Sec. 630.20(a) allows for the collection of blood and
blood components from a donor who is determined to be not eligible to
donate under any provision of Sec. 630.10(e) and (f) or Sec.
630.15(a), if the donation is for autologous use only as prescribed by
the donor's physician, and the donor has a hemoglobin level no less
than 11.0 grams of hemoglobin per deciliter of blood or a hematocrit
value no less than 33 percent, and the responsible physician determines
and documents that the donor's health permits the collection procedure.
Sec. 630.20(b) allows for plasma to be collected under a
Source Plasma collection program for further manufacturing use into in
vitro products for which there are no alternative sources from a donor
who is determined to be not eligible to donate under any provision of
Sec. 630.10(e) and (f) or Sec. 630.15(a), if the donor meets the
criteria in Sec. 630.10(f)(1) through (6) and the responsible
physician determines and documents for each donation that the donor's
health permits the collection procedure, and the collection takes place
under the medical oversight specified in the approved plasmapheresis
program.
Sec. 640.21(e)(4) allows, for a period not to exceed 30
calendar days, a donor to serve as a dedicated plateletpheresis donor
for a single recipient, in accordance with Sec. 610.40(c)(1), as often
as is medically necessary, provided in part, that the donor is in good
health, as determined and documented by the responsible physician.
FDA redesignated Sec. 606.160(b)(1)(ix) to Sec. 606.160(b)(1)(x),
and redesignated Sec. 606.160(b)(1)(x) to Sec. 606.160(b)(1)(ix).
Also, FDA replaced previous cross-reference to Sec. 630.6 with new
cross-reference to Sec. 630.40 in Sec. 606.160(b)(1)(x) and
(b)(1)(xi).
FDA revised Sec. 606.160(e) to require establishments to maintain
two records to include the following sections: (1) A record of all
donors found to be ineligible or deferred at that location; so that
blood and blood components from an ineligible donor are not collected
and/or released while the donor is ineligible or deferred and (2)
establishments must maintain at all locations operating under the same
license or under common management a cumulative record of donors
deferred from donation were reactive for evidence of infection due to
HIV, HBV, or HCV. In addition, establishments other than Source Plasma
establishments must include in this cumulative record donors deferred
for evidence of infection due to HTLV or Chagas disease; (3) the
cumulative record must be updated at least monthly to add donors newly
deferred for the reasons described herein; (4) in addition,
establishments must revise the cumulative record to remove donors who
have been requalified under Sec. 610.41(b).
Under final Sec. 606.145(c), in the event a transfusion service
identifies platelets as bacterially contaminated, the transfusion
service must not release the product and must notify the blood
collection establishment that provided the platelets. In addition, the
transfusion service must take appropriate steps to identify the
organism; these steps may include contracting with the collection
establishment or a laboratory to identify the organism. The transfusion
service must further notify the blood collection establishment either
by providing information about the species of the contaminating
organism when the transfusion service has been able to identify it, or
by advising the blood collection establishment when the transfusion
service has determined that the species cannot be identified.
Under final Sec. 630.5(d), collection establishments must
establish, maintain, and follow SOPs for obtaining rapid emergency
medical services for donors when medically necessary. Under final Sec.
630.10(b), collection establishments must provide educational material
concerning relevant transfusion-transmitted infections to donors before
donation when donor education about that relevant transfusion-
transmitted infection is necessary to assure the safety, purity, and
potency of blood and blood components.
Under Sec. 630.10(c)(1) and (2), collection establishments may
perform certain activities, provided that these activities are
addressed in their SOPs.
FDA requires under Sec. 630.15(a)(1)(ii)(B), that for a dedicated
donation based on the intended recipient's documented exceptional
medical need, the responsible physician determines and documents that
the health of the donor would not be adversely affected by donating.
Under Sec. 630.15(a)(2) collection establishments may collect more
frequently than once in 8 weeks for collections resulting in a single
unit of Whole Blood or Red Blood Cells, or once in 16 weeks for
apheresis collections resulting in two units of Red Blood Cells, when
the donor is determined under Sec. 630.10 to be eligible to undergo a
therapeutic phlebotomy, provided that the container label conspicuously
states the disease or condition of the donor that necessitated
phlebotomy. However, no disease state labeling is required when the
conditions under Sec. 630.15(a)(2)(i) through (iii) are met.
Under Sec. 630.20(c), a collection establishment may collect blood
and blood components from a donor who is determined to be not eligible
to donate under any provision of Sec. 630.10(e) and (f) or Sec.
630.15(a), if the donation is restricted for use solely by a specific
transfusion recipient based on documented exceptional medical need, and
the responsible physician determines and documents that the donor's
health permits the collection procedure, and that the donation presents
no undue medical risk to the transfusion recipient.
FDA redesignated Sec. 630.6 to Sec. 630.40, which requires
collection establishments under Sec. 630.40(a) to make reasonable
attempts to notify any donor, including an autologous donor, who has
been deferred based on the results of tests for evidence of infection
with a relevant transfusion-transmitted infection(s), as required under
Sec. 610.41(a); or any donor who has been deferred as required under
Sec. 630.30(b)(3) because their donated platelets have been determined
under Sec. 606.145(d) to be contaminated with an organism that is
identified as likely to be associated with a bacterial infection that
is endogenous to the bloodstream of
[[Page 29890]]
the donor; and any donor who has been determined not to be eligible as
a donor based on eligibility criteria under Sec. Sec. 630.10 and
630.15.
Under Sec. 640.21(c), a Whole Blood donor must not serve as the
source of platelets for transfusion if the donor has recently ingested
a drug that adversely affects platelet function, unless the unit is
labeled to identify the ingested drug that adversely affects platelet
function.
FDA separated Sec. 640.72(a)(2) into Sec. 640.72(a)(2)(i) and
(ii), and redesignated the cross-reference previously provided in Sec.
640.72(a)(2) from Sec. 640.63 to Sec. 630.10, and added cross-
reference to Sec. 630.15. Final Sec. 640.72(a)(2)(i) requires
establishments that collect plasma to maintain records, including a
separate and complete record of initial and periodic examinations,
tests, laboratory data, and interviews etc., as required in Sec. Sec.
630.10, 630.15, 640.65, 640.66, and 640.67, except as provided in Sec.
640.72(a)(2)(ii). Final Sec. 640.72(a)(2)(ii) provides that negative
results for testing for evidence of infection due to relevant
transfusion-transmitted infections required in Sec. 610.40, and the
volume or weight of plasma withdrawn from a donor need not be recorded
on the individual donor record if such information is maintained on the
premises of the plasmapheresis center where the donor's plasma has been
collected.
Under Sec. 640.72(a)(4), collection establishments must maintain
records of the medical history and physical examination of the donor
conducted in accordance with Sec. 630.15(b)(1) and, where applicable,
Sec. 630.15(b)(5), and must document the eligibility of the donor as a
plasmapheresis donor, and, when applicable, as an immunized donor.
Description of Respondents: Licensed and unlicensed, registered
blood establishments that collect blood and blood components for
transfusion, licensed blood establishments that collect Source Plasma,
and registered and unregistered transfusion services.
As required by section 3506(c)(2)(B) of the Paperwork Reduction
Act, FDA provided an opportunity for public comment on the information
collection requirements of the proposed rule (72 FR 63416 at 63434).
Based on information received from FDA's database systems, there
are approximately 1,265 licensed blood collection establishments and
approximately 416 licensed Source Plasma establishments, for a total of
1,681 licensed blood collection establishments. Also, there are
approximately 680 total unlicensed, registered blood collection
establishments. The approximate total of 2,361 collection
establishments, includes the 1,265 licensed blood collection
establishments, 416 licensed Source Plasma establishments, and 680
total unlicensed, registered blood collection establishments. FDA
estimates that there are 4,961 total transfusion services. Most of
these transfusion services are not required to register with FDA.
The recordkeeping and third party disclosure estimates are based on
information provided by industry, CMS, GAO, HHS, and FDA experience.
Based on this information, FDA estimates that collection establishments
annually collect approximately 40 million units of Whole Blood and
blood components, which includes approximately 25 million donations of
Source Plasma from approximately 2 million donors, and approximately 15
million \1\ donations of Whole Blood and apheresis Red Blood Cell
donations from approximately 10.9 million donors, including
approximately 225,000 (1.5 percent of 15 million) autologous donations.
Assuming each autologous donor makes an average of 2 donations, FDA
estimates that there are approximately 112,500 autologous donors.
---------------------------------------------------------------------------
\1\ These estimates are based on the 2011 National Blood
Collection and Utilization Survey Report, which estimated that a
total of 15,721,000 Whole Blood and Red Blood Cell units were
collected in 2011. The 2011 report noted a decline in the numbers of
Whole Blood and Red Blood Cell units collected and transfused.
---------------------------------------------------------------------------
FDA estimates the information collection burden as follows:
Table 1--Estimated Annual Recordkeeping Burden \1\
----------------------------------------------------------------------------------------------------------------
Number of Average
21 CFR section Number of records per Total annual burden per Total hours
recordkeepers recordkeeper records recordkeeping
----------------------------------------------------------------------------------------------------------------
606.100(b) (Maintenance of SOPs) 2,361 1 2,361 24 56,664
\2\.............................
606.100(b) (Maintenance of SOPs) 4,961 1 4,961 10 49,610
\3\.............................
606.160(b)(1)(i) \4\............. 2,361 16,942 40,000,000 0.17 6,800,000
630.15(a)(1)(ii)(B).............. 1,945 1 1,945 1 1,945
630.20(c)........................ 1,945 1 1,945 1 1,945
640.72(a)(4)..................... 416 4,808 2,000,000 0.08 160,000
------------------------------------------------------------------------------
Total........................ .............. .............. .............. ............. 7,070,164
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
\2\ The recordkeeping requirements in Sec. Sec. 606.171, 630.5(d), and 630.10(c)(1) and (2) are included in
the estimate for Sec. 606.100(b).
\3\ The recordkeeping requirements in Sec. 606.100(b)(22) is included in the estimate for Sec. 606.100(b).
\4\ The recordkeeping requirements in Sec. Sec. 606.110(a)(2); 606.160(e); 630.5(b)(1)(i); 630.10(f)(2) and
(4); 630.10(g)(2)(i); 630.15(a)(1)(ii)(A) and (a)(1)(ii)(B); 630.15(b)(2), (b)(7)(i) and (b)(7)(iii);
630.20(a) and (b); and 640.21(e)(4), are included in the estimate for Sec. 606.160(b)(1)(i).
Table 2--Estimated One-Time Recordkeeping Burden \1\
----------------------------------------------------------------------------------------------------------------
Number of
21 CFR section Number of records per Total annual Hours per Total hours
recordkeepers recordkeeper records record
----------------------------------------------------------------------------------------------------------------
606.100(b) (Review and Modify 1,574 1 1,574 40 62,960
SOPs) \2\......................
606.100(b) (Review and Modify 787 1 787 60 47,220
SOPs) \2\......................
606.100(b) (Review and Modify 4,961 1 4,961 16 79,376
SOPs)..........................
606.100(b)(22) (Establish SOPs). 1,488 1 1,488 16 23,808
-------------------------------------------------------------------------------
[[Page 29891]]
Total....................... .............. .............. .............. .............. 213,364
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
\2\ The recordkeeping requirements in Sec. Sec. 606.171; 630.5(d); and 630.10(c)(1) and (2), are included in
the estimate for Sec. 606.100(b).
Table 3--Estimated Annual Third-Party Disclosure Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of Average burden
21 CFR section Number of disclosures per Total annual per disclosure Total hours
respondents respondent disclosures (in hours)
--------------------------------------------------------------------------------------------------------------------------------------------------------
606.145(c)......................................................... 4,961 0.28 1,400 0.02 28
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
Recordkeeping: As shown in table 1, under Sec. 606.100(b), FDA
estimates that for the 2,361 recordkeepers, which includes
approximately 1,265 licensed blood collection establishments,
approximately 416 licensed Source Plasma establishments, and
approximately 680 total unlicensed, registered blood collection
establishments, it will take approximately 24 hours annually to review
and maintain SOPs. The recordkeeping requirements in Sec. Sec.
606.171, 630.5(d), and 630.10(c)(1) and (2) are included in the
estimate for Sec. 606.100(b).
In addition, the information collection burden under Sec.
606.100(b)(22), for the transfusion services to maintain their SOPs is
included in the information collection burden estimate under Sec.
606.100(b).
The information collection burden for Sec. Sec. 606.110(a)(2);
606.160(e); 630.5(b)(1)(i); 630.10(f)(2) and (4); 630.10(g)(2)(i);
630.15(a)(1)(ii)(A) and (B); 630.15(b)(2), (b)(7)(i) and (b)(7)(iii);
630.20(a) and (b); and 640.21(e)(4), refer to the requirement to
maintain records for donor selection under Sec. 606.160(b)(1)
specifically Sec. 606.160(b)(1)(i) and are included in the information
collection burden estimate under this regulation.
In table 1, under Sec. 630.15(a)(1)(ii)(B) and Sec. 630.20(c),
FDA calculates the information collection burden that for the 1,945
recordkeepers, which includes approximately 1,265 licensed blood
collection establishments and approximately 680 registered blood
collection establishments. The donation would be used solely by a
specified recipient based on documented medical need, and thus would
occur rarely. Consequently, the burden to collection establishments is
minimal.
The revisions to Sec. 606.160(b)(1)(ix) through (xi) are technical
amendments and do not result in any new information collection burden.
The information collections for these sections have been approved under
OMB control number 0910-0116.
FDA is not calculating the information collection burden for final
Sec. 606.100(b)(20) and (21) because these regulations have not been
changed only redesignated. The information collection for final Sec.
606.100(b)(20) and (21) have been approved under OMB control number
0910-0116.
Under Sec. 606.160(e), FDA is not calculating the information
collection burden specifically for establishments to maintain donor
records because there is either minimal or no additional burden
associated with the final Sec. 606.160(e) because establishments have
either been maintaining these records or providing access to these
records at locations operating under the same license or under common
management under current regulation(s) or guidance(s), or as part of
their usual and customary business practice. In addition, the number of
ineligible donors for which the establishments must maintain records
has been decreased from the proposed rule in this final rule, which
reduces the information collection burden for this requirement. The
information collection for Sec. 606.160(e) have been approved as part
of Sec. 606.160 under OMB control number 0910-0116.
FDA is not calculating the information collection burden for Sec.
640.72(a)(2)(i), because the information collection for maintaining a
complete record of all initial and periodic examinations, tests,
laboratory data, interviews, etc., for final Sec. 630.10 (redesignated
from Sec. 640.63) and Sec. Sec. 640.65, 640.66, and 640.67 have been
approved under OMB control number 0910-0116. In addition, the
information collection cross-referenced under Sec. 630.15, is included
in the information collection burden estimate for Sec.
606.160(b)(1)(i). FDA is not calculating the information collection
burden for Sec. 640.72(a)(2)(ii), because there is no additional
burden and is covered under OMB control number 0910-0116.
As shown in table 2, under Sec. 606.100(b), FDA estimates that for
the 2,361 recordkeepers, two-thirds or 1,574 of the collection
establishments will each expend, as a one-time burden, to reconcile
their SOPs with the requirements. FDA estimates for the remaining one-
third or 787 of the collection establishments each will expend
additional time to establish and reconcile their SOPs with the
requirements. The one-time recordkeeping requirements in Sec. Sec.
606.171, 630.5(d), and 630.10(c)(1) and (2) are included in the
estimate for Sec. 606.100(b).
In table 2, under Sec. 606.100(b)(22), FDA estimates that for the
4,961 transfusion services potentially impacted by this rule, 40
percent are following the voluntary standards for testing, speciation,
and notifying the blood establishment, as usual and customary practice.
For the remaining 60 percent (2,977) transfusion services,
approximately one-half (1,488) would be impacted by the rule and each
of these would expend, as a one-time burden, and to create SOPs
consistent with the requirements.
Third Party Disclosure: In table 3, under Sec. 606.145(c), FDA
estimates that for the approximate 4,961 transfusion services, there
would be 1,400 total notifications per year to blood collection
establishments (700 notifications per year that platelets are
bacterially contaminated and 700 notifications per year concerning the
identity or non-identity of the species of the contaminating organism).
The labeling requirements under Sec. 630.15(a)(2), are consistent
with the
[[Page 29892]]
current requirement under Sec. 640.3(d) that donations from a donor
``shall not be used as a source of Whole Blood unless the container
label conspicuously indicates the donor's disease that necessitated
withdrawal of blood.'' FDA is not calculating the information
collection burden for Sec. 630.15(a)(2) because the burden is included
in the calculation for Sec. 640.3(d). In addition, Sec. 630.15(a)(2)
reduces the information collection burden by not requiring labeling
under the conditions specified in the regulation. The information
collection burden in Sec. 630.40(d) is approved under OMB control
number 0910-0116.
Under Sec. 630.10(b), FDA requires collection establishments to
provide the donor with educational material. FDA is not calculating the
information collection burden for this regulation because
establishments collecting blood and blood components perform this
activity as a usual and customary business practice and there is
minimal new information collection burden for this requirement.
The information collection burden in final Sec. 630.40 resulting
from the redesignation of Sec. 630.6 has been approved under OMB
control number 0910-0116. Under final Sec. 630.40, FDA considers the
changes in text from ``communicable disease'' to ``relevant
transfusion-transmitted infection(s)'', ``suitable'' to ``eligible'',
and ``suitability'' to ``eligibility'', to be technical amendments that
do not confer any new burden. FDA is not calculating the information
collection burden under Sec. 606.145(d) for the additional requirement
that establishments that collect blood or blood components make
reasonable attempts to notify any donor whose donated platelets have
been determined to be contaminated with an organism that is identified
as likely to be associated with a bacterial infection that is
endogenous to the bloodstream of the donor, because establishments
perform this activity as a usual and customary business practice and
there is minimal new information collection burden for this
requirement. The third party disclosure burden under Sec.
630.30(b)(4), is covered under Sec. 630.40.
Under Sec. 640.21(c), FDA requires the establishments to label
donations received from platelet donors who have recently ingested a
drug that adversely affects platelet function to identify the ingested
drug. FDA is not calculating the information collection burden for this
regulation as there is minimal additional burden for this requirement
because establishments collecting blood and blood components perform
this activity as a usual and customary business practice.
The collections of information under Sec. 640.120 has been
approved under OMB control number 0910-0338. FDA is not calculating
information collection burden for Sec. 640.120, because the changes
that were made will not have an impact on the current burden estimated
for industry.
The information collection provisions in this final rule have been
submitted to OMB for review as required by section 3507(d) of the
Paperwork Reduction Act of 1995.
Before 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 control number.
VIII. References
The following references have been placed on display in the
Division of Dockets Management (see ADDRESSES) and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
(FDA has verified the Web site addresses, but FDA is not responsible
for any subsequent changes to the Web site after this document
publishes in the Federal Register.)
1. HHS, Blood Action Plan, FDA/CBER, July 1997.
2. U.S. House of Representatives, Committee on Government Reform and
Oversight, Subcommittee on Human Resources and Intergovernmental
Relations, ``Protecting the Nation's Blood Supply from Infectious
Agents: The Need for New Standards to Meet New Threats,'' August 2,
1996, http://www.gpo.gov/fdsys/pkg/CRPT-104hrpt746/html/CRPT-104hrpt746.htm.
3. U.S. General Accounting Office, ``Blood Supply: FDA Oversight and
Remaining Issues of Safety,'' February 25, 1997, http://www.gao.gov/products/PEMD-97-1.
4. Stramer, S. L., F. B. Hollinger, L. Katz, et al., ``Emerging
Infectious Disease Agents and Their Potential Threat to Transfusion
Safety,'' Transfusion, August 2009; 49:1S-29S.
5. Stramer, S. L. and R. Y. Dodd, ``Transfusion-Transmitted Emerging
Infectious Diseases: 30 Years of Challenges and Progress,''
Transfusion, October 2013, 53:2375-2383.
6. FDA, ``Guidance for Industry: Implementation of Acceptable Full-
Length Donor History Questionnaire and Accompanying Materials for
Use in Screening Donors of Blood and Blood Components,'' October
2006, http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm073445.htm.
7. FDA, ``Guidance for Industry: Implementation of an Acceptable
Full-Length and Abbreviated Donor History Questionnaires and
Accompanying Materials for Use in Screening Donors of Source
Plasma,'' February 2013, http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/BloodDonorScreening/UCM341088.pdf.
8. FDA, ``Guidance for Industry: Implementation of an Acceptable
Abbreviated Donor History Questionnaire and Accompanying Materials
for Use in Screening Frequent Donors of Blood and Blood
Components,'' May 2013, http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm351107.htm.
9. ``Transmission of HIV Possibly Associated with Exposure of Mucous
Membrane to Contaminated Blood,'' Morbidity and Mortality Weekly
Report, July 11, 1997; 46(27):620-623.
10. FDA Memorandum: ``Revised Recommendations for the Prevention of
Human Immunodeficiency Virus (HIV) Transmission by Blood and Blood
Products,'' April 1992, http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/OtherRecommendationsforManufacturers/MemorandumtoBloodEstablishments/UCM062834.pdf.
11. FDA, ``Guidance for Industry: Revised Preventive Measures to
Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob
Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood
and Blood Products,'' May 2010, http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/UCM213415.pdf.
12. Dumont, L. J., S. Kleinman, J. R. Murphy, et al., ``Screening of
Single-Donor Apheresis Platelets for Bacterial Contamination: The
PASSPORT Study Results,'' Transfusion, March 2010; 50:589-599.
13. Yomtovian, R. A. and M. Brecher, ``pH and Glucose Testing of
Single-Donor Apheresis Platelets Should be Discontinued in Favor of
a More Sensitive Detection Method,'' Transfusion 2005; 4:646-648.
14. Jacobs, M. R., C. E. Good, H. M. Lazarus, et al., ``Relationship
Between Bacterial Load, Species Virulence, and Transfusion Reaction
with Transfusion of Bacterially Contaminated Platelets,'' Clinical
Infectious Disease, 2008; 46:1214-1220.
15. FDA, ``Fatalities Reported to FDA Following Blood Collection and
Transfusion: Annual Summary for Fiscal Year 2012,'' http://
www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/
ReportaProblem/
[[Page 29893]]
TransfusionDonationFatalities/ucm346639.htm.
16. College of American Pathologists, ``Commission on Laboratory
Accreditation: Laboratory Accreditation Program, Transfusion
Medicine Checklist,'' September 27, 2007.
17. AABB Association Bulletin #03-12, ``Further Guidance on Methods
to Detect Bacterial Contamination of Platelet Components,'' October
2003.\2\
---------------------------------------------------------------------------
\2\ There is a new version of this document that continues to
implement this standard.
---------------------------------------------------------------------------
18. Eder, A. F. and M. Goldman, ``How Do I Investigate Septic
Transfusion Reactions and Blood Donors with Culture-Positive
Platelet Donations?'' Transfusion, August 2011; 51:1662-1668.
19. Gold, J. S., S. Bayar, and R. R. Salem, ``Association of
Streptococcus bovis Bacteremia with Colonic Neoplasia and
Extracolonic Malignancy,'' Archives of Surgery, 2004; 139(7):760-
765.
20. AABB ``Public Conference: Secondary Bacterial Screening of
Platelet Components,'' July 17, 2012.
21. Domen, R. E., I. D. Grewal, N. V. Hirschler, et al., ``An
Evaluation of the Need for Shared Blood Donor Deferral Registries,''
International Journal for Quality in Health Care, 1997; 9:35-41.
22. Ellis, F. R., L. I. Friedman, B. F. Wirak, et al., ``A
Computerized National Blood Donor Deferral Register,'' The Journal
of the American Medical Association, 1975; 232(7):722-724.
23. Plasma Protein Therapeutics Association, ``National Donor
Deferral Registry (NDDR)''
24. FDA, ``Guidance for Industry: Use of Serological Tests to Reduce
the Risk of Transmission of Trypanosoma cruzi Infection in Whole
Blood and Blood Components Intended for Transfusion,'' December
2010, http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm235855.htm.
25. Blood Products Advisory Committee, 94th meeting, April 1, 2009,
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/UCM155628.pdf.
26. Blood Products Advisory Committee, 67th meeting, September 15,
2000, http://www.fda.gov/ohrms/dockets/ac/00/agenda/3649a1.pdf.
27. Ortel, T. L., ``Antiphospholipid Syndrome: Laboratory Testing
and Diagnostic Strategies,'' American Journal of Hematology, 2012;
87:S75-S81.
28. FDA, ``Guidance for Industry: Donor Screening for Antibodies to
HTLV-II,'' August 1997, http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm170786.htm.
29. FDA, ``Guidance for Industry: Requalification Method for Reentry
of Blood Donors Deferred Because of Reactive Test Results for
Antibody to Hepatitis B Core Antigen (Anti-HBc),'' May 2010, http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/UCM210268.pdf.
30. FDA Memorandum: ``Recommendations to Decrease the Risk of
Transmitting Acquired Immune Deficiency Syndrome (AIDS) from Blood
Donors,'' March 24, 1983.
31. AABB Association Bulletin #03-14, ``Deferral for Risk of
Leishmaniasis Exposure,'' October 10, 2003.
32. Bai, N., ``Donor Fatigue. The Red Cross Has Banned Chronic
Fatigue Syndrome Sufferers from Giving Blood. But Does a Virus
Really Cause the Disease?'' Scientific American, July 2011;
305(1):26.
33. Young, S., A. Fink, S. Geiger, et al., ``Community Blood Donors'
Knowledge of Anemia and Design of a Literacy-Appropriate Educational
Intervention,'' Transfusion, January 2010; 50:75-79.
34. FDA, ``Guidance for Industry: Recommendations for Blood
Establishments: Training of Back-Up Personnel, Assessment of Blood
Donor Suitability and Reporting Certain Changes to an Approved
Application,'' November 2010, http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/UCM190373.pdf.
35. FDA, ``Guidance for Industry: Assessing Donor Suitability and
Blood and Blood Product Safety in Cases of Known or Suspected West
Nile Virus Infection,'' June 2005, http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm080286.pdf.
36. FDA, ``Guidance for Industry: Revised Recommendations for the
Assessment of Donor Suitability and Blood Product Safety in Cases of
Suspected Severe Acute Respiratory Syndrome (SARS) or Exposure to
SARS,'' September 2003, http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm080301.pdf.
37. FDA, Draft ``Guidance for Industry: Precautionary Measures to
Reduce the Possible Risk of Transmission of Zoonoses by Blood and
Blood Products from Xenotransplantation Product Recipients and Their
Intimate Contacts,'' February 2002, http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm080375.pdf.
38. FDA Memorandum: ``Deferral of Blood and Plasma Donors Based on
Medications,'' July 28, 1993, http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/OtherRecommendationsforManufacturers/MemorandumtoBloodEstablishments/UCM062813.pdf.
39. FDA, ``Guidance for Industry: Recommendations for Assessment of
Donor Suitability and Blood and Blood Product Safety in Cases of
Possible Exposure to Anthrax,'' October 2001, http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm062638.pdf.
40. HHS, NIH ``The Seventh Report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure,'' August 2004.
41. Trouern-Trend, J. J., R. G. Cable, S. J. Badon, et al., ``A
Case-Controlled Multicenter Study of Vasovagal Reactions in Blood
Donors: Influence of Sex, Age, Donation Status, Weight, Blood
Pressure, and Pulse,'' Transfusion, March 1999; 39:316-320.
42. Wiltbank, T. B., G. F. Giordano, H. Kamel, et al., ``Faint and
Prefaint Reactions in Whole-Blood Donors: An Analysis of Predonation
Measurements and Their Predictive Value,'' Transfusion, September
2008; 48:1799-1808.
43. Blood Product Advisory Committee, 92nd meeting, September 10,
2008, http://www.fda.gov/ohrms/dockets/ac/08/agenda/2008-4379A(draft).pdf.
44. Blood Product Advisory Committee, 98th meeting, July 27, 2010,
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/UCM218990.pdf.
45. HHS, U.S. Public Health Service, Advisory Committee on Blood
Safety and Availability, 35th meeting, December 17, 2008, http://www.hhs.gov/ash/bloodsafety/advisorycommittee/minutes/dec2008_minutes.pdf.
46. FDA, ``Public Workshop: Hemoglobin Standards and Maintaining
Adequate Iron Stores in Blood Donors,'' November 8-9, 2011, http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm268757.htm.
47. Weber, J. P., P. C. Walsh, C. A. Peters, et al., ``Effect of
Reversible Androgen Deprivation on Hemoglobin and Serum
Immunoreactive Erythropoietin in Men,'' American Journal of
Hematology, March 1991; 36:190-194.
48. Ryan, D. H., Chapter 2. Examination of Blood Cells. In: Prachal,
J. T., K. Kaushansky, M. A. Lichtman, T. J. Kipps, and U. Seligsohn,
eds. Williams Hematology. 8th ed. New York: McGraw-Hill; 2010.
49. Cable, R. G., W. R. Steele, R. S. Melmed, et al., ``The
Difference Between Fingerstick and Venous Hemoglobin and Hematocrit
Varies by Sex and Iron Stores,'' NHLBI Retrovirus Epidemiology Donor
Study-II (REDS-II). Transfusion, May 2012; 52:1031-1040.
50. Cable, R. G., S. A. Glynn, J. E. Kiss, et al., ``Iron Deficiency
in Blood Donors: the REDS-II Donor Iron Status Evaluation (RISE)
Study,'' NHLBI Retrovirus Epidemiology Donor Study-II (REDS-II).
Transfusion, April 2012; 52:702-711.
51. LeBlond, R. F., D. D. Brown, and R. L. DeGowin, Chapter 4,
``Vital Signs, Anthropometric Data, and Pain,'' DeGowin's Diagnostic
Examination, 9th ed. New York: McGraw-Hill; 2009.
[[Page 29894]]
52. Blood Products Advisory Committee, 100th meeting, April 28-29,
2011, http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/UCM251509.pdf.
53. FDA, ``Guidance for Industry: Recommendations for Collecting Red
Blood Cells by Automated Apheresis Methods,'' January 2001.
Technical Correction February 2001, http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm076756.htm.
54. FDA, ``Guidance for Industry: Variances for Blood Collection
From Individuals with Hereditary Hemochromatosis,'' August 2001,
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm080393.pdf.
55. Tan, L., M. K. Khan, and J. C. Hawk III, ``Use of Blood
Therapeutically Drawn From Hemochromatosis Patients,'' Transfusion,
September 1999; 39:1018-1026.
56. HHS Memorandum: Summary of the Advisory Committee Meeting on
Blood Safety and Availability Meeting, April 29-30, 1999, http://www.hhs.gov/ash/bloodsafety/summaries/sumapr99.html.
57. Jeffrey, G. and P. C. Adams, ``Blood from Patients with
Hereditary Hemochromatosis-a Wasted Resource?'' Transfusion, June
1999; 39:549-550.
58. Shaz, B. H., D. A. Kessler, C. A. Hillyer, et al., ``Evaluating
the Role of Blood Collection Centers in Public Health: A Status
Report,'' Transfusion Medicine Reviews, January 2012; 26:58-67.
59. Kessler, D. A., R. Davey, J. Wilson, et al., ``A Financial
Analysis of Collecting Blood from Hereditary Hemochromatosis
Patients under Variance,'' Transfusion, 2003; 43: Abstract
Supplement, 167A:AP112.
60. McPherson, R. A., ``Specific Proteins'' Henry's Clinical
Diagnosis and Management by Laboratory Methods, 2007; (21): 31-242,
and 1409.
61. Laubach, J., P. Richardson, and K. Anderson, ``Multiple
Myeloma,'' Annual Reviews of Medicine, February 2011; 62:249-264.
62. FDA, ``Guidance for Industry: Informed Consent Recommendations
for Source Plasma Donors Participating in Plasmapheresis and
Immunization Programs,'' June 2007, http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm062905.pdf.
63. FDA Memorandum: ``Donor Deferral Due to Red Blood Cell Loss
During Collection of Source Plasma by Automated Plasmapheresis,''
December 4, 1995, http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/OtherRecommendationsforManufacturers/MemorandumtoBloodEstablishments/UCM062626.pdf.
64. FDA, ``Guidance for Industry and FDA Review Staff: Collection of
Platelets by Automated Methods,'' December 2007, http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm073382.htm.
65. Laub, R., S. Baurin, D. Timmerman, et al., ``Specific Protein
Content of Pools of Plasma for Fractionation from Different Sources:
Impact of Frequency of Donations,'' Vox Sanguinis: The International
Journal of Transfusion Medicine, October 2010; 99:220-231.
66. Lewis, S. L., S. G. Kutvirt, P. N. Bonner, et al., ``Plasma
Proteins and Lymphocyte Phenotypes in Long-Term Plasma Donors,''
Transfusion, July 1994; 34:578-585.
67. FDA Memorandum: ``Revised Recommendations for Testing Whole
Blood, Blood Components, Source Plasma and Source Leukocytes for
Antibody to Hepatitis C Virus Encoded Antigen (Anti-HCV),'' August
5, 1993, http://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/otherrecommendationsformanufacturers/memorandumtobloodestablishments/ucm062811.pdf.
68. Katz, L., K. Palmer, E. McDonnell, et al., ``Frequent
Plateletpheresis Does Not Clinically Significantly Decrease Platelet
Counts in Donors,'' Transfusion, September 2007; 47:1601-1606.
69. Lazarus, E. F., J. Browning, J. Norman, et al., ``Sustained
Decreases in Platelet Count Associated with Multiple, Regular
Plateletpheresis Donations,'' Transfusion, June 2001; 41:756-761.
70. Page, E. A., J. F. Harrison, E. J. Jadlow, et al., ``Impairment
of Short-Term Memory Associated with Low Iron Stores in a Volunteer
Multidose Plateletpheresis Donor,'' Transfusion Medicine, October
2008; 18:312-314.
71. Page, E. A., J. E. Coppock, and J. F. Harrsion, ``Study of Iron
Stores in Regular Plateletphereis Donors,'' Transfusion Medicine,
February 2010; 20:22-29.
72. Macher, S., S. Sipurzynski-Budra[beta], K. Rosskopf, et al.,
``Influence of Multicomponent Apheresis on Donors' Haematological
and Coagulation Parameters, Iron Storage and Platelet Function,''
Vox Sanguinis: The International Journal of Transfusion Medicine,
October 2012; 103:194-200.
73. U.S. General Accounting Office, Report to Chairman, Subcommittee
on Human Resources, Committee on Government Reform and Oversight,
House of Representatives, ``Blood Plasma Safety: Plasma Product
Risks Are Low if Good Manufacturing Practices Are Followed,''
September 9, 1998, http://www.gao.gov/archive/1998/he98205.pdf.
74. Plasma Protein Therapeutics Association, Quality Standards of
Excellence, Assurance and Leadership (QSEAL), Certification Program.
75. FDA Proposed Rule: Safety Reporting Requirements for Human Drug
and Biologicals (68 FR 12406, March 14, 2003), http://www.fda.gov/OHRMS/DOCKETS/98fr/03-5204.pdf.
76. FDA, Exceptions and Alternative Procedures Approved Under 21 CFR
640.120, http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/RegulationoftheBloodSupply/ExceptionsandAlternativeProcedures/default.htm.
77. Final Regulatory Impact Analysis, Final Regulatory Flexibility
Analysis, and Unfunded Mandates Reform Act Analysis for Requirements
for Blood and Blood Components Intended for Transfusion or for
Further Manufacturing Use, http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.
List of Subjects
21 CFR Part 606
Blood, Labeling, Laboratories, Reporting and recordkeeping
requirements.
21 CFR Parts 610 and 660
Biologics, Labeling, Reporting and recordkeeping requirements.
21 CFR Part 630
Blood, Reporting and recordkeeping requirements.
21 CFR Part 640
Blood, Labeling, Reporting and recordkeeping requirements.
21 CFR Part 820
Medical devices, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act, the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, 21 CFR Chapter I is amended as follows:
PART 606--CURRENT GOOD MANUFACTURING PRACTICE FOR BLOOD AND BLOOD
COMPONENTS
0
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.
0
2. In Sec. 606.3, revise paragraphs (a) and (c) to read as follows:
Sec. 606.3 Definitions.
* * * * *
(a) Blood means a product that is a fluid containing dissolved and
suspended elements which was collected from the vascular system of a
human.
* * * * *
(c) Blood component means a product containing a part of human
blood
[[Page 29895]]
separated by physical or mechanical means.
* * * * *
Sec. 606.40 [Amended]
0
3. In Sec. 606.40(a)(1), remove ``suitability'' and add in its place
``eligibility''.
0
4. Amend Sec. 606.100 as follows:
0
a. Revise paragraph (b) introductory text;
0
b. In paragraph (b)(1), remove ``suitability'' and add in its place
``eligibility'';
0
c. Revise paragraph (b)(20); and
0
d. Add paragraphs (b)(21) and (b)(22).
The revisions and additions read as follows:
Sec. 606.100 Standard operating procedures.
* * * * *
(b) Establishments must establish, maintain, and follow written
standard operating procedures for all steps in the collection,
processing, compatibility testing, storage, and distribution of blood
and blood components for allogeneic transfusion, autologous
transfusion, and further manufacturing purposes; for all steps in the
investigation of product deviations related to Sec. 606.171; and for
all steps in recordkeeping related to current good manufacturing
practice and other applicable requirements and standards. Such
procedures must be available to the personnel for use in the areas
where the procedures are performed. The written standard operating
procedures must include, but are not limited to, descriptions of the
following, when applicable:
* * * * *
(20) Procedures for donor deferral as prescribed in Sec. 610.41 of
this chapter.
(21) Procedures for donor notification and notification of the
referring physician of an autologous donor, including procedures for
the appropriate followup if the initial attempt at notification fails,
as prescribed in Sec. 630.40 of this chapter.
(22) Procedures to control the risks of bacterial contamination of
platelets, including all steps required under Sec. 606.145.
* * * * *
Sec. 606.110 [Amended]
0
5. Amend Sec. 606.110 as follows:
0
a. In paragraph (a), remove ``qualified licensed physician'' and add in
its place ``responsible physician'' and remove ``certified in writing''
and add in its place ``determined and documented''; and
0
b. In paragraph (b), remove ``640.63'' and add in its place ``630.10,
630.15''.
Sec. 606.121 [Amended]
0
6. Amend Sec. 606.121 as follows:
0
a. In paragraph (c)(11) remove ``communicable disease agents'' and add
in its place ``relevant transfusion-transmitted infections''; and
remove ``Sec. Sec. 610.40(i) and 640.65(b)'' and add in its place
``Sec. 640.65(b)'';
0
b. In paragraph (c)(12) remove ``communicable disease agent(s)'' and
add in its place ``relevant transfusion-transmitted infection(s)'';
0
c. In paragraphs (h)(2) and (3), remove ``640.5(a), (b),'' and add in
its place ``640.5(b)''; and
0
d. In paragraph (i)(5), remove ``suitability'' and add in its place
``eligibility''; remove ``Sec. 640.3'' and add it its place ``Sec.
630.10''; and remove ``communicable disease agents'' and add in its
place ``relevant transfusion-transmitted infections''.
Sec. 606.122 [Amended]
0
7. In Sec. 606.122(e), remove ``communicable disease agents'' and add
in its place ``relevant transfusion-transmitted infections''.
0
8. Add Sec. 606.145 to subpart H to read as follows:
Sec. 606.145 Control of bacterial contamination of platelets.
(a) Blood collection establishments and transfusion services must
assure that the risk of bacterial contamination of platelets is
adequately controlled using FDA approved or cleared devices or other
adequate and appropriate methods found acceptable for this purpose by
FDA.
(b) In the event that a blood collection establishment identifies
platelets as bacterially contaminated, that establishment must not
release for transfusion the product or any other component prepared
from the same collection, and must take appropriate steps to identify
the organism.
(c) In the event that a transfusion service identifies platelets as
bacterially contaminated, the transfusion service must not release the
product and must notify the blood collection establishment that
provided the platelets. The transfusion service must take appropriate
steps to identify the organism; these steps may include contracting
with the collection establishment or a laboratory to identify the
organism. The transfusion service must further notify the blood
collection establishment either by providing information about the
species of the contaminating organism when the transfusion service has
been able to identify it, or by advising the blood collection
establishment when the transfusion service has determined that the
species cannot be identified.
(d) In the event that a contaminating organism is identified under
paragraph (b) or (c) of this section, the collection establishment's
responsible physician, as defined in Sec. 630.3(i) of this chapter,
must determine whether the contaminating organism is likely to be
associated with a bacterial infection that is endogenous to the
bloodstream of the donor, in accordance with a standard operating
procedure developed under Sec. 606.100(b)(22). This determination may
not be further delegated.
0
9. In Sec. 606.160, revise paragraphs (b)(1)(ix) through (xi), and (e)
to read as follows:
Sec. 606.160 Records.
* * * * *
(b) * * *
(1) * * *
(ix) The donor's postal address provided at the time of donation
where the donor may be contacted within 8 weeks after donation.
(x) Records of notification of donors deferred or determined not to
be eligible for donation, including appropriate followup if the initial
attempt at notification fails, performed under Sec. 630.40 of this
chapter.
(xi) Records of notification of the referring physician of a
deferred autologous donor, including appropriate followup if the
initial attempt at notification fails, performed under Sec. 630.40 of
this chapter.
* * * * *
(e) Records of deferred donors. (1) Establishments must maintain at
each location a record of all donors found to be ineligible or deferred
at that location so that blood and blood components from an ineligible
donor are not collected and/or released while the donor is ineligible
or deferred; and
(2) Establishments must maintain at all locations operating under
the same license or under common management a cumulative record of
donors deferred from donation under Sec. 610.41 of this chapter
because their donation tested reactive under Sec. 610.40(a)(1) of this
chapter for evidence of infection due to HIV, HBV, or HCV. In addition,
establishments other than Source Plasma establishments must include in
this cumulative record donors deferred from donation under Sec. 610.41
of this chapter because their donation tested reactive under Sec.
610.40(a)(2) of this chapter for evidence of infection due to HTLV or
Chagas disease.
(3) The cumulative record described in paragraph (e)(2) of this
section must be updated at least monthly to add
[[Page 29896]]
donors newly deferred under Sec. 610.41 of this chapter due to
reactive tests for evidence of infection due to HIV, HBV, or HCV, and,
if applicable, HTLV or Chagas disease.
(4) Establishments must revise the cumulative record described in
paragraph (e)(2) of this section to remove donors who have been
requalified under Sec. 610.41(b) of this chapter.
PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS
0
10. The authority citation for 21 CFR part 610 continues 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.
0
11. Revise the heading for subpart E to read as follows:
Subpart E--Testing Requirements for Relevant Transfusion-
Transmitted Infections
0
12. Add Sec. 610.39 to subpart E to read as follows:
Sec. 610.39 Definitions.
The definitions set out in Sec. 630.3 of this chapter apply to
this subpart.
0
13. Amend Sec. 610.40 as follows:
0
a. Revise paragraph (a);
0
b. Revise paragraph (b);
0
c. Revise paragraph (c) heading;
0
d. Remove paragraph (c)(2) and redesignate paragraphs (c)(3) and (4) as
paragraphs (c)(2) and (3);
0
e. In redesignated paragraph (c)(2)(i), remove ``communicable disease
agents listed in paragraphs (a)(5) and (a)(6) of this section'' and add
in its place ``relevant transfusion-transmitted infections listed in
Sec. 630.3(h)(iv) of this chapter'';
0
f. In paragraph (d), remove ``communicable disease agents'' and add in
its place ``relevant transfusion-transmitted infections''; and remove
``or by a serological test for syphilis under paragraph (i) of this
section'';
0
g. Revise paragraph (e);
0
h. In paragraph (f), remove ``Health Care Financing Administration''
and add in its place ``Centers for Medicare and Medicaid Services'';
0
i. In paragraph (g) introductory text, remove ``communicable disease
agents'' in both places it appears and add in each place ``relevant
transfusion-transmitted infections''; and remove ``paragraphs (a) and
(i)'' and add in its place ``paragraph (a)'';
0
j. In paragraph (h)(1), remove ``a communicable disease agent(s)
designated in paragraphs (a) and (i)'' in both places it appears and
add in each place ``relevant transfusion-transmitted infection(s)
designated in paragraph (a)'';
0
k. In paragraphs (h)(2)(ii) introductory text, (h)(2)(ii)(C), and
(h)(2)(iv) introductory text, remove ``communicable disease agent(s)''
wherever it appears and add in its place ``relevant transfusion-
transmitted infection(s)'';
0
l. In paragraph (h)(2)(iv)(A), remove ``suitable'' and add in its place
``eligible'';
0
m. In paragraph (h)(2)(vi), remove ``paragraph (i)'' and add in its
place ``paragraph (a)''; and remove ``consistent with Sec. 640.5 of
this chapter,'';
0
n. In paragraph (h)(2)(vii), remove ``Sec. 610.40(i)'' and add in its
place ``Sec. 640.65(a)(2)(ii) and (b)(1)(i)''; and remove ``Sec.
640.65(b)(2)'' and add in its place ``Sec. 640.65(b)(2)(i) through
(b)(2)(iv)''; and
0
o. Remove paragraph (i).
The revisions 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 and blood components for transfusion or for use in
manufacturing a product, including donations intended as a component
of, or used to manufacture, a medical device, must comply with the
following requirements:
(1) Test each donation for evidence of infection due to the
relevant transfusion-transmitted infections described in Sec.
630.3(h)(1)(i) through (iii) of this chapter (HIV, HBV, and HCV).
(2) Test each donation for evidence of infection due to the
relevant transfusion-transmitted infections described in Sec.
630.3(h)(1)(iv) through (vii) of this chapter (HTLV, syphilis, West
Nile virus, and Chagas disease). The following exceptions apply:
(i) To identify evidence of infection with syphilis in donors of
Source Plasma, you must test donors for evidence of such infection in
accordance with Sec. 640.65(b) of this chapter, and not under this
section.
(ii) You are not required to test donations of Source Plasma for
evidence of infection due to the relevant transfusion-transmitted
infections described in Sec. 630.3(h)(1)(iv), (vi), and (vii) of this
chapter (HTLV, West Nile virus, and Chagas disease).
(iii) For each of the relevant transfusion-transmitted infections
described in Sec. 630.3(h)(1)(iv) through (vii) of this chapter (HTLV,
syphilis, West Nile virus, and Chagas disease):
(A) If, based on evidence related to the risk of transmission of
that relevant transfusion-transmitted infection, testing each donation
is not necessary to reduce adequately and appropriately the risk of
transmission of such infection by blood or a blood component, you may
adopt an adequate and appropriate alternative testing procedure that
has been found acceptable for this purpose by FDA.
(B) If, based on evidence related to the risk of transmission of
that relevant transfusion-transmitted infection, testing previously
required for that infection is no longer necessary to reduce adequately
and appropriately the risk of transmission of such infection by blood
or a blood component, you may stop such testing in accordance with
procedures found acceptable for this purpose by FDA.
(3) For each of the relevant transfusion-transmitted infections
described in Sec. 630.3(h)(1)(viii) through (x) of this chapter (CJD,
vCJD, malaria) and Sec. 630.3(h)(2) of this chapter (other
transfusion-transmitted infections):
(i) You must test for evidence of infection when the following
conditions are met:
(A) A test(s) for the relevant transfusion-transmitted infection is
licensed, approved or cleared by FDA for use as a donor screening test
and is available for such use; and
(B) Testing for the relevant transfusion-transmitted infection is
necessary to reduce adequately and appropriately the risk of
transmission of the relevant transfusion-transmitted infection by
blood, or blood component, or blood derivative product manufactured
from the collected blood or blood component.
(ii) You must perform this testing on each donation, unless one of
the following exceptions applies:
(A) Testing of each donation is not necessary to reduce adequately
and appropriately the risk of transmission of such infection by blood,
blood component, or blood derivative product manufactured from the
collected blood or blood component. When evidence related to the risk
of transmission of such infection supports this determination, you may
adopt an adequate and appropriate alternative testing procedure that
has been found acceptable for this purpose by FDA.
(B) Testing of each donation is not necessary to reduce adequately
and appropriately the risk of transmission of such infection by blood,
blood component, or blood derivative product manufactured from the
collected blood or blood component. When evidence related to the risk
of transmission of
[[Page 29897]]
such infection supports this determination, you may stop such testing
in accordance with procedures found acceptable for this purpose by FDA.
(4) Evidence related to the risk of transmission of a relevant
transfusion-transmitted infection that would support a determination
that testing is not necessary, or that testing of each donation is not
necessary, to reduce adequately and appropriately the risk of
transmission of such infection by blood or blood component, as
described in paragraphs (a)(2)(iii)(A) and (B) of this section, or by
blood, blood component, or blood derivative, as described in paragraphs
(a)(3)(ii)(A) and (B) of this section, includes epidemiological or
other scientific evidence. It may include evidence related to the
seasonality or geographic limitation of risk of transmission of such
infection by blood or blood component, or other information related to
when and how a donation is at risk of transmitting a relevant
transfusion-transmitted infection. It may also include evidence related
to the effectiveness of manufacturing steps (for example, the use of
pathogen reduction technology) that reduce the risk of transmission of
the relevant transfusion-transmitted infection by blood, blood
components, or blood derivatives, as applicable.
(b) Testing using one or more licensed, approved, or cleared
screening tests. To perform testing for evidence of infection due to
relevant transfusion-transmitted infections as required in paragraph
(a) of this section, you must use screening tests that FDA has
licensed, approved, or cleared 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 relevant transfusion-transmitted infections.
(c) Exceptions to testing for dedicated donations, medical devices,
and samples. * * *
* * * * *
(e) Further testing. You must further test each donation, including
autologous donations, found to be reactive by a donor screening test
performed under paragraphs (a) and (b) of this section using a
licensed, approved, or cleared supplemental test, when available. If no
such supplemental test is available, you must perform one or more
licensed, approved, or cleared tests as adequate and appropriate to
provide additional information concerning the reactive donor's
infection status. Except:
(1) For autologous donations:
(i) You must further test under this section, at a minimum, the
first reactive donation in each 30 calendar day period; or
(ii) If you have a record for that donor of a positive result on
further testing performed under this section, you do not have to
further test an autologous donation.
(2) You are not required to perform further testing of a donation
found to be reactive by a treponemal donor screening test for syphilis.
* * * * *
0
14. Amend Sec. 610.41 as follows:
0
a. In paragraph (a) introductory text, remove ``communicable disease
agent(s) listed in Sec. 610.40(a) or reactive for a serological test
for syphilis under Sec. 610.40(i)'' and add in its place ``relevant
transfusion-transmitted infection(s) under Sec. 610.40(a)'';
0
b. Revise paragraph (a)(1);
0
c. In paragraph (a)(2), remove ``communicable disease agent(s) listed
in'' and add in its place ``relevant transfusion-transmitted
infection(s) under'';
0
d. In paragraphs (a)(3) and (4), remove ``suitable'' and add in its
place ``eligible'';
0
e. In paragraph (a)(5), remove ``communicable disease agent(s)
described under Sec. 610.40(a) or reactive with a serological test for
syphilis under Sec. 610.40(i)'' and add in its place ``relevant
transfusion-transmitted infections(s) under Sec. 610.40(a)''; and
0
f. In paragraph (b), remove ``suitable'' and add in its place
``eligible''.
The revisions read as follows:
Sec. 610.41 Donor deferral.
(a) * * *
(1) You are not required to defer a donor who tests reactive for
anti-HBc or anti-HTLV, types I and II, on only one occasion. However,
you must defer the donor if further testing for HBV or HTLV has been
performed under Sec. 610.40(e) and the donor is found to be positive,
or if a second, licensed, cleared, or approved screening test for HBV
or HTLV has been performed on the same donation under Sec. 610.40(a)
and is reactive, or if the donor tests reactive for anti-HBc or anti-
HTLV, types I and II, on more than one occasion;
* * * * *
Sec. 610.42 [Amended]
0
15. In Sec. 610.42(a), remove ``or reactive for syphilis under Sec.
610.40(i)''; and remove ``communicable disease agent(s)'' and add in
its place ``relevant transfusion-transmitted infection(s)''.
Sec. 610.44 [Amended]
0
16. In paragraph (a)(1) remove ``communicable disease agents listed
in'' and add in its place ``relevant transfusion-transmitted infections
under''; and in paragraph (a)(2) remove ``communicable disease agent''
and add in its place ``relevant transfusion-transmitted infection''.
Sec. 610.46 [Amended]
0
17. Amend Sec. 610.46 as follows:
0
a. In paragraph (a)(2), remove ``a supplemental (additional, more
specific) test'' and add in its place ``further testing'';
0
b. In paragraph (a)(3), remove ``supplemental (additional, more
specific) test results'' and add in its place ``results of further
testing''; and remove ``there is no available supplemental test that is
approved for such use by FDA'' and add in its place ``further testing
under paragraph (a)(2) of this section is not available'';
0
c. In paragraph (a)(4), remove ``supplemental (additional, more
specific) test'' and add in its place ``further testing''; and remove
``there is no available supplemental test that is approved for such use
by FDA'' and add in its place ``further testing is not available''; and
0
d. In paragraph (b)(2), remove ``supplemental (additional, more
specific) test'' and add in its place ``further testing''; and remove
``there is no available supplemental test that is approved for such use
by FDA'' and add in its place ``further testing is not available''; and
0
e. In paragraph (b)(3), remove in the first sentence ``the supplemental
(additional, more specific) test'' and add in its place ``further
testing''; remove in the first sentence ``there is no available
supplemental test that is approved for such use by FDA,'' and add in
its place ``further testing is not available''; remove in the last
sentence ``supplemental (additional, more specific) test results'' and
add in its place ``results of further testing''; and remove in the last
sentence ``there is no available supplemental test that is approved for
such use by FDA'' and add in its place ``further testing is not
available''.
Sec. 610.47 [Amended]
0
18. Amend 610.47 as follows:
0
a. In paragraph (a)(2), remove ``a supplemental (additional, more
specific) test'' and add in its place ``further testing'';
0
b. In paragraph (a)(3), remove in the first sentence ``supplemental
(additional, more specific) test results''
[[Page 29898]]
and add in its place ``results of further testing''; and remove in the
first sentence ``there is no available supplemental test that is
approved for such use by FDA'' and add in its place ``further testing
is not available'';
0
c. In paragraph (a)(4), remove ``supplemental (additional, more
specific) test'' and add in its place ``further testing''; and remove
``there is no available supplemental test that is approved for such use
by FDA'' and add in its place ``further testing is not available''; and
0
d. In paragraph (b)(2), remove ``supplemental (additional, more
specific) test'' and add in its place ``further testing''; and remove
``there is no available supplemental test that is approved for such use
by FDA'' and add in its place ``further testing is not available''; and
0
e. In paragraph (b)(3), remove in the first sentence ``supplemental
(additional, more specific) test'' and add in its place ``further
testing''; remove in the first sentence ``there is no available
supplemental test that is approved for such use by FDA'' and add in its
place ``further testing is not available''; remove in the last sentence
``supplemental (additional, more specific) test results'' and add in
its place ``results of further testing''; and remove in the last
sentence ``there is no available supplemental test that is approved for
such use by FDA'' and add in its place ``further testing is not
available''.
PART 630--REQUIREMENTS FOR BLOOD AND BLOOD COMPONENTS INTENDED FOR
TRANSFUSION OR FOR FURTHER MANUFACTURING USE
0
19. The authority citation for part 630 continues to read as follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 371; 42
U.S.C. 216, 262, 264.
0
20. Revise the heading for part 630 to read as set forth above.
0
21. Add subpart C with the heading to read as follows:
Subpart C--Donor Notification
0
22. Redesignate Sec. 630.6 as Sec. 630.40, and further redesignate
newly designated Sec. 630.40 to subpart C.
0
23. Amend newly designated Sec. 630.40 as follows:
0
a. Revise the section heading;
0
b. In paragraph (a), revise the first sentence; and remove the word
``supplemental'' from the second and third sentences and add in its
place ``further'';
0
c. In paragraphs (b) introductory text and (b)(1), remove ``suitable''
and add in its place ``eligible'';
0
d. In paragraph (b)(3), remove ``communicable disease agent(s)'' and
add in its place ``relevant transfusion-transmitted infection(s)''; and
remove ``supplemental (i.e., additional, more specific) tests'' and add
in its place ``further testing'';
0
e. In paragraph (c), remove ``suitable'' and add in its place
``eligible'';
0
f. In paragraph (d)(1) introductory text, remove ``communicable disease
agent(s)'' and add in its place ``relevant transfusion-transmitted
infection(s) or whose platelets indicate evidence of a bacterial
infection that is endogenous to the bloodstream of the donor'';
0
g. In paragraph (d)(1)(i), remove ``communicable disease agent(s)'' and
add in its place ``relevant transfusion-transmitted infection(s)''; and
0
h. In paragraph (d)(1)(iii), remove ``communicable disease agent(s)''
and add in its place ``relevant transfusion-transmitted infection(s)'';
and remove ``supplemental (i.e., additional, more specific) tests'' and
add in its place ``further testing'';
The revisions read as follows:
Sec. 630.40 Requirements for notifying deferred donors.
(a) Notification of donors. You, an establishment that collects
blood or blood components, must make reasonable attempts to notify any
donor, including an autologous donor, who has been deferred based on
the results of tests for evidence of infection with a relevant
transfusion-transmitted infection(s) as required by Sec. 610.41(a) of
this chapter; any donor who has been deferred as required under Sec.
630.30(b)(3) because their donated platelets have been determined under
Sec. 606.145(d) of this chapter to be contaminated with an organism
that is identified as likely to be associated with a bacterial
infection that is endogenous to the bloodstream of the donor; and any
donor who has been determined not to be eligible as a donor based on
eligibility criteria under Sec. Sec. 630.10 and 630.15. * * *
* * * * *
0
24. Add subparts A and B to part 630 to read as follows:
Subpart A--General Provisions
Sec.
630.1 Purpose and scope.
630.3 Definitions.
Subpart B--Donor Eligibility Requirements
Sec.
630.5 Medical supervision.
630.10 General donor eligibility requirements.
630.15 Donor eligibility requirements specific to Whole Blood, Red
Blood Cells and Plasma collected by apheresis.
630.20 Exceptions for certain ineligible donors.
630.25 Exceptions from certain donor eligibility requirements for
infrequent plasma donors.
630.30 Donation suitability requirements.
630.35 Requalification of previously deferred donors.
Subpart A--General Provisions
Sec. 630.1 Purpose and scope.
(a) What is the purpose of subparts A, B, and C of this part? The
purpose of these subparts, together with Sec. Sec. 610.40 and 610.41
of this chapter, is to provide certain minimum criteria for each
donation of blood and blood components, for:
(1) Determining the eligibility of a donor of blood and blood
components;
(2) Determining the suitability of the donation of blood and blood
components; and
(3) Notifying a donor who is deferred from donation.
(b) Who must comply with subparts A, B, and C of this part? Blood
establishments that manufacture blood and blood components, as defined
in Sec. 630.3(a) and (b), must comply with subparts A, B, and C of
this part.
Sec. 630.3 Definitions.
As used in this part and in part 610, subpart E, and part 640 of
this chapter:
(a) Blood means a product that is a fluid containing dissolved and
suspended elements which was collected from the vascular system of a
human.
(b) Blood component means a product containing a part of blood
separated by physical or mechanical means.
(c) Donor means a person who: (1) Donates blood or blood components
for transfusion or for further manufacturing use; or
(2) Presents as a potential candidate for such donation.
(d) Eligibility of a donor means the determination that the donor
is qualified to donate blood and blood components.
(e) Infrequent plasma donor means a donor who has:
(1) Not donated plasma by plasmapheresis or a co-collection of
plasma with another blood component in the preceding 4 weeks; and
(2) Not donated more than 12.0 liters of plasma (14.4 liters of
plasma for donors weighing more than 175 pounds) in the past year.
(f) Intimate contact with risk for a relevant transfusion-
transmitted infection means having engaged in an
[[Page 29899]]
activity that could result in the transfer of potentially infectious
body fluids from one person to another.
(g) Physician substitute means a trained and qualified person(s)
who is:
(1) A graduate of an education program for health care workers that
includes clinical training;
(2) Currently licensed or certified as a health care worker in the
jurisdiction where the collection establishment is located;
(3) Currently certified in cardiopulmonary resuscitation; and
(4) Trained and authorized under State law, and/or local law when
applicable, to perform the specified functions under the direction of
the responsible physician.
(h) Relevant transfusion-transmitted infection means:
(1) Any of the following transfusion-transmitted infections:
(i) Human immunodeficiency virus, types 1 and 2 (referred to,
collectively, as HIV);
(ii) Hepatitis B virus (referred to as HBV);
(iii) Hepatitis C virus (referred to as HCV);
(iv) Human T-lymphotropic virus, types I and II (referred to,
collectively, as HTLV);
(v) Treponema pallidum (referred to as syphilis);
(vi) West Nile virus;
(vii) Trypanosoma cruzi (referred to as Chagas disease);
(viii) Creutzfeldt-Jakob disease (referred to as CJD);
(ix) Variant Creutzfeldt-Jakob disease (referred to as vCJD); and
(x) Plasmodium species (referred to as malaria).
(2) A transfusion-transmitted infection not listed in paragraph
(h)(1) of this section when the following conditions are met:
(i) Appropriate screening measures for the transfusion-transmitted
infection have been developed and/or an appropriate screening test has
been licensed, approved, or cleared for such use by FDA and is
available; and
(ii) The disease or disease agent:
(A) May have sufficient incidence and/or prevalence to affect the
potential donor population; or
(B) May have been released accidentally or intentionally in a
manner that could place potential donors at risk of infection.
(i) Responsible physician means an individual who is:
(1) Licensed to practice medicine in the jurisdiction where the
collection establishment is located;
(2) Adequately trained and qualified to direct and control
personnel and relevant procedures concerning the determination of donor
eligibility; collection of blood and blood components; the immunization
of a donor; and the return of red blood cells or other blood components
to the donor during collection of blood component(s) by apheresis; and
(3) Designated by the collection establishment to perform the
activities described in paragraph (i)(2) of this section.
(j) Suitability of the donation means a determination of whether
the donation is acceptable for transfusion or for further manufacturing
use.
(k) Trained person means an individual, including a physician
substitute, who is authorized under State law, and/or local law when
applicable, and adequately instructed and qualified to perform the
specified functions under the direction of the responsible physician.
(l) Transfusion-transmitted infection means a disease or disease
agent:
(1) That could be fatal or life-threatening, could result in
permanent impairment of a body function or permanent damage to a body
structure, or could necessitate medical or surgical intervention to
preclude permanent impairment of body function or permanent damage to a
body structure; and
(2) For which there may be a risk of transmission by blood or blood
components, or by a blood derivative product manufactured from blood or
blood components, because the disease or disease agent is potentially
transmissible by that blood, blood component, or blood derivative
product.
Subpart B--Donor Eligibility Requirements
Sec. 630.5 Medical supervision.
(a) Who must determine the eligibility of a donor? The responsible
physician must determine the eligibility of a donor of blood or blood
components in accordance with this subchapter.
(b) Which activities related to the collection of blood and blood
components, other than Source Plasma and plasma collected by
plasmapheresis, may the responsible physician delegate?
(1) The responsible physician may delegate the following activities
to a physician substitute or other trained person:
(i) Determining the eligibility of a donor and documenting
assessments related to that determination, except the responsible
physician must not delegate:
(A) The examination and determination of the donor's health
required in Sec. 630.10(f)(2) for donors with blood pressure
measurements outside specified limits, or for certain more frequent
donations under Sec. 630.15(a)(1)(ii);
(B) The determination of the health of the donor required in
Sec. Sec. 630.10(f)(4), 630.20(a), and 640.21(e)(4) of this chapter.
The responsible physician may make this determination by telephonic or
other offsite consultation; or
(C) The determination of the health of the donor and the
determination that the blood or blood component collected would present
no undue medical risk to the transfusion recipient, as required in
Sec. 630.20(c). The responsible physician may make these
determinations by telephonic or other offsite consultation.
(ii) Collecting blood or blood components;
(iii) Returning red blood cells to the donor during apheresis;
(iv) Obtaining the informed consent of a plateletpheresis donor as
described in Sec. 640.21(g) of this chapter; or
(v) Other activities provided that the Director, Center for
Biologics Evaluation and Research, determines that delegating the
activities would present no undue medical risk to the donor or to the
transfusion recipient, and authorizes the delegation of such
activities.
(2) The responsible physician need not be present at the collection
site when activities delegated under paragraph (b)(1) of this section
are performed, provided that the responsible physician has delegated
oversight of these activities to a trained person who is adequately
trained and experienced in the performance of these activities and is
also adequately trained and experienced in the recognition of and
response to the known adverse responses associated with blood
collection procedures.
(c) Which activities related to the collection of Source Plasma and
plasma collected by plasmapheresis may the responsible physician
delegate?
(1) Donor eligibility and blood component collection activities.
(i) The responsible physician may delegate to a physician substitute or
other trained person any of the activities described in paragraph
(c)(1)(i)(A) of this section, provided that the responsible physician
or a physician substitute is on the premises at the collection site:
(A) The activities listed in paragraphs (b)(1)(i) through (iii) and
(b)(1)(v) of this section, with respect to Source Plasma and plasma
collected by plasmapheresis. However, the responsible physician must
not delegate:
[[Page 29900]]
(1) The examination and determination of the donor's health
required in Sec. 630.10(f)(2) for donors with blood pressure
measurements outside specified limits, or in Sec. 630.15(b)(7) for
certain donors who have experienced red blood cell loss;
(2) The determination of the health of the donor required in
Sec. Sec. 630.10(f)(4) and 630.20(a) and (b). The responsible
physician may make this determination by telephonic or other offsite
consultation;
(3) The determination of the health of the donor and the
determination that the blood component would present no undue medical
risk to the transfusion recipient, as required in Sec. 630.20(c). The
responsible physician may make this determination by telephonic or
other offsite consultation.
(4) The determination related to a donor's false-positive reaction
to a serologic test for syphilis in accordance with Sec.
640.65(b)(2)(iii) of this chapter; and
(5) The determination to permit plasmapheresis of a donor with a
reactive serological test for syphilis in accordance with Sec.
640.65(b)(2)(iv) of this chapter.
(B) The collection of Source Plasma in an approved collection
program from a donor who is otherwise determined to be ineligible.
(C) The collection of a blood sample in accordance with Sec.
640.65(b)(1)(i) of this chapter.
(ii) The responsible physician, who may or may not be present when
these activities are performed, may delegate to a physician substitute
the following activities:
(A) Approval and signature for a plasmapheresis procedure as
provided in Sec. 640.65(b)(1)(ii) of this chapter; and
(B) Review and signature for accumulated laboratory data, the
calculated values of each component, and the collection records in
accordance with Sec. 640.65(b)(2)(i) of this chapter. However, the
responsible physician must not delegate the decision to reinstate the
deferred donor in accordance with that provision.
(2) Donor immunization. The responsible physician must not delegate
activities performed in accordance with Sec. 640.66 of this chapter,
except that:
(i) The responsible physician may delegate to a physician
substitute or other trained person the administration of an
immunization other than red blood cells to a donor in an approved
collection program, provided that the responsible physician or a
physician substitute is on the premises at the collection site when the
immunization is administered.
(ii) The responsible physician may delegate to a physician
substitute the administration of red blood cells to a donor in an
approved collection program, provided that the responsible physician
has approved the procedure and is on the premises at the collection
site when the red blood cells are administered.
(3) Medical history, physical examination, informed consent, and
examination before immunization. Provided that such activities are
performed under the supervision of the responsible physician, the
responsible physician may delegate to a physician substitute the
activities described in Sec. 630.15(b)(1), (2), and (5). The
responsible physician is not required to be present at the collection
site when the physician substitute performs these activities under
supervision.
(4) Infrequent plasma donors. (i) For infrequent plasma donors
other than those described in paragraph (c)(4)(ii) of this section, the
responsible physician may delegate to a trained person the activities
listed in paragraphs (b)(1)(i) through (iii) and (b)(1)(v) of this
section and the informed consent requirements described in Sec.
630.15(b)(2). The responsible physician or a physician substitute need
not be present at the collection site when any of these activities are
performed, provided that the responsible physician has delegated
oversight of these activities to a trained person who is not only
adequately trained and experienced in the performance of these
activities but also adequately trained and experienced in the
recognition of and response to the known adverse responses associated
with blood collection procedures. However, the responsible physician
must not delegate:
(A) The examination and determination of the donor's health
required in Sec. 630.10(f)(2) for donors with blood pressure
measurements outside specified limits, or in Sec. 630.15(b)(7) for
certain donors who have experienced red blood cell loss; or
(B) The determination of the health of the donor required in Sec.
630.10(f)(4).
(ii) For infrequent plasma donors who are otherwise ineligible or
are participating in an approved immunization program, the responsible
physician may delegate only in accordance with paragraphs (c)(1)
through (3) of this section.
(d) Must rapid emergency medical services be available?
Establishments that collect blood or blood components must establish,
maintain, and follow standard operating procedures for obtaining rapid
emergency medical services for donors when medically necessary. In
addition, establishments must assure that an individual (responsible
physician, physician substitute, or trained person) who is currently
certified in cardiopulmonary resuscitation is located on the premises
whenever collections of blood or blood components are performed.
Sec. 630.10 General donor eligibility requirements.
(a) What factors determine the eligibility of a donor? You, an
establishment that collects blood or blood components, must not collect
blood or blood components before determining that the donor is eligible
to donate or before determining that an exception to this provision
applies. To be eligible, the donor must be in good health and free from
transfusion-transmitted infections as can be determined by the
processes in this subchapter. A donor is not eligible if the donor is
not in good health or if you identify any factor(s) that may cause the
donation to adversely affect:
(1) The health of the donor; or
(2) The safety, purity, or potency of the blood or blood component.
(b) What educational material must you provide to the donor before
determining eligibility? You must provide educational material
concerning relevant transfusion-transmitted infections to donors before
donation when donor education about that relevant transfusion-
transmitted infection, such as HIV, is necessary to assure the safety,
purity, and potency of blood and blood components. The educational
material must include an explanation of the readily identifiable risk
factors closely associated with exposure to the relevant transfusion-
transmitted infection. You must present educational material in an
appropriate form, such as oral, written or multimedia, and in a manner
designed to be understood by the donor. The educational material must
instruct the donor not to donate blood and blood components when a risk
factor is present. When providing educational material to donors under
this section, you may include in those materials the information
required to be provided to donors under paragraph (g)(2)(ii)(E) of this
section.
(c) When must you determine the eligibility of a donor? You must
determine donor eligibility on the day of donation, and before
collection. Except:
(1) When a donor is donating blood components that cannot be stored
for more than 24 hours, you may determine the donor's eligibility and
collect a sample for testing required under Sec. 610.40 of this
chapter, no earlier than
[[Page 29901]]
2 calendar days before the day of donation, provided that your standard
operating procedures address these activities.
(2) In the event that, upon review, you find that a donor's
responses to the donor questions before collection were incomplete,
within 24 hours of the time of collection, you may clarify a donor's
response or obtain omitted information required under paragraph (e) of
this section, provided that your standard operating procedures address
these activities.
(d) How must you determine the eligibility of a donor? You must
determine the donor's eligibility before collection of blood or blood
components, by the following procedures:
(1) You must consult the records of deferred donors maintained
under Sec. 606.160(e)(1) and (2) of this chapter. Exception: If pre-
collection review of the record described in Sec. 606.160(e)(2) of
this chapter is not feasible because you cannot consult the cumulative
record at the collection site, you must consult the cumulative record
prior to release of any blood or blood component prepared from the
collection.
(2) Assure that the interval since the donor's last donation is
appropriate;
(3) Assess the donor's medical history; and
(4) Perform a physical assessment of the donor.
(e) How do you assess the donor's medical history? Before
collection you must conduct a medical history interview as described in
this section to determine if the donor is in good health; to identify
risk factors closely associated with exposure to, or clinical evidence
of a relevant transfusion-transmitted infection; and to determine if
there are other conditions that may adversely affect the health of the
donor or the safety, purity, or potency of the blood or blood
components or any product manufactured from the blood or blood
components. Your assessment must include each of the following factors:
(1) Factors that make the donor ineligible to donate because of an
increased risk for, or evidence of, a relevant transfusion-transmitted
infection. A donor is ineligible to donate when information provided by
the donor or other reliable evidence indicates possible exposure to a
relevant transfusion-transmitted infection if that risk of exposure is
still applicable at the time of donation. Information and evidence
indicating possible exposure to a relevant transfusion-transmitted
infection include:
(i) Behaviors associated with a relevant transfusion-transmitted
infection;
(ii) Receipt of blood or blood components or other medical
treatments and procedures associated with possible exposure to a
relevant transfusion-transmitted infection;
(iii) Signs and/or symptoms of a relevant transfusion-transmitted
infection;
(iv) Institutionalization for 72 hours or more consecutively in the
past 12 months in a correctional institution;
(v) Intimate contact with risk for a relevant transfusion-
transmitted infection; and
(vi) Nonsterile percutaneous inoculation.
(2) Other factors that make the donor ineligible to donate. A donor
is ineligible to donate when donating could adversely affect the health
of the donor, or when the safety, purity, or potency of the blood or
blood component could be affected adversely. Your assessment of the
donor must include each of the following factors:
(i) Symptoms of a recent or current illness;
(ii) Certain medical treatments or medications;
(iii) Travel to, or residence in, an area endemic for a
transfusion-transmitted infection, when such screening is necessary to
assure the safety, purity, and potency of blood and blood components
due to the risks presented by donor travel and the risk of transmission
of that transfusion-transmitted infection by such donors;
(iv) Exposure or possible exposure to an accidentally or
intentionally released disease or disease agent relating to a
transfusion-transmitted infection, if you know or suspect that such a
release has occurred;
(v) Pregnancy at the time of, or within 6 weeks prior to, donation;
(vi) Whether, in the opinion of the interviewer, the donor appears
to be under the influence of any drug, alcohol or for any reason does
not appear to be providing reliable answers to medical history
questions, or if the donor says that the purpose of donating is to
obtain test results for a relevant transfusion-transmitted infection;
and
(vii) The donor is a xenotransplantation product recipient.
(f) How do you perform a physical assessment of the donor? You must
determine on the day of donation, and before collection that the donor
is in good health based on the following, at a minimum:
(1) Temperature. The donor's oral body temperature must not exceed
37.5 [deg]C (99.5[emsp14][deg]F), or the equivalent if measured at
another body site;
(2) Blood pressure. The donor's systolic blood pressure must not
measure above 180 mm of mercury, or below 90 mm of mercury, and the
diastolic blood pressure must not measure above 100 mm of mercury or
below 50 mms of mercury. A donor with measurements outside these limits
may be permitted to donate only when the responsible physician examines
the donor and determines and documents that the health of the donor
would not be adversely affected by donating.
(3) Hemoglobin or hematocrit determination. You must determine the
donor's hemoglobin level or hematocrit value by using a sample of blood
obtained by fingerstick, venipuncture, or by a method that provides
equivalent results. Blood obtained from the earlobe is not acceptable.
(i) Allogeneic donors must have a hemoglobin level or hematocrit
value that is adequate to assure donor safety and product potency. The
following minimum standards apply.
(A) Female allogeneic donors must have a hemoglobin level that is
equal to or greater than 12.5 grams of hemoglobin per deciliter of
blood, or a hematocrit value that is equal to or greater than 38
percent. Recognizing that lower levels are also within normal limits
for female donors, you may collect blood from female allogeneic donors
who have a hemoglobin level between 12.0 and 12.5 grams per deciliter
of blood, or a hematocrit value between 36 and 38 percent, provided
that you have taken additional steps to assure that this alternative
standard is adequate to ensure that the health of the donor will not be
adversely affected due to the donation, in accordance with a procedure
that has been found acceptable for this purpose by FDA.
(B) Male allogeneic donors must have a hemoglobin level that is
equal to or greater than 13.0 grams of hemoglobin per deciliter of
blood, or a hematocrit value that is equal to or greater than 39
percent.
(ii) An autologous donor must have a hemoglobin level no less than
11.0 grams of hemoglobin per deciliter of blood, or a hematocrit value
no less than 33 percent.
(4) Pulse. The donor's pulse must be regular and between 50 and 100
beats per minute. A donor with an irregular pulse or measurements
outside these limits may be permitted to donate only when the
responsible physician determines and documents that the health of the
donor would not be adversely affected by donating.
[[Page 29902]]
(5) Weight. The donor must weigh a minimum of 50 kilograms (110
pounds).
(6) Skin examination. (i) The donor's phlebotomy site must be free
of infection, inflammation, and lesions; and
(ii) The donor's arms and forearms must be free of punctures and
scars indicative of injected drugs of abuse.
(g) Are there additional requirements for determining the
eligibility of the donor? You must obtain the following from the donor
on the day of donation:
(1) Proof of identity and postal address. You must obtain proof of
identity of the donor and a postal address where the donor may be
contacted for 8 weeks after donation; and
(2) Donor's acknowledgement. (i) Prior to each donation, you must
provide information to the donor addressing the elements specified in
paragraphs (g)(2)(ii)(A) through (E) of this section and obtain the
donor's acknowledgement that the donor has reviewed the information.
You must establish procedures in accordance with Sec. 606.100 of this
chapter to assure that the donor has reviewed this material, and
provide for a signature or other documented acknowledgement.
(ii) The donor acknowledgement must not include any exculpatory
language through which the donor is made to waive or appear to waive
any of the donor's legal rights. It must, at a minimum clearly address
the following:
(A) The donor has reviewed the educational material provided under
paragraph (b) of this section regarding relevant transfusion-
transmitted infections;
(B) The donor agrees not to donate if the donation could result in
a potential risk to recipients as described in the educational
material;
(C) A sample of the donor's blood will be tested for specified
relevant transfusion-transmitted infections;
(D) If the donation is determined to be not suitable under Sec.
630.30(a) or if the donor is deferred from donation under Sec. 610.41
of this chapter, the donor's record will identify the donor as
ineligible to donate and the donor will be notified under Sec. 630.40
of the basis for the deferral and the period of deferral;
(E) The donor has been provided and reviewed information regarding
the risks and hazards of the specific donation procedure; and
(F) The donor has the opportunity to ask questions and withdraw
from the donation procedure.
(h) What must you do when a donor is not eligible? You must not
collect blood or blood components from a donor found to be ineligible
prior to collection based on criteria in Sec. Sec. 630.10 or 630.15,
or deferred under Sec. 610.41 of this chapter or Sec. 630.30(b)(2),
unless this subchapter provides an exception. You must defer donors
found to be ineligible and you must notify the donor of their deferral
under Sec. 630.40.
Sec. 630.15 Donor eligibility requirements specific to Whole Blood,
Red Blood Cells and Plasma collected by apheresis.
(a) What additional donor eligibility requirements apply when you,
an establishment that collects blood or blood components, collect Whole
Blood or Red Blood Cells by apheresis?
(1) Donation frequency must be consistent with protecting the
health of the donor.
(i) For a collection resulting in a single unit of Whole Blood or
Red Blood Cells collected by apheresis, donation frequency must be no
more than once in 8 weeks, and for apheresis collections resulting in
two units of Red Blood Cells, the donor must not donate more than once
in 16 weeks.
(ii) The limitations in paragraph (a)(1)(i) of this section apply
unless the responsible physician examines the donor at the time of
donation and one of the following conditions exists:
(A) The donation is for autologous use as prescribed by the donor's
physician and the responsible physician determines and documents that
the donation may proceed; or
(B) The donation is a dedicated donation based on the intended
recipient's documented exceptional medical need and the responsible
physician determines and documents that the health of the donor would
not be adversely affected by donating.
(2) Therapeutic phlebotomy. When a donor who is determined to be
eligible under Sec. 630.10 undergoes a therapeutic phlebotomy under a
prescription to promote the donor's health, you may collect from the
donor more frequently than once in 8 weeks for collections resulting in
a single unit of Whole Blood or Red Blood Cells, or once in 16 weeks
for apheresis collections resulting in two units of Red Blood Cells,
provided that the container label conspicuously states the disease or
condition of the donor that necessitated phlebotomy. However, no
labeling for the disease or condition is required under this section
if:
(i) The donor meets all eligibility criteria;
(ii) The donor undergoes a therapeutic phlebotomy as prescribed by
a licensed health care provider treating the donor for:
(A) Hereditary hemochromatosis; or
(B) Another disease or condition, when the health of a donor with
that disease or condition will not be adversely affected by donating,
and the donor's disease or condition will not adversely affect the
safety, purity, and potency of the blood and blood components, or any
products manufactured from them, and the collection is in accordance
with a procedure that has been found acceptable for this purpose by
FDA; and
(iii) You perform without charge therapeutic phlebotomies for all
individuals with that disease or condition.
(b) What additional donor eligibility requirements apply when you,
an establishment that collects blood or blood components, collect
Source Plasma or plasma by plasmapheresis?
(1) Medical history and physical examination. Except as provided in
Sec. 630.25:
(i) The responsible physician must conduct an appropriate medical
history and physical examination of the donor on the day of the first
donation or no more than 1 week before the first donation and at
subsequent intervals of no longer than 1 year.
(ii) The responsible physician must examine the donor for medical
conditions that would place the donor at risk from plasmapheresis. If
the donor is determined to be at risk, you must defer the donor from
donating.
(iii) The responsible physician must conduct a new medical history
and physical examination of a donor who does not return for 6 months.
(2) What requirements apply to obtaining informed consent?
(i) The responsible physician must obtain the informed consent of a
plasma donor on the first day of donation or no more than 1 week before
the first donation, and at subsequent intervals of no longer than 1
year.
(ii) The responsible physician must obtain the informed consent of
a plasma donor who does not return within 6 months of the last
donation.
(iii) The responsible physician must explain the risks and hazards
of the procedure to the donor. The explanation must include the risks
of a hemolytic transfusion reaction if the donor is given the cells of
another donor and the risks involved if the donor is immunized. The
explanation must be made in such a manner that the donor may give their
consent and has a clear opportunity to refuse the procedure.
(iv) If a donor is enrolled in a new program, such as an
immunization or special collection program, the responsible physician
must again obtain
[[Page 29903]]
an informed consent specific for that program.
(3) Weight. You must weigh a donor at each donation.
(4) Total protein level. You must determine the donor's total
plasma protein level before each plasmapheresis procedure. The donor
must have a total plasma protein level of no less than 6.0 grams per
deciliter and no more than 9.0 grams per deciliter in a plasma sample
or a serum sample.
(5) Examination before immunization. (i) No more than 1 week before
the first immunization injection for the production of high-titer
antibody plasma, the responsible physician must conduct an appropriate
medical history and physical examination, as described in paragraph
(b)(1) of this section, in addition to assessing the general donor
eligibility requirements under Sec. 630.10. It is not necessary to
repeat the medical history and physical examination requirement in
paragraph (b)(1) of this section, if the immunized donor's plasma is
collected within 3 weeks of the first immunization injection.
(ii) You are not required to repeat the medical history and
physical examination required under paragraph (b)(1) of this section
for a donor currently participating in a plasmapheresis collection
program and determined to be eligible under Sec. 630.10 unless the
medical history and physical examination are due under paragraph
(b)(1)(i) or (b)(1)(iii) of this section.
(6) Deferral of donors due to red blood cell loss. (i) You must
defer a donor from donating plasma by plasmapheresis for 8 weeks if the
donor has donated a unit of Whole Blood, or a single unit of Red Blood
Cells by apheresis. However, you may collect plasma by plasmapheresis
after a donation of Whole Blood or a single unit of Red Blood Cells by
apheresis after at least 2 calendar days have passed, provided that the
extracorporeal volume of the apheresis device is less than 100
milliliters.
(ii) You must defer a donor from donating plasma by plasmapheresis
for a period of 16 weeks if the donor donates two units of Red Blood
Cells during a single apheresis procedure;
(iii) You must defer a donor for 8 weeks or more if the cumulative
red blood cell loss in any 8 week period could adversely affect donor
health.
(7) Exceptions to deferral due to red blood cell loss. You are not
required to defer a Source Plasma donor from donating plasma by
plasmapheresis due to red blood cell loss if the following conditions
are met:
(i) The responsible physician examines the donor at the time of the
current donation and determines and documents that the donor is in good
health and the donor's health permits the plasmapheresis;
(ii) The donor's plasma possesses a property, such as an antibody,
antigen, or protein deficiency that is transitory, of a highly unusual
or infrequent specificity, or of an unusually high titer;
(iii) The special characteristics of the donor's plasma and the
need for plasmapheresis of the donor under Sec. 630.20(b) are
documented at your establishment; and
(iv) The extracorporeal volume of the apheresis device is less than
100 milliliters.
(8) Malaria. Freedom from risk of malaria is not required for a
donor of Source Plasma.
(9) You must comply with other requirements for collection of
plasma in part 640 of this chapter and this part including restrictions
on frequency of collection as specified in Sec. Sec. 640.32 and 640.65
of this chapter.
Sec. 630.20 Exceptions for certain ineligible donors.
After assessing donor eligibility under Sec. Sec. 630.10 and
630.15, an establishment may collect blood and blood components from a
donor who is determined to be not eligible to donate under any
provision of Sec. 630.10(e) and (f) or Sec. 630.15(a) if one of the
following sets of conditions are met:
(a) The donation is for autologous use only as prescribed by the
donor's physician, the donor has a hemoglobin level no less than 11.0
grams of hemoglobin per deciliter of blood or a hematocrit value no
less than 33 percent, and the responsible physician determines and
documents that the donor's health permits the collection procedure; or
(b) The donation is collected under a Source Plasma collection
program which has received prior written approval from the Director,
Center for Biologics Evaluation and Research, to collect plasma for
further manufacturing use into in vitro products for which there are no
alternative sources, the donor meets the criteria in Sec. 630.10(f)(1)
through (6), and the responsible physician determines and documents for
each donation that the donor's health permits the collection procedure,
and the collection takes place under the medical oversight specified in
the approved plasmapheresis program.
(c) The donation is restricted for use solely by a specific
transfusion recipient based on documented exceptional medical need, and
the responsible physician determines and documents that the donor's
health permits the collection procedure, and that the donation presents
no undue medical risk to the transfusion recipient.
Sec. 630.25 Exceptions from certain donor eligibility requirements
for infrequent plasma donors.
For an infrequent plasma donor who is not participating in an
immunization program, establishments are not required to:
(a) Perform a medical history and physical examination of the donor
under Sec. 630.15(b)(1);
(b) Perform a test for total protein under Sec. 630.15(b)(4);
(c) Determine the total plasma or serum protein and immunoglobulin
composition under Sec. 640.65(b)(1)(i) of this chapter; or
(d) Review the data and records as required in Sec.
640.65(b)(2)(i) of this chapter.
Sec. 630.30 Donation suitability requirements.
(a) When is a donation suitable? A donation is suitable when:
(1) The donor is not currently deferred from donation as determined
by review of the records of deferred donors required under Sec.
606.160(e) of this chapter;
(2) The results in accordance with Sec. Sec. 630.10 through 630.25
indicate that the donor is in good health and procedures were followed
to ensure that the donation would not adversely affect the health of
the donor;
(3) The results in accordance with Sec. 630.10(e) indicate that
the donor is free from risk factors for, or evidence of, relevant
transfusion-transmitted infections and other factors that make the
donor ineligible to donate;
(4) The donor's blood is tested in accordance with Sec. 610.40 of
this chapter, and is negative or nonreactive, unless an exception
applies under Sec. 610.40(h) of this chapter; and
(5) The donation meets other requirements in this subchapter.
(b) What must you do when the donation is not suitable? (1) You
must not release the donation for transfusion or further manufacturing
use unless it is an autologous donation, or an exception is provided in
this chapter.
(2) You must defer the donor when a donation is determined to be
unsuitable based on the criteria in paragraphs (a)(1) through (4) of
this section.
(3) You must defer the donor of bacterially contaminated platelets
when the contaminating organism is identified in accordance with Sec.
606.145(d) of this chapter as likely to be associated with a bacterial
infection that is endogenous to the bloodstream of the donor.
[[Page 29904]]
(4) You must notify the deferred donor in accordance with the
notification requirements in Sec. 630.40.
Sec. 630.35 Requalification of previously deferred donors.
Establishments may determine a deferred donor to be eligible as a
donor of blood and blood components if, at the time of the current
collection, the donor meets the eligibility criteria in this part,
except for the record of the previous deferral, and you determine that
the criteria that were the basis for the previous deferral are no
longer applicable. Criteria for the previous deferral are no longer
applicable if the following conditions are met:
(a) The previous deferral was for a defined period of time and that
time period has passed, or the deferral was otherwise temporary, such
as a deferral based on eligibility criteria described in Sec. Sec.
630.10(f)(1) through (5) or 630.15(b)(4); or
(b) For a donor deferred for reasons other than under Sec.
610.41(a) of this chapter, you determine that the donor has met
criteria for requalification by a method or process found acceptable
for such purpose by FDA.
PART 640--ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS
0
25. 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. 640.3 [Removed]
0
26. Remove Sec. 640.3.
Sec. 640.4 [Amended]
0
27. In Sec. 640.4, remove and reserve paragraph (a); and in paragraph
(e), remove ``Sec. 640.3'' and add in its place ``Sec. 630.10 of this
chapter''.
Sec. 640.5 [Amended]
0
28. Amend Sec. 640.5 as follows:
0
a. In the introductory text, remove ``at the time of collecting the
unit of blood'';
0
b. Remove and reserve paragraph (a); and
0
c. In heading and text of paragraph (f), remove ``communicable disease
agents'' wherever it appears and add in its place ``relevant
transfusion-transmitted infections''.
0
29. Revise Sec. 640.12 to read as follows:
Sec. 640.12 Eligibility of donor.
Establishments must determine the eligibility of donors of the
source blood for Red Blood Cells in accordance with Sec. Sec. 630.10
and 630.15 of this chapter.
Sec. 640.14 [Amended]
0
30. In 640.14, remove ``Sec. 640.5(a), (b),'' and add in its place
``Sec. 640.5(b)''.
0
31. Revise Sec. 640.21 to read as follows:
Sec. 640.21 Eligibility of donors.
(a) Establishments must determine the eligibility of donors of
platelets derived from Whole Blood and donors of platelets collected by
plateletpheresis in accordance with Sec. Sec. 630.10 and 630.15 of
this chapter, except as provided in this section.
(b) A plateletpheresis donor must not serve as the source of
platelets for transfusion if the donor has recently ingested a drug
that adversely affects platelet function.
(c) A Whole Blood donor must not serve as the source of platelets
for transfusion if the donor has recently ingested a drug that
adversely affects platelet function unless the unit is labeled to
identify the ingested drug that adversely affects platelet function.
(d) If you are collecting platelets by plateletpheresis, you must
assess and monitor the donor's platelet count.
(1) You must take adequate and appropriate steps to assure that the
donor's platelet count is at least 150,000 platelets per microliter (/
[mu]L) before plateletpheresis begins. Exception: If you do not have
records of a donor's platelet count from prior donations and you are
not able to assess the donor's platelet count either prior to or
immediately following the initiation of the collection procedure, you
may collect platelets by plateletpheresis, but you must not collect 9.0
x 10\11\ or more platelets from that donor.
(2) You must defer from platelet donation a donor whose pre-
donation platelet count is less than 150,000 platelets/[mu]L until a
subsequent pre-donation platelet count indicates that the donor's
platelet count is at least 150,000 platelets/[mu]L; and
(3) You must take appropriate steps to assure that the donor's
intended post-donation platelet count will be no less than 100,000
platelets/[mu]L.
(e) Frequency of plateletpheresis collection. (1) The donor may
donate no more than a total of 24 plateletpheresis collections during a
12-month rolling period.
(2) When you collect fewer than 6 x 10\11\ platelets, you must wait
at least 2 calendar days before any subsequent plateletpheresis
collection. You must not attempt to collect more than 2 collections
within a 7 calendar day period.
(3) When you collect 6 x 10\11\ or more platelets, you must wait at
least 7 calendar days before any subsequent plateletpheresis
collection.
(4) Exception. For a period not to exceed 30 calendar days, a donor
may serve as a dedicated plateletpheresis donor for a single recipient,
in accordance with Sec. 610.40(c)(1) of this chapter, as often as is
medically necessary, provided that the donor is in good health, as
determined and documented by the responsible physician, and the donor's
platelet count is at least 150,000 platelets/[mu]L, measured at the
conclusion of the previous donation or before initiating
plateletpheresis for the current donation.
(f) Deferral of plateletpheresis donors due to red blood cell loss.
(1) You must defer a donor from donating platelets by plateletpheresis
or a co-collection of platelets and plasma by apheresis for 8 weeks if
the donor has donated a unit of Whole Blood, or a single unit of Red
Blood Cells by apheresis unless at least 2 calendar days have passed
and the extracorporeal volume of the apheresis device is less than 100
milliliters.
(2) You must defer a donor from donating platelets for a period of
16 weeks if the donor donates two units of Red Blood Cells during a
single apheresis procedure.
(3) You must defer a donor for 8 weeks or more if the cumulative
red blood cell loss in any 8 week period could adversely affect donor
health.
(g) The responsible physician must obtain the informed consent of a
plateletpheresis donor on the first day of donation, and at subsequent
intervals no longer than 1 year.
(1) The responsible physician must explain the risks and hazards of
the procedure to the donor; and
(2) The explanation must be made in such a manner that the donor
may give consent, and has a clear opportunity to refuse the procedure.
0
32. Revise Sec. 640.22(c) to read as follows:
Sec. 640.22 Collection of source material.
* * * * *
(c) If plateletpheresis is used, the procedure for collection must
be as prescribed in Sec. Sec. 640.21, 640.64 (except paragraph (c)),
and 640.65, or as described in an approved biologics license
application (BLA) or an approved supplement to a BLA.
* * * * *
Sec. 640.23 [Amended]
0
33. In Sec. 640.23(a), remove ``Sec. 640.5(a), (b),'' and add in its
place ``Sec. 640.5(b)''.
Sec. 640.27 [Removed]
0
34. Remove Sec. 640.27.
0
35. Revise Sec. 640.31 to read as follows:
[[Page 29905]]
Sec. 640.31 Eligibility of donors.
(a) Whole Blood donors must meet the criteria for donor eligibility
prescribed in Sec. Sec. 630.10 and 630.15 of this chapter.
(b) Collection establishments must determine the eligibility of
plasmapheresis donors in accordance with Sec. Sec. 630.10 and 630.15
of this chapter.
Sec. 640.32 [Amended]
0
36. In Sec. 640.32(b), remove ``Sec. Sec. 640.62, 640.64'' and add in
its place ``Sec. 640.64''.
Sec. 640.33 [Amended]
0
37. In Sec. 640.33(a), remove ``Sec. 640.5(a), (b),'' and add in its
place ``Sec. 640.5(b)''.
0
38. Revise Sec. 640.51 to read as follows:
Sec. 640.51 Eligibility of donors.
(a) Whole blood donors must meet the criteria for eligibility
prescribed in Sec. Sec. 630.10 and 630.15 of this chapter.
(b) Collection establishments must determine the eligibility of
plasmapheresis donors in accordance with Sec. Sec. 630.10 and 630.15
of this chapter.
Sec. 640.52 [Amended]
0
39. In Sec. 640.52(b), remove ``Sec. Sec. 640.62, 640.64'' and add in
its place ``Sec. 640.64''.
Sec. 640.53 [Amended]
0
40. In Sec. 640.53(a), remove ``Sec. 640.5(a), (b),'' and add in its
place ``Sec. 640.5(b)''.
Sec. 640.61 [Removed]
0
41. Remove Sec. 640.61.
Sec. 640.62 [Removed]
0
42. Remove Sec. 640.62.
Sec. 640.63 [Removed]
0
43. Remove Sec. 640.63.
Sec. 640.64 [Amended]
0
44. In Sec. 640.64, remove and reserve paragraph (a).
0
45. Amend Sec. 640.65 as follows:
0
a. In paragraph (b)(1)(i), revise the first sentence;
0
b. In paragraph (b)(1)(ii), remove ``physician on the premises'' and
add its place ``responsible physician'';
0
c. Revise paragraph (b)(2)(i); and
0
d. In paragraphs (b)(2)(iii) and (iv) remove ``physician on the
premises'' and add in its place ``responsible physician''.
The revisions read as follows:
Sec. 640.65 Plasmapheresis.
* * * * *
(b) * * *
(1)(i) Except as provided under Sec. 630.25 of this chapter, the
responsible physician must draw a sample of blood from each donor on
the day of the initial physical examination or plasmapheresis,
whichever comes first, and at least every 4 months thereafter. * * *
* * * * *
(2)(i) Except as provided under Sec. 630.25 of this chapter, the
responsible physician must review the accumulated laboratory data,
including any tracings of the plasma or serum protein electrophoresis
pattern, the calculated values of the protein composition of each
component, and the collection records within 14 calendar days after the
sample is drawn to determine whether or not the donor should be
deferred from further donation. If a determination is not made within
14 calendar days, the donor must be deferred pending such a
determination. The responsible physician must sign the review. If the
protein composition is not within normal limits established by the
testing laboratory, or if the total protein level is less than 6.0
grams per deciliter or more than 9.0 grams per deciliter in a plasma
sample or serum sample, the donor must be deferred from donation until
the protein composition returns to acceptable levels. Reinstatement of
the donor into the plasmapheresis program when the donor's protein
composition values have returned to an acceptable level must first be
approved by the responsible physician.
* * * * *
0
46. In Sec. 640.66, revise the first sentence and remove the second
sentence. The revisions read as follows:
Sec. 640.66 Immunization of donors.
If specific immunization of a donor is to be performed, the
selection, scheduling and administration of the antigen, and the
evaluation of each donor's clinical response, shall be by the
responsible physician. * * *
Sec. 640.67 [Amended]
0
47. In Sec. 640.67, remove ``communicable disease agents'' and add in
its place ``relevant transfusion-transmitted infections''.
0
48. In Sec. 640.69, add paragraphs (e) and (f) to read as follows:
Sec. 640.69 General requirements.
* * * * *
(e) Restrictions on distribution. Establishments must ensure that
Source Plasma donated by paid donors not be used for further
manufacturing into injectable products until the donor has a record of
being found eligible to donate in accordance with Sec. 630.10 of this
chapter and a record of negative test results on all tests required
under Sec. 610.40(a) of this chapter on two occasions in the past 6
months.
(f) Hold. Source Plasma donated by paid donors determined to be
suitable for further manufacturing into injectable products must be
held in quarantine for a minimum of 60 calendar days before it is
released for further manufacturing. If, after placing a donation in
quarantine under this section, the donor is subsequently deferred under
Sec. 610.41 of this chapter, or you subsequently determine a donor to
be ineligible under Sec. 630.10 of this chapter due to risk factors
closely associated with exposure to, or clinical evidence of, infection
due to a relevant transfusion-transmitted infection, you must not
distribute quarantined donations from that donor for further
manufacturing use to make an injectable product.
Sec. 640.71 [Amended]
0
49. Amend Sec. 640.71 as follows:
0
a. In paragraph (a) introductory text, remove ``the following tests''
and add in its place ``testing performed in accordance with Sec.
610.40 of this chapter and Sec. 640.65(b)'';
0
b. Remove paragraphs (a)(1) through (4); and
0
c. In paragraph (b)(1), remove ``licensed physician'' and add in its
place ``responsible physician''.
0
50. In Sec. 640.72, revise paragraphs (a)(2) through (4) to read as
follows:
Sec. 640.72 Records.
(a) * * *
(2)(i) For each donor, establishments must maintain records
including a separate and complete record of initial and periodic
examinations, tests, laboratory data, and interviews, etc., as required
in Sec. Sec. 630.10 and 630.15 of this chapter and Sec. Sec. 640.65,
640.66, and 640.67, except as provided in paragraph (a)(2)(ii) of this
section.
(ii) Negative results for testing for evidence of infection due to
relevant transfusion-transmitted infections required in Sec. 610.40 of
this chapter, and the volume or weight of plasma withdrawn from a donor
need not be recorded on the individual donor record if such information
is maintained on the premises of the plasmapheresis center where the
donor's plasma has been collected.
(3) The original or a clear copy or other durable record which may
be electronic of the donor's consent for participation in the
plasmapheresis program or for immunization.
(4) Records of the medical history and physical examination of the
donor conducted in accordance with Sec. 630.15(b)(1) of this chapter
and, where applicable, Sec. 630.15(b)(5) of this chapter must document
the eligibility of the donor as a plasmapheresis donor and,
[[Page 29906]]
when applicable, as an immunized donor.
* * * * *
0
51. Revise Sec. 640.120 to read as follows:
Sec. 640.120 Alternative procedures.
(a) The Director, Center for Biologics Evaluation and Research, may
issue an exception or alternative to any requirement in subchapter F of
chapter I of title 21 of the Code of Federal Regulations regarding
blood, blood components, or blood products. The Director may issue such
an exception or alternative in response to:
(1) A written request from an establishment. Licensed
establishments must submit such requests in accordance with Sec.
601.12 of this chapter;
(2) An oral request from an establishment, if there are difficult
circumstances and submission of a written request is not feasible.
Establishments must follow up such oral request by submitting written
requests under paragraph (a)(1) of this section within 5 working days.
(b) To respond to a public health need, the Director may issue a
notice of exception or alternative to any requirement in subchapter F
of chapter I of title 21 of the Code of Federal Regulations regarding
blood, blood components, or blood products, if a variance under this
section is necessary to assure that blood, blood components, or blood
products will be available in a specified location or locations to
address an urgent and immediate need for blood, blood components, or
blood products or to provide for appropriate donor screening and
testing.
(c) If the Director issues such an exception or alternative orally,
the Director will follow up by issuing a written notice of the
exception or alternative. Periodically, FDA will provide a list of
approved exceptions and alternative procedures on the FDA Center for
Biologics Evaluation and Research Web site.
0
52. Add subpart M, consisting of Sec. Sec. 640.125 and 640.130, to
part 640 to read as follows:
Subpart M--Definitions and Medical Supervision
Sec.
640.125 Definitions.
640.130 Medical supervision.
Sec. 640.125 Definitions.
The definitions set out in Sec. 630.3 of this chapter apply to the
use of those defined terms in this part.
Sec. 640.130 Medical supervision.
The requirements for medical supervision established in Sec. 630.5
of this chapter supplement the regulations in this part.
PART 660--ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR
LABORATORY TESTS
0
53. 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.
0
54. Revise Sec. 660.31 to read as follows:
Sec. 660.31 Eligibility of donor.
Donors of peripheral blood for Reagent Red Blood Cells must meet
all the criteria for donor eligibility under Sec. Sec. 630.10 and
630.15 of this chapter.
PART 820--QUALITY SYSTEM REGULATION
0
55. The authority citation for 21 CFR part 820 continues to read as
follows:
Authority: 21 U.S.C. 351, 352, 360, 360c, 360d, 360e, 360h,
360i, 360j, 360l, 371, 374, 381, 383; 42 U.S.C. 216, 262, 263a, 264.
Sec. 820.1 [Amended]
0
56. In Sec. 820.1(a)(1), remove ``Manufacturers of human blood and
blood components are not subject to this part, but are subject to part
606 of this chapter'' and add in its place ``Manufacturers of blood and
blood components used for transfusion or for further manufacturing are
not subject to this part, but are subject to subchapter F of this
chapter''.
Dated: May 15, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-12228 Filed 5-21-15; 8:45 am]
BILLING CODE 4164-01-P