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[12 November 2023]{.smallcaps}

Dockets Management Branch (HFA-305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, MD 20852

Re: Docket Number 2006N-0221, 8 November 2007: Requirements for Human
Blood and Blood Components Intended for Further Manufacturing Use,
Proposed Rule

On 8 November 2007, the Food and Drug Administration published in the
Federal Register a proposed rule entitled "Requirements for Human Blood
and Blood Components Intended for Further Manufacturing Use." America's
Blood Centers (ABC) would like to take this opportunity to provide our
comments.

For your information, ABC member centers supply about half of the United
States of America's blood and blood components for transfusion.

ABC commends the FDA for their efforts to update the 600 Series of the
Code of Federal Regulations (CFR) governing blood and blood components.
Updating the CFR to include scientific and industry advances is vital to
assure the safety, purity and potency of the volunteer blood supply.

ABC has numerous comments concerning this proposed rule. A summary of
comments to the most critical issues is below while detailed comments to
the entire contents of the proposed rule are attached.

1.  **ABC strongly endorses the concept of separating donor eligibility
    from product suitability. Donor eligibility occurs prior to
    collection of products while product suitability occurs prior to the
    release of products for use. Product suitability determination
    includes a review of donor records and suitability documentation.**

2.  **The proposed rule includes several changes to the use of donor
    deferral registries (DDRs), including: entering all deferrals
    including deferrals due to mini-physical findings; a single DDR at
    all locations; and that DDRs be checked prior to collection.
    Additionally, the FDA requested comments regarding the feasibility
    of a national DDR. ABC does not concur with any of these
    recommendations due to technical limitations that still exist
    including, but not limited, to computer down times, connectivity
    from remote locations, as well as the questionable scientific
    validity of the use of DDR in ensuring the safety of the blood
    supply. Lastly, we believe the 8 hours/week estimate of record
    keeping burden is woefully inadequate and underestimates the time
    required to maintain a DDR.**

3.  **This proposed rule would require additional supplemental testing
    to determine a deferred donor's infection status. This is a medical
    and public health issue and amounts to the practice of medicine. The
    blood bank industry should not be burdened with this requirement.
    Additionally, to make this even feasible, the FDA would have to
    adopt another approach to approving supplemental/confirmatory
    tests.**

4.  **This proposed rule includes additional requirements for donor
    screening that contradicts the AABB Donor History Questionnaire that
    the FDA participated in the development of and endorses as adequate.
    Examples include: criteria for dental work, increased medication
    listings, major surgical procedures, travel to endemic areas of
    transfusion transmitted infections, xenotransplantation, and the
    definition of intimate contact. ABC does not concur with these
    changes. Also, the proposal to add lower limits for blood pressures
    and addition of the requirement for measuring a donor's pulse are
    unnecessary and do not increase the safety of the blood donation
    process for the donor.**

5.  **ABC does not concur with the inclusion of "relevant
    transfusion-transmitted infections" (RTTI). The proposed list
    includes diseases whose inclusion we do not concur with, as well as
    leaves open the opportunity to add any disease in the future without
    the opportunity to challenge creating an insoluble dilemma for the
    blood banking community. We recommend the entire definition of RTTI
    be deleted.**

6.  **As we have commented in other responses to draft guidances, we
    again request that the qualification to determine donor eligibility
    be clarified such that collection establishment qualifies
    individuals. Likewise, we request that emergency services
    availability be clarified to include 911 services.**

7.  **ABC again strongly disagrees with the interpretation of donor
    eligibility on the day of donation. The interpretation as outlined
    in the proposed rule would deny retrospective clarification of
    incomplete information on donor questionnaires.**

8.  **FDA solicited comments regarding bacterial contamination testing,
    specifically regarding identification of all cultures, deferral and
    notification of donors with positive cultures, and whether all blood
    components should be tested. ABC does not concur with any of these
    recommendations and believe all of these to be within the purview of
    the medical director as the practice of medicine.**

Further explanations and supporting documentation to these comments and
others are in the attached. Thank you for the opportunity to comment. If
you have any questions regarding our comments please contact Ruth
Sylvester, Director Regulatory Services at (202) 654-2983 or
<rsylvester@americasblood.org>

Yours truly,

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Celso Bianco, MD

Executive Vice President

**21 CFR Section 606.160(e)(1) --** *Establishments must maintain a
record of all ineligible donors so that blood and blood components are
not collected from such individuals while they are ineligible or
deferred; and*

**21 CFR Section 606.160(e)(2)** -- *Establishments must provide, to
appropriate personnel at all locations operating under the same license
or under common management, a collective list of ineligible donors with
sufficient information to prevent the collection of blood and blood
components from any donors currently identified at each location as not
eligible to donate under Sec. 630.10(f) and (g)(1) through (g)(6) of
this chapter, or deferred based on test results under Sec. 610.41 of
this chapter.*

**21 CFR Section 630.10(a)** -- *What factors determine the eligibility
of a donor? You must not collect blood and blood components before you
determine that the donor is eligible to donate. A donor is not eligible
if the donor is not in good health or if you identify factors that may
adversely affect: (1) The health of the donor or (2) The safety, purity,
or potency of the blood or blood components collected from the donor.*

**21 CFR Section 630.10(d)(1)** -- *How must you determine the
eligibility of a donor? Before collection, you must determine the
donor\'s eligibility by the following procedures:*

*(1) Assessing the donor's deferral status by checking the collective
list of ineligible donors required under Sec. 606.160(e)(2) of this
chapter;*

**Preamble, Section C, Records (Proposed § 606.160(e)):**

*We are interested in receiving comments on:*

• *The information that should be included on a donor deferral registry
used in common by all donor screening locations of a collecting
establishment operating under a common organization (e.g., under the
same license number);*

• *The adequacy of the criteria listed in proposed Sec. 630.10(f) and
(g)(1) through (g)(6) to prevent the collection of blood and blood
components that may be harmful to the donor or that may result in an
unsuitable product due to possible exposure of the donor to a
transfusion-transmitted infection; and*

• *The technical feasibility of complying with the proposed
requirement.*

*We are also seeking comments on the feasibility of sharing donor
deferral lists between licensed establishments for deferrals required by
the FDA. Such national deferral registries have existed for Source
Plasma collections for many years. ...under proposed Sec. 606.160(e)(2),
if a collecting establishment collected blood at four locations and
three mobile sites, donors deferred from further donation at any of the
seven sites would be listed on a donor deferral registry available at
all seven sites. The requirement to review the record of ineligible
donors before collection and to make the record of ineligible donors
available to collecting establishments operating under a common
organization would improve blood safety by reducing the likelihood of
accidental release of potentially infectious units. We are considering
whether to include, in the final rule, a provision requiring that donor
deferral records be used and disclosed only for purposes consistent with
subchapter F of 21 CFR Chapter I. We request comment on this proposal,
including the following specific issues:*

• *Whether the current practices and protections adequately protect the
confidentiality of donor records;*

• *Whether those current practices and protections will still be
adequate if FDA requires that establishments make donor deferral records
available at all collection sites operating under the same license or
common management; and* • *Whether a regulation limiting the use and
disclosure of such records would actually further the goal of protecting
the confidentiality of the records. In addition, we request comment on
the following:*

• *We believe that few, if any, blood collection establishments are
HIPAA-covered entities under the HIPAA Privacy Rule. However, to
evaluate the impact of this rule on any such HIPAA-covered entities, we
are seeking public comment from any facilities that may be covered by
the HIPAA Privacy Rule, regarding whether or how HIPAA requirements may
impact their ability to comply with this proposed rule.*

**Background/Discussion:** Scientific data showing limited, if any,
value of DDRs -- Given the logistical difficulties associated with DDR
maintenance (see below), it is useful to review the contribution of DDRs
to blood safety. Recently, data have accumulated showing the very
limited or complete lack of value of the DDR in enhancing the safety of
the blood supply. Cable et al (Transfusion 2008;48:34-43) reviewed the
donation records of the American Red Cross from 1995 through 2002,
encompassing 10.2 million first time donors. His group searched the
records of donors who tested repeatedly reactive for HIV, HBV and HCV to
determine if any had returned to donate. A total of 1107 first time
donors who were repeatedly reactive returned for a subsequent donation.
Of those, only seven (two HCV and five HBV) of the returning donors
tested nonreactive. Of the 10.2 million donations, these seven were the
only donations interdicted by the DDR. Investigation into the initial
testing of these donors was consistent with false positive results. The
authors thus concluded that checking over 10 million donations against
the DDR had not prevented the release of any unsafe units. Zou et al
(Transfusion 2006;46:1997-2003) investigated blood donors permanently
deferred for their answers to questions regarding risk of viral
hepatitis or of intravenous drug use. The deferred donors were found to
have higher hepatitis marker rates than those who were not deferred, but
no significant findings were identified for other markers, or for donors
entered into the DDR on the basis of answers to other deferral
questions. Furthermore, the hepatitis markers among the deferred donors
would have been identified by routine donor screening tests. In another
study, Zou et al (Transfusion 2005;45:1593-1600) showed that donors
returning after a temporary deferral for potential exposure to
infectious agents did not appear to pose a greater risk than
non-deferred first-time or repeat donors. Current practice and
operational feasibility -- The establishment's maintenance of a DDR has
been a requirement of the FDA since the 1970's with the implementation
of hepatitis B virus testing. Originally maintained as a manual list,
the vast majority of the DDRs are now maintained in the Blood
Establishment Computer System (BECS). Prior to the transition to
computerized DDRs, donor names were checked against the DDR after
collection. Once computerization occurred, many blood collection centers
began checking potential donors against the DDR prior to collection and
this process is routinely performed by many blood establishments today.
However, they revert to a post donation check of the DDR when computers
are not available, such as during computer outages or on some mobile
collection operations where computer access may be limited or not
available. During periods of computer downtime at some sites, a
duplicate paper deferral list may be available for donor medical history
screening. For some mobile collections, the latest deferral list is
imported into the mobile computer terminals before departure for the
blood drive or the mobile computer terminals are connected via wireless
to the network server or a paper list is utilized. (Geographical
isolation of some mobile locations imposes limitations on connectivity
via wireless technology). For many organizations with multiple fixed
locations and mobile operations -- some of which operate nationwide --
systems are stand-alone at each of the blood collection sites.
Therefore, a particular blood collection site has access only to the DDR
*for that* site. While many license holders have plans to upgrade to a
system that is not stand-alone, this may not be attainable for several
years. While we agree that it may be preferable to review the DDR prior
to drawing a donation, a requirement to do so would effectively shut
down many mobile operations and would impact others when computer
outages occur, having a significant negative impact on blood
availability. Privacy concerns -- In addition to technical challenges in
their use, DDRs pose significant risks of identity theft. The Federal
Trade Commission recently released the results of a survey conducted in
2006 that showed that 8.3 million (3.7%) American adults were victims of
identity theft in 2005. Recently, a Presidential Commission looking at
the issue of Identify Theft issued a report entitled Combating Identify
Theft, A Strategic Plan. One of the key recommendations of this report
was to decrease the unnecessary use of Social Security Numbers (SSN) in
the public domain. Because of these concerns, many blood centers no
longer use the donor's SSN as the unique donor identification number in
their DDR. Even without the SSN, several donor centers have faced the
problems of lost or compromised computers and the need to notify donors
of the potential breach of personal information. The loss or theft of
paper backup deferral lists, particularly from mobile blood drives that
are by their nature less secure than fixed donation sites, is an
additional concern about the security of this information. Although
HIPPA issues are not the primary concern of blood collectors as the
majority of them are not covered entities, it should be noted that
identity theft occurrences may facilitate unauthorized access to private
medical information. The concept of a national DDR -- Further extension
of multiple existing DDRs to a national DDR with other license holders
is not achievable. In a recent editorial (Transfusion 2008;48:6-7), Paul
Holland, MD, discussed the challenges of maintaining a DDR without a
unique blood donor identification system, such as the SSN, in today's
mobile population. He concludes that the ever increasing amount of
manpower expended in the upkeep of the DDR could be better used in other
areas that would have an impact on blood safety and that the time has
come to reexamine the need for a DDR. Without access to a nationwide
unique identifier such as a SSN it is not possible to share DDRs widely
due to duplication of names and birthdates. Many facilities already
spend tremendous resources in an effort to prevent duplication of donor
records *and* to keep separate the records that belong to donors with
similar/same names and dates of birth; this problem would grow even
larger in a national DDR system, while as noted above adding virtually
no safety to the blood supply. The system developed for plasma donors
can not be adapted to meet the very different needs for collection of
labile cellular products. A national DDR (nDDR) based on positive viral
markers for HIV, HBV and HCV seems to work well for the plasma industry
and its paid donors. The nDDR is dependent on use of the SSN. A plasma
center must check every new donor that presents at their facility
against the nDDR, and will recheck each donor on an annual basis at the
time of the annual physical; this is a far less complicated process than
maintenance of a national blood DDR with a required donor query prior to
every donation. Additionally, plasma centers operate within the confines
of a fixed location; they do not run mobile operations. For these
reasons, this nation-wide plasma system is not applicable to the blood
community. In addition it is inappropriate for blood center personnel to
be in a position of informing a presenting donor that he/she is deferred
without having access to the necessary information to help the donor
understand the reason for the deferral. Furthermore, with the
requirement that *all* deferrals must be entered on the registry it is
also quite possible that a donor will be deferred by one
establishment/license holder for a reason that another establishment
would not consider to be a cause for deferral.

> **Recommendation -- Note: For purposes of these comments a "collective
> list of ineligible donors" is used interchangeably with "donor
> deferral registry" and will be indicated as DDR.**
>
> **21 CFR Section 606.160(e)(1) --** The proposed requirement that
> *all* deferrals, including deferrals for medical history or physical
> exam findings, must be entered into the establishment's DDR is
> burdensome and should be modified. The requirement should be amended
> to state that deferrals that impact recipient safety need to be
> recorded in the DDR, as well as those judged by the medical director
> to have a significant impact on donor safety. The inclusion of other
> deferral categories does nothing to enhance the safety of blood
> transfusion, and is overly burdensome.
>
> **21 CFR Section 606.160(e)(2) --** The requirement to maintain a DDR
> at all locations operating under the same license or common management
> should be deleted. The proposals described in Part 606.160(e)(1) and
> (2) and 630.10(a) and (d)(1) as written cannot be carried out in all
> collection sites and would not allow for the collection of donors at a
> significant number of locations, due to the inability to maintain such
> a list.
>
> **21 CFR Section 630.10(a) and (d)(1) --** DDR review should be
> defined as a requirement for donation suitability, not donor
> eligibility. Determination of eligibility should occur based on the
> health history questionnaire and physical exam that is performed prior
> to the collection. Review of the DDR is a part of record review and,
> as such, should be a part of determining that the donation is suitable
> for release. It is important that this be the case because it is
> impractical for all mobile blood collection sites to be able to
> conduct a DDR review as a part of determining donor eligibility prior
> to collecting a blood product.
>
> **Preamble C. Records --** A national DDR (shared between different
> license holders) is neither medically necessary nor technically
> achievable.

**Proposed Rule Section VI. The Paperwork Reduction Act of 1995
(Proposed § 606.160(e))**

*We are proposing to revise current § 606.160(e). Paragraph (e) would
require collecting establishments to maintain a list identifying
ineligible donors (otherwise known as a deferral list or donor deferral
registry) and to provide this list to appropriate personnel to prevent
the collection of blood and blood components from such individuals.
Table 1. -- Estimated Annual Recordkeeping Burden. 21 CFR section
606.160(e)...Hours per Record -- 8*

> **Response to Request for Comment: The estimated burden for
> recordkeeping related to the DDR of 8 hours per week is not realistic.
> The estimate may be adequate for an establishment that operates only
> at fixed locations with computer intra-connectivity or that is
> currently able to perform this activity by updating laptops. This
> would only be the case if they only have a few laptops to update, and
> if there are no complications with the update. In actuality, the
> estimated recording burden is inadequate for there are a multitude of
> circumstances that would increase the processing time for updating
> laptops: lack of direct connectivity, daily updating of laptops, and
> system downtime. Additionally, establishments that provide a new hard
> copy DDR prior to each mobile blood drive would spend many hours (in
> excess of 8 hours per week) to accomplish this activity. According to
> the proposed CFR language a facility that updates the DDR and makes it
> available *on a weekly basis* would not be in compliance with the
> regulation. Therefore, the calculation based on per week activity
> (annual frequency of 52) is totally inaccurate. The footnote to Table
> 1 states "there are no capital costs or operating and maintenance
> costs associated with this collection of information." This is an
> inaccurate statement/estimation. Please see background information on
> preceding pages.**

**21 CFR Section 610.40(e) --** *You must further test each donation,
including autologous donations, found to be reactive by a screening test
performed under paragraphs (a) and (b) of this section using one or more
FDA-approved supplemental (additional, more specific) test(s), or other
appropriate, additional tests. You must perform such further testing as
necessary and appropriate to determine the deferred donor\'s infection
status for the purpose of donor notification required under Sec. 630.40
of this chapter, except: (1) For autologous donations, you must further
test under this paragraph, at a minimum, the first reactive donation in
each 30-day period; or (2) If you have a record for that donor of a
positive result on a supplemental (additional, more specific) test
approved for such use by FDA, you do not have to further test an
autologous donation.*

**Preamble, D.2 Testing further with one or more supplemental
(additional, more specific) test(s) --** *The intent of this section is
to allow for the use of multiple screening tests to \`\`confirm\'\'
infection or to provide additional information on the presence of the
analyte when described in guidance, as appropriate. It is not FDA\'s
intention to move away from confirmatory or supplemental testing where
such an approved test exists, but rather to recognize that under certain
circumstances alternative testing schemes may provide confirmatory or
supplemental testing information*

**Background/Discussion:** While we agree with the concept of additional
testing for donations found to be repeatedly reactive by a screening
test prior to donor counseling, we believe that many of the current FDA
licensed tests having a supplemental and/or confirmatory claim have
outlived their usefulness for a variety of reasons including limited
availability, poor lot to lot consistency and, most importantly, very
poor specificity and sensitivity that often are significantly worse than
that of the accompanying screening test. Therefore, when
supplemental-confirmatory results are obtained, those results are often
inaccurate. The finding of a false-positive confirmatory test in an
uninfected donor is alarming, and since incorrect, raises questions
about the competence of the US blood donor screening system since these
anxious donors then spend their time and money to be investigated and
re-tested by their private physicians. These donors become extremely
frustrated when they are told by their physician that they had negative
test results. They return to the blood collecting facility, demanding
reimbursement of the unnecessary expenses (often not covered by their
health plans) and reinstatement as blood donors. Some centers will
provide partial reimbursement, others will not. Few will attempt to
reinstate the donors because of FDA regulations. Due to the limited
number of licensed supplemental-confirmatory tests currently available,
and the absence of tests in development for the US blood donor screening
market, we strongly believe that changes to the
supplemental-confirmatory approach are needed. One approach is to state
that further testing to accurately and appropriately establish the
deferred donor's infection status is the practice of medicine and should
conform to the standard of care, allowing the blood center physician to
choose the most appropriate tests available, whether including specific
FDA validated claims for supplemental-confirmatory testing or not. The
stringent regulatory requirements for FDA approval of a
supplementary-confirmatory claim discourage license submissions. It is
appropriate to re-think the current licensing paradigm for
supplemental-confirmatory tests and significantly reduce the burden to
licensure. This can be easily facilitated by using tests that are
already licensed for blood donor screening and through the years have
been validated to show sensitivity and specificity superior to FDA
licensed supplemental-confirmatory assays. Clinical studies validating a
screening claim, which are currently very robust, could be followed by
very limited additional studies to achieve a blood donor
supplemental-confirmatory claim that in addition could be used for donor
reentry. As such we agree with the use of a second licensed screening
test in a dual test strategy and the use of licensed nucleic acid test
or FDA-cleared rapid tests in algorithms where they serve as donor
supplemental tests. However, it should be noted that even with the use
of HIV NAT as a supplemental test for donors who are HIV-1/HIV-2 repeat
reactive, only 5% or fewer tests are RNA positive leaving 95% or more of
HIV-1/HIV-2 repeat reactive donations that still require testing by the
obsolete western blot (WB) licensed in 1991 or the immunofluorescence
assay (IFA) licensed in 1992. We are still on version 1.0 for both of
these tests. In a CDC study comparing various algorithms for HIV
confirmation, they concluded that alternate algorithms using
combinations of currently approved HIV tests function as well as, if not
better than, the current algorithm with more flexibility, improved
accuracy and lower cost. This study (Owen etal., 2008 J Clin Microbiol)
compared 6 EIAs, 4 rapid tests and 3 NAT assays in various algorithms to
the current FDA-required testing algorithm using samples from 621 HIV-1
and 34 HIV-2 infected individuals, 183 specimens from 15 HIV-1
seroconverters and 513 uninfected individuals. The results indicate that
the alternate algorithm strategies not only compared favorably for
diagnosing established infection but functioned better in diagnosing
early infection and did so with fewer discordant or indeterminate
results that require follow-up testing. The FDA-required licensure
process for a supplemental-confirmatory claim not only has prevented
improvement of the supplemental-confirmatory tests used, but has
prevented further technological advancements for the confirmation of
other disease agents. In the case of HTLV infection, there have not been
any supplemental-confirmatory tests available since donor screening
began in 1989. From 2000-2004, the Red Cross had 30,429 HTLV-repeatedly
reactive donors (Stramer et al. Transfusion 2006;46:703-707) with
another 7,801 in 2007-2008 and likely a comparable number for 2005-2006.
Through creative approaches consisting of a dual EIA algorithm (using
assays without FDA licensed supplemental-confirmatory claims) and an
unlicensed algorithm for further confirmation of concordant repeat
reactive donations, only 29% of those reactive have required further
testing by more complex confirmatory assays including the 5% that
confirmed positive (Stramer et al. Transfusion 2006). However, none of
the concordantly reactive donors or donors deferred due to reactivity
twice on the same assay can be reentered due to the absence of a
licensed confirmatory test. Although the use of the current HTLV
algorithm has helped notification, FDA requirements have precluded
reentry of any false positive donor since 1989. The most alarming issue
that we face with the use of the current FDA-licensed
supplemental/confirmatory tests is specificity. Each year tens of
thousands of donors are told that they are false positive or
"indeterminate" after confirmatory testing, and that, while we are
confident they are uninfected, they remain unsuitable blood donors
unless they undergo complex reentry algorithms often times requiring an
FDA variance request performed on a case-by-case basis to grant approval
for reentry. The Red Cross alone has deferred 59,533 donors for HIV, HCV
and HBV since 2003 of which 36,725 would be eligible for reentry, but
for which only 2332 (6%) have attempted to undergo the process (Stramer
et al. AABB 2008 accepted abstract). In addition to the time and
expenditure necessary from blood centers to reenter such donors, in many
cases these donors, because of the mixed message they have received,
have no confidence in the blood donor system. One solution to this issue
would be alternate approaches such as dual test strategies that would
not result in indefinite deferral of discordantly reactive donors, or if
deferred, make their reentry process into the blood donor pool less
complex.

> **Recommendation --We propose two options. First, the FDA should
> consider rewriting section 21 CFR Section 610.40(e) to allow
> supplemental-confirmatory testing following a repeatedly reactive
> screening result to be considered the practice of medicine. Second, if
> the FDA chooses to adopt the language in 21 CFR Section 610.40(e), it
> is imperative that FDA seriously consider alternate approaches to the
> approval of supplemental-confirmatory tests and testing claims for
> existing screening tests/rapid tests that would encourage test kit
> manufacturers to participate in the licensure process. This may be as
> simple as taking existing FDA licensed screening tests and allowing
> their use in dual test algorithms that have been shown to have a very
> high positive predictive value.**

**21 CFR Section 630.1(a)(1) and (2)** -- *What is the purpose of
subparts A, B, and C of this part? The purpose of these subparts,
together with 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*

**Preamble, Section F. Definitions** -- *We are defining eligibility of
a donor in proposed §630.3(d) and suitability of the donation in
proposed § 630.3(i) so as to distinguish between the acceptability of a
donor for donation and the acceptability of the donation for transfusion
or for further manufacturing use.*

> **Comment -- We strongly agree with the use of terms donor eligibility
> and product suitability. This is very helpful in clarifying many
> donor/donation requirements.**

**21 CFR Section 630.3(e)** -- *Intimate contact means an activity that
could result in an exchange of body fluids, including blood or saliva,
with another individual.*

**21 CFR Section 630.10 (f)** *-- What factors make the donor ineligible
because of an increased risk for, or evidence of, a relevant
transfusion-transmitted infection?*

*The donor is ineligible to donate when information provided by the
donor or other reliable evidence indicates possible exposure to a
relevant transfusion-transmitted infection. Information that a donor has
participated in any of the following renders the donor ineligible if
that risk of exposure is still applicable at the time of donation:*

*(5) Intimate contact with an individual who is at an increased risk for
exposure to, or is known to be infected with, a relevant
transfusion-transmitted infection that is spread by such type of
intimate contact; and*

**Background/Discussion:** ABC is concerned about the explicit inclusion
of "exchange of saliva" in the definition of "intimate contact."
Proposed 21 CFR 630.10(f)(5) requires that a donor is ineligible to
donate if he or she has engaged in "intimate contact with an individual
who is at increased risk of exposure to, or is known to be infected
with, a relevant transfusion transmitted infection that is spread by
such type of intimate contact." Of primary concern, this requirement is
in stark conflict with standard public health messages that emphasize
the *de minimis* risk of personal contact (including kissing) with
individuals infected with HIV and other parenterally transmitted
infections. It is obvious that one common method of exchanging saliva is
through kissing. Thus, since most people would interpret kissing as
"intimate contact" according to the proposed FDA definition, donor
deferral criteria would contradict the last two decades of public health
messaging concerning the safety of personal contact with persons
infected with HIV and HCV. This would undoubtedly create massive
confusion in the blood donor population. The proposed definition is
without supporting scientific data. Available epidemiologic data do not
support the transmission of any of the relevant transfusion transmitted
infections by saliva, except in the unusual situation of saliva transfer
by means of a human bite breaking the skin, which has transmitted HBV
infection. Exchange of saliva is not considered to be a route of
infection for agents specifically identified in proposed 21 CFR
630.3(g)(i-viii). It is therefore unclear whether proposed 21 CFR
630.10(f)(5) would actually apply to saliva exchange or not.
Furthermore, intimate contact ("sexual contact", "lived with") should
not be applied to all RTTIs (e.g. CJD (which is further addressed
below), vCJD, or malaria) as these diseases are not spread by sexual or
close personal contact. These same issues concerning the definition of
intimate contact were discussed with FDA staff during development of the
uniform DHQ. At that time, it was clear that explicitly deferring a
donor due to the exchange of saliva with a person exposed to or infected
with HIV, HCV, or HBV would contradict scientific data and would send an
inaccurate public health message. The DHQ utilizes and defines "sexual
contact" and "lived with" to cover these issues. New terminology should
not be introduced as it would be confusing.

> **Recommendation -- 21 CFR 630.3(e ) -- The section should be
> reworded:**
>
> **(e) Intimate contact means an activity (sexual contact or living
> with) that could result in an exchange of blood with another
> individual. Furthermore, a definition of "sexual contact" and "living
> with" (consistent with its use in the approved AABB Donor History
> Questionnaire (DHQ) materials) should be included in the guidance
> document that provides recommendations for complying with the rule. 21
> CFR Section 630.10(f)(5) -- The guidance document that provides
> recommendations for complying with the rule must clarify that malaria
> and vCJD, even though identified in the rule as relevant
> transfusion-transmitted infections (RTTIs), are not spread by intimate
> contact, and that donors are not subject to disqualification for
> intimate contact with these infections**.

**21 CFR Section 630.3(g)** -- *Relevant transfusion-transmitted
infection means:*

*(1) Any of the following transfusion-transmitted infections:*

*(i) Human immunodeficiency virus, types 1 and 2 (HIV);*

*(ii) Hepatitis B virus (HBV);*

*(iii) Hepatitis C virus (HCV);*

*(iv) Human T-lymphotropic virus, types I and II (HTLV);*

*(v) Treponema pallidum (syphilis);*

*(vi) Creutzfeldt-Jakob disease (CJD);*

*(vii) Variant Creutzfeldt-Jakob disease (vCJD); and*

*(viii) Plasmodium sp. (malaria).*

*(2) Other transfusion-transmitted infections not listed in paragraph
(g)(1) of this section: (i) For which appropriate screening measures are
developed and/or an appropriate screening test for donor specimens is
licensed, approved, or cleared for such use by FDA and is available; and
(ii) That: (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 donors at
risk of infection.*

**Preamble: F. Definitions --** *We are defining relevant
transfusion-transmitted infection in proposed Sec. 630.3(g)(1) to
identify the currently recognized disease agents that are associated
with transmission from the donor to the recipient by transfusion,
infusion, or injection of a blood component or blood derivative.. .. In
the proposed rule entitled \`\`Requirements for Testing Human Blood
Donors for Evidence of Infection Due to Communicable Disease Agents\'\'
(64 FR 45340, August 19, 1999), we solicited comments, with supporting
data, from the public in regard to the value of donor 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. After reviewing the comments and
submitted scientific data, we determined that the comments did not
provide sufficient supporting data to justify eliminating the
requirements for screening and testing the donor for syphilis. We
continue to consider this issue, including any further studies that
address the issues of transfusion-related syphilis infection or testing
for syphilis as a surrogate marker for other communicable diseases; and
we again request comments and data concerning whether establishments
could discontinue syphilis testing without adversely affecting the
safety of the blood supply. If we receive adequate data, we will
eliminate or modify this testing requirement in the final rule.*

**Background/Discussion:** CJD **--** There is no report of human
transfusion transmission of classic CJD. (Zou S, Fang CT, Schonberger
LB. Transfusion transmission of human prion diseases. Trans Med Revs
2008;22:58-69). The American Red Cross lookback study on recipients of
blood from donors who subsequently were diagnosed with CJD reveals no
evidence this has occurred. 429 recipients of blood from 34 such donors
have been followed for a total of 2023 person-years without any cases of
CJD. 145 recipients survived for five or more years after transfusion.
This observation is statistically significant (P = 0.0156) when compared
to the frequency of clinical vCJD in recipients of blood from donors who
subsequently developed vCJD. Inclusion of CJD in the list of RTTIs is
inappropriate. Nevertheless, we are not recommending any change in
current donor eligibility or product suitability criteria relating to
classic CJD. Syphilis -- In a published study (Prevalence of circulating
*Treponema pallidum* DNA and RNA in blood donors with confirmed-positive
syphilis tests. Transfusion 2002;42:94-99) Orton and colleagues used
nucleic acid amplification to test for the presence of *T. pallidum* DNA
(91) and/or RNA (97) in a total of 169 platelet products from donors
with confirmed positive serological tests for syphilis. No sample was
found positive. Platelets represent the worst case scenario, since
storage of RBCs and whole blood at refrigerator temperatures is lethal
to *T. pallidum*. (Turner TB, Diseker TH. Duration of infectivity of
*Treponema pallidum* in citrated blood stored under conditions in blood
banks. Bull Johns Hopkins Hosp 1941;68:269-79 and Kilmer JA. A note on
the survival of *Treponema pallidum* in preserved citrated human blood
and plasma. Am J Syph Gonorrhea Vener Dis 1942;26:156-8). With respect
to the surrogate value of syphilis testing, Herrera et al (Serologic
test for syphilis as a surrogate marker for human immunodeficiency virus
infection among United States blood donors. Transfusion 1997;37:836-840)
concluded that amongst almost 5 million blood units analyzed, syphilis
testing would have removed only 0.2 HIV window-period donations in 1994,
when the window period was much longer than it is now. More recently,
ARC estimated the surrogate role of syphilis testing for other
significant RTTIs using data from collections between 2002 and 2006.
There were significantly higher frequencies of HIV, HCV, HBsAg and HTLV
positive donations among those with positive syphilis tests for the
2005-2006 period. However, the actual sensitivity of the syphilis test
for identifying such samples was between 1.6% and 5.9%. Given that HIV,
HCV and HBV testing relies upon redundant serologic and NAT procedures,
the syphilis test provides no additional security in detecting such
prevalent infections. Accordingly, ARC has also evaluated the
relationship between a new confirmed positive syphilis test and test
results for HIV, HCV, HBsAg and HTLV among repeat donors by looking at
data from 2002 -- 2006. There were 390 new syphilis infections among
just over 5 million donations. However, of the 171 HIV infections, only
2 were found in the syphilis positive group, for a sensitivity of 1.2%
and a PPV of 0.5%. There were no HCV, HBsAg or HTLV seroconversions
among the syphilis positive group. Accounting for the current length of
the window period, it is estimated that the syphilis test might identify
approximately 0.04 HIV window period donations annually in the Red Cross
donor population. Thus, the current surrogate value of the syphilis test
appears to be negligible. Likewise the 1995 NIH Consensus Development
Conference Report on Infectious Disease Testing for Blood Transfusions
concluded that serologic tests for syphilis have very little value as
surrogate markers for HIV/HBV/HCV/HTLV.

> **Recommendation -- CJD is not a relevant transfusion-transmitted
> disease and should be removed from the definition. Serological tests
> for syphilis do not add to the safety of blood products transfused in
> the United States. The requirement to perform such testing should be
> deleted.**

**21 CFR Section 630.3(j)** -- *Trained personnel means authorized
individuals, including physician substitutes, who are adequately
instructed and qualified to perform specified functions under the
direction of the responsible physician*

> **Recommendation -- The section should be reworded:**
>
> **(j)Trained personnel means authorized individuals, including
> physician substitutes, who are adequately instructed and qualified to
> perform functions under the direction of the responsible physician as
> specified in the establishment's standard operating procedures. The
> establishment's procedures should define what constitutes "adequately
> instructed" and "qualified to perform" relevant functions.**

**21 CFR Section 630.3(k)** -- *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 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 the blood and blood
components collected, or by a blood derivative product manufactured from
the collected blood or blood components, because the disease agent or
disease is potentially transmissible by that blood, blood component, or
blood derivative product.*

**Preamble, F. Definitions** -- *The definition of a
transfusion-transmitted infection differs from a relevant
transfusion-transmitted infection in that the existence of sufficient
incidence and/or prevalence to affect the potential donor population is
not a part of the definition. Available screening and testing methods
may also be limited. One example of such a transfusion transmitted
infection is leishmania.*

**Background/Discussion:** ABC recognizes the need to develop a guidance
document as agents emerge, but sees no positive value in defining TTI in
the proposed rule. As written, the definition lacks precision and
provides no useful information for industry. Furthermore, reference to
this definition in proposed 21CFR 630.10(g) will create an insoluble
dilemma for the blood community in determining the conditions in which
to establish deferral criteria for travel or residence. The AABB
Transfusion Transmitted Disease Committee has developed an incomplete
listing of no fewer than 69 agents that meet, or potentially meet, the
proposed definition of TTI. To comply with the proposed requirements,
for each of these agents, would not be possible, practical, or
effective. Furthermore, having a formal definition of TTI in a
regulation would likely lead to unexpected pressures and requirements to
regulate for each and every infection found to be transmissible by
transfusion, even if such transmission were exceedingly rare or remotely
plausible. It is the opinion of ABC that the current system of Guidances
has proven safe and effective in the management of emergent threats to
blood safety such as WNV, SARS and vCJD. No other rulemaking appears to
be necessary. Even in the absence of FDA guidance industry has taken the
lead and published recommendations when necessary. For example, AABB
Association Bulletin 06-04 *Recommendations for Blood Collection
Facilities in Response to Epidemic Mumps in the Midwest* was published
in April 2006. Finally, ABC recognizes that *Leishmania* spp. appear to
fit the proposed definition of TTI, however, it illustrates some of the
problems outlined above. For example, it is not necessary to defer
donors who have lived, or traveled in Mediterranean countries where
Leishmania occurs.

> **Recommendation -- The definition of transfusion-transmitted
> infection (TTI) and all references to it should be deleted.**

**21 CFR Section 630.5(a)-(d)** -- (a) *Who must determine the
eligibility of a donor? The responsible physician authorized by you, as
described in Sec. 630.3(l), must determine the eligibility of a donor of
blood or blood components in accordance with this part. (b) Must the
responsible physician be present at the collecting establishment at all
times? Except as provided in paragraphs (c) and (d) of this section and
Sec. 630.15(b)(1) and (b)(4), you must assure that the responsible
physician is in attendance when any of the following activities are
performed at the collecting establishment: (1) Determining the
eligibility of a donor; (2) Collecting blood or blood components; (3)
Collecting Source Plasma in an approved collection program from donors
who are otherwise determined to be unsuitable; (4) Returning red blood
cells to the donor during plasmapheresis; or (5) Immunizing a donor in
an approved hyperimmunization program. (c) What specified functions of
the responsible physician in the collection of Source Plasma may be
performed by a physician substitute? You may authorize a physician
substitute to perform any specified function listed in paragraph (b) of
this section in the collection of Source Plasma except for red blood
cell immunizations performed under paragraph (b)(5) of this section."
(d) What specified functions of the responsible physician in the
collection of blood and blood components may be performed by a physician
substitute or trained personnel? In the absence of the responsible
physician, you may authorize a physician substitute or trained personnel
to determine donor eligibility and collect blood and blood components*

**Background/Discussion:** The proposed requirement is unclear about the
personnel required for the collection of plasma components involving the
return of red blood cells in programs that do not collect Source Plasma.
Section 630.5 (b)(4) "returning red blood cells to the donor during
plasmapheresis" would require the presence of a physician substitute in
the collection of Source Plasma. Red cells are now routinely returned to
donors during plasma collection by automated equipment, both as a
separate plasma donation and as part of procedures collecting red cells
and/or apheresis platelets. With modern automated equipment that is
continuously attached to the donor, return of red cells does not pose a
special risk, and there is no need for a responsible physician or
physician substitute to be present during collection from Source Plasma
or Whole Blood donors.

> **Recommendation -- The guidance document should clarify that trained
> personnel, instructed and qualified by the collection establishment,
> may determine eligibility and collect blood and blood components,
> including plasma components collected by a procedure involving the
> return of red blood cells to the donor.**

**21 CFR Section 630.5(e)** -- *Must emergency medical services be
available? Yes, you must establish, maintain, and follow standard
operating procedures for providing within 15 minutes emergency medical
services for donors when medically necessary.*

**Preamble, Section G. Medical Supervision --** *The collecting
establishment would be required in proposed § 630.5(e) to have SOPs for
providing emergency medical services to a donor within 15 minutes when
necessary. Although we currently require the presence of appropriately
trained medical personnel, our current regulations do not directly
address the availability of emergency medical services, which a donor
may require. We are interested in receiving comments on what would be
considered as appropriate for available emergency medical services*

**Background/Discussion:** The establishment of standard procedures for
providing emergency medical services within 15 minutes, if necessary for
donors seems appropriate. It is a widely accepted fact that the most
qualified medical professionals to respond to an emergency are trained,
practicing emergency physicians or emergency medical technicians using
the proper equipment, who have the ability to transport an unstable
patient to an appropriate health care setting. Furthermore, there are
several publications in the peer reviewed literature showing that
emergency medical personnel frequently respond to calls within a time
frame that meets the requirements of this section. (Lerner et al, The J.
of Emergency Medicine 2003;25:171-174; Pons et al. ibid 2002;23:43-48).

> **Recommendation -- In an effort to provide clarity to the proposed
> regulation, we recommend that the section be reworded to include
> public emergency medical services. (e) Must emergency medical services
> be available? Yes, you must establish, maintain, and follow standard
> operating procedures for providing within 15 minutes emergency medical
> services, which may include public emergency medical services, for
> donors when medically necessary.**

**21 CFR Section 630.10(b)** -- *What educational material must you
provide to the donor before determining eligibility? Before determining
eligibility, you must provide the donor with educational material
containing useful and current information concerning the relevant
transfusion-transmitted infections defined in Sec. 630.3(g). The
educational material must include an explanation of the signs and
symptoms of and the readily identifiable risk factors closely associated
with exposure to the relevant transfusion-transmitted infections. You
must present educational material in an appropriate form, e.g., in oral,
written or multimedia, and in a manner designed to be understood by the
donor. The educational material must state that the donor may not donate
blood and blood components when such signs and symptoms or risk factors
are present.*

**Preamble, Section H. General Donor Eligibility Requirements, 1.
Educational Materials** *The proposed rule would also require that
educational material include behavioral risks and signs and symptoms for
hepatitis and other relevant transfusion transmitted infections
determined to present a risk to the blood supply. We are soliciting
comments on this provision, particularly on how comprehensive the
educational material should be and the format or style in which it is
presented.*

**Background/Discussion:** The signs, symptoms and risk factors for HIV
infection already appear in the AABB DHQ Educational Materials and all
other FDA approved donor history materials. Many of the risk factors
adequately cover risks for other RTTIs including hepatitis B and C. We
do not consider it appropriate to add additional items to this section.
In fact, we question the value of including a signs and symptoms section
in the current DHQ materials. Most of the signs and symptoms are
decidedly non-specific and can be found in numerous other medical
conditions. For example, a woman having night sweats could simply be
menopausal. Further one would expect the other items would be picked up
by the routine donor questions, beginning with, "Are you feeling well
and healthy today?" This question would capture swollen lymph nodes,
sores in mouth, cough, and shortness of breath or diarrhea that won't go
away. Coughs and shortness of breath would also be identified by the
question regarding problems the donor has with his lungs. Fevers would
be identified when a donor has their temperature taken during the
mini-physical. In addition, issues such as mouth sores, blue or purple
spots on mouth or skin, etc are indicative of well established AIDS. It
is highly unlikely that persons who are already ill with HIV infection
would be coming to donate blood. The AABB Donor History Task Force
recommended the removal of this list of signs and symptoms at the time
the uniform DHQ was developed due to the non-specific nature of the
list. FDA did not agree with this at the time, but it is surely time to
reconsider. It is well known that the denser the reading material
presented to donors, the less comprehension occurs. This was supported
by the task force consultants -- National Center for Health Statistics
(NCHS) -- on comprehension of written materials at that time. In a
discussion with NCHS and recent reevaluation of the Educational
Materials, it was determined this information is repetitive in getting
at the question for donors to consider which is, "Am I sick?" It was
felt the density of the materials strained donor attention. Further, it
was noted that in the absence of very specific and unique
signs/symptoms, it is better to keep the Educational Materials as simple
as possible to enable the donor to focus on the more specific questions.

> **Recommendation -- We do not agree with the proposed requirement that
> signs and symptoms of relevant transfusion-transmitted infections
> (RTTIs) be included in the education materials. The section should be
> reworded: (b) What educational material must you provide to the donor
> before determining eligibility? Before determining eligibility, you
> must provide the donor with educational material containing useful and
> current information concerning the relevant transfusion-transmitted
> infections defined in Sec. 630.3(g). You must present educational
> material in an appropriate form, e.g., in oral, written or multimedia,
> and in a manner designed to be understood by the donor.**

**21 CFR Section 630.10(c)** -- *When must you determine the eligibility
of a donor? You must determine donor eligibility on the day of donation,
and before collection. 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
and Sec. 640.5 of this chapter, 1 day before the donation. You must have
standard operating procedures in place for identifying such components.*

**Preamble, Section H, General Donor Eligibility Requirements 2.
Assessment of the Donor's Eligibility to Donate Current *-- ****Proposed
§ 630.10(c) would require that the collecting establishment perform an
assessment of the donor's eligibility on the day of donation, and before
collection. An exception would be allowed for the collection of blood
components that cannot be stored for more than 24 hours, such as
granulocytes for transfusion. For such components, the collecting
establishment may perform a donor assessment and the testing required
under § 610.40(a) and (b) 1 day before the collection of such products.
Establishments would be required o have SOPs in place to identify such
components*

**Background/Discussion:** Eligibility determination on day of
collection -- The current and proposed regulatory language has been
interpreted by FDA such that components collected from a donor whose
eligibility was not adequately determined on the day of collection have
been deemed unsuitable for use. While it is unfortunate that an error
occurred in the original donor eligibility determination, the
suitability of the donation should not be linked to the eligibility of
the donor unless the missing data cannot be reasonably assessed during
the dating period of the component. De-linkage would permit the product
to be deemed suitable for transfusion, thus preserving the availability
of an adequate blood supply. Examples of missing data that can
accurately be determined during the dating period of the component are
those elements that would not change. These include, but are not limited
to, travel history, history of disease, history of transfusion, "living
with" someone with hepatitis, and history of CJD. Other data are related
to the donor's health and have no bearing on the suitability of the
product and are irrelevant after the collection. These include, but are
not limited to, donor's weight, blood pressure, pulse, and general
health status. Short shelf-life products -- A more reasonable approach
to collecting a sample the same day or one day prior to collection of a
short shelf-life product would be to allow apheresis donors who have
donated within the previous 30 days, and were cleared on all testing, to
serve as a granulocyte donor based on the results of the prior donation.
The granulocyte donation would be tested as well, but the product would
be released prior to the availability of those results. Should any of
the results be reactive, the hospital would be notified immediately.
Generally, granulocyte recipients are gravely ill and the administration
of the granulocytes is a last treatment option to help them clear a
bacterial/fungal infection.

> **Recommendation -- Eligibility determination on day of collection --
> While we agree that it is desirable to complete the donor eligibility
> determination prior to collection, we oppose an interpretation of this
> requirement (assessment of a donor's eligibility on the day of
> donation, and before collection) that would deny a retrospective
> eligibility determination (e.g., in the case of missing or
> incompletely explained questionnaire responses due to GMP error). We
> recommend that FDA clarify, in a guidance document that contains
> recommendations for complying with the regulations, interpretive
> criteria that will prevent the needless destruction of life-saving
> blood components. Short shelf-life products -- We agree that
> collecting a sample for testing at the same time a short shelf-life
> product is collected may not be feasible; however, it is also probable
> that a sample collected within the previous 24 hours may not be able
> to be tested prior to release of the product. We recommend that
> facilities be permitted to collect a sample for donor testing three
> (3) days prior to product collection. Alternatively, we believe that a
> donor who has donated within the previous 30 days in accordance with
> proposed rule 640.21(d) and current rule 610.40(c)(1) would be
> acceptable.**

**21 CFR Section 630.10(d)(2)** -- *How must you determine the
eligibility of a donor? Before collection, you must determine the
donor\'s eligibility by the following procedures: (2) Assuring that the
interval since the donor\'s last donation is appropriate, taking into
account the donor\'s participation, if any, in other blood or blood
component collection programs;*

**Background/Discussion:** While earlier versions of the DHQ asked a
similar question, it was not a requirement by the FDA or AABB. The AABB
Donor History Task Force subsequently removed the question addressing
donation at other sites, with FDA approval, and placed emphasis on
asking very specific questions to identify donors who have given blood,
platelets, plasma or double red cells by apheresis at specific time
intervals. The current approach to questioning by specific types of
donations should capture all donations regardless of the facility where
the donor last donated.

> **Recommendation --this section should be reworded: (2) Assuring that
> the interval since the donor\'s last donation is appropriate;**

**21 CFR Section 630.10(e)** -- *How do you assess the donor\'s medical
history? Before collection, you must take a medical history designed to
determine if the donor is in good health and if health care
practitioners have ever advised the donor not to donate; to identify
risk factors closely associated with exposure to, or clinical evidence
of, infection due to a relevant transfusion transmitted infection; and
to determine if there are other conditions that may adversely affect the
donor or the safety, purity, or potency of the blood or blood components
or any product produced from the blood or blood components.*

**Background/Discussion:** Although a question asking whether the donor
was advised against donation by a health care practitioner was on an
earlier version of the DHQ, neither the FDA nor AABB required collection
facilities to ask a specific question regarding this issue. The question
was eliminated with the approval of FDA, in a subsequent version of the
DHQ. The rationale for the elimination of this query was based on the
fact that this is a nonspecific query and becomes a reiterative issue
when donors are asked this question at each donation. For instance, if a
donor was told by a physician in 1993 not to donate until a simple
bacterial infection cleared, in theory, the answer to this query would
always be "YES." Although the reason for deferral is long past, the
donor will have to answer "YES" to this question at each and every
visit, a situation that is a waste of time for both donor and health
historian, and which adds nothing to the safety of the blood supply.
Furthermore, most primary care physicians (and even specialists) are not
familiar with the specific eligibility requirements for donors and as
such are rarely in a position to make such a determination. Instead, the
donor is directly queried regarding very specific risk factors such a
heart disease, lung disease, cancer, antibiotics, history of hepatitis
and other specific infectious diseases. The phrase "if health care
practitioners have ever advised the donor not to donate" does not add to
the safety of the blood products but will complicate the donation
process.

> **Recommendation -- We recommend that the statement, "and healthcare
> practitioner ever advised the donor not to donate" be deleted from the
> final rule.**

**21 CFR Section 630.10(f)** -- *What factors make the donor ineligible
because of an increased risk for, or evidence of, a relevant
transfusion-transmitted infection? The donor is ineligible to donate
when information provided by the donor or other reliable evidence
indicates possible exposure to a relevant transfusion-transmitted
infection. Information that a donor has participated in any of the
following renders the donor ineligible if that risk of exposure is still
applicable at the time of donation:*

*(1)Social behaviors...*

*(2) Medical treatments and procedures associated with exposure to
relevant transfusion transmitted infections;*

*(3) Signs and symptoms of relevant transfusion-transmitted infections;*

*(4) Institutionalization in a correctional institution;*

*(5) Intimate contact with an individual who is at an increased risk for
exposure to, or is known to be infected with, a relevant
transfusion-transmitted infection that is spread by such type of
intimate contact; and*

*(6) Nonsterile percutaneous...*

**Preamble, H. 2. Assessment of the Donor's Eligibility to Donate --
Institutionalization** (630.10(f)(4) *A collecting establishment would
determine whether a donor is currently an inmate of a correctional
institution or has been incarcerated within the last 12 months, and if
so, whether the risk of exposure related to that incarceration is still
applicable at the time of donation. Current guidance recommends that a
donor not be eligible to donate if incarcerated in a correctional
institution for more than 3 consecutive days during the past 12 months.*

**Background/Discussion:** 21 CFR Section 630.10(f)(2) -- We believe
that existing screening questions on donor forms adequately cover issues
of medical treatments and procedures. These would include dura mater
transplant, blood transfusion, organ, tissue or bone marrow transplant
and use of clotting factor concentrates. We are concerned that the
wording of the proposal is too broad and might be applied
inappropriately to situations that are not as yet agreed upon by the
agency, industry and the public. The Guidance process is a more
appropriate venue for recommendations for specific medical treatments
and procedures that may affect donor and/or patient safety. 21 FR
Section 630.10(f)(3) -- The response to 630.10(b) -- see elsewhere in
this document -- applies o this section as well with respect to the
requirement for 'signs and symptoms of relevant transfusion-transmitted
infections'. 21 CFR Section 630.10(f)(5) -- See comments to 630.3(e)
elsewhere in this document that are relevant to intimate contact.

> **Recommendation -- We recommend that 21 CFR Sections 630.10(f)(2) and
> (3) be deleted from the final rule.**
>
> **Comment -- We agree with the principle of deferral from blood
> donation based on incarceration (21 CFR Section 630.10(f)(4)) and with
> the principle of addressing the time period in a guidance document
> rather than codifying it in the CFR. In addition, we agree that
> institutionalization is adequately addressed in current guidance
> recommendations and the currently used donor history screening
> questionnaires. Please see our response elsewhere in this document to
> 21 CFR Section 630.3(e) -- definition of intimate contact.**

**21 CFR Section 630.10(g)** -- *What other factors make the donor
ineligible to donate because of risk to the health of the donor, or to
the safety, purity, or potency of the blood or blood component? You must
assess the donor for each of the following factors to determine whether
donating could adversely affect the health of the donor, or whether the
safety, purity, or potency of the blood or blood component could be
affected, and if so, you must determine the donor to be ineligible:*

*(1) Medical or dental treatment, or symptoms of a recent or current
illness;*

*(2) Medication;*

*(3) Major surgical procedure;*

*(4) Travel to, or residence in, an area endemic for a
transfusion-transmitted infection;*

*(5) Xenotransplantation product recipient or intimate contact of a
xenotransplantation product recipient*

*(6) Exposure or possible exposure to a released disease agent or
disease relating to a transfusion-transmitted infection, if you know or
suspect that such a release has occurred;*

*(7)Pregnancy ...; and*

*(8) Unreliable answers to medical history questions due to the apparent
influence of drugs or alcohol, or due to another reason affecting the
reliability of the donor\'s answers.*

**Preamble, Section H. 2. Assessment of the Donor's Eligibility to
Donate *-- ****Major surgical procedure (Proposed § 630.10(g)(3)). We
would require establishments to defer donors who have experienced major
surgery within the past 12 months. This deferral is to protect the donor
whose health may be compromised by the donation and to address the
possibility that the donor may have unknowingly received blood or blood
components during surgery.*

**Preamble, H. 2. Assessment of the Donor's Eligibility to Donate --**
*Travel to endemic areas for transfusion-transmitted infections -- It is
known that several transfusion-transmitted infections exist for which
the risk is closely associated with a geographic area, e.g., leishmania.
Typically, such infections would not be \`\`relevant
transfusion-transmitted infections\'\' requiring broader screening and
testing because they do not have sufficient incidence or prevalence in
the potential donor population. This provision is designed to identify
donors who may be at risk for additional transfusion-transmitted
infections. Because donors harboring such infections may be
asymptomatic, or the signs and symptoms may be mild enough to go
undetected at the time of donation, we would require the collecting
establishment to assess whether the donor has visited or is a former
resident of endemic areas known to harbor the disease agent or disease,
whether the risk of exposure is still applicable at the time of
donation, and, if so, determine the donor ineligible to donate.*

**Background/Discussion:** Dental procedures-- The question regarding
dental treatment was removed from the AABB DHQ, with FDA approval, based
on published information demonstrating that bacteremia from dental
procedures was very transient (15 minutes or less) and that even if the
donor was scheduled to donate immediately after a dental procedure, by
the time a donor traveled to the blood collection facility, the donor
would no longer be bacteremic (PM Ness, HA Perkins. Transient bacteremia
after dental procedures and other minor manipulations,
Transfusion1980;20(1):82--85). Medication -- The CFR should be clear
that the medications currently covered by FDA guidance are the only ones
that *must* be evaluated. Other medications may be screened for at the
discretion of each institution's medical director. Major surgical
procedure -- A requirement for a 12 month deferral (as explained in the
Preamble) after "major surgery" is not medically warranted because the
existing questions on the DHQ adequately protect donor and recipient
safety. Donors must feel healthy and well on the day of donation, must
pass the focused physical examination and must have an acceptable
hemoglobin concentration. If a donor meets these requirements, and all
other eligibility requirements, within an interval shorter than 12
months after surgery, he or she is qualified to donate blood. In
addition, donors are asked specifically about blood transfusion in the
last 12 months. If a donor is not certain whether or not they were
transfused, most donor centers would defer the donor for 12 months from
the date of surgery or until they are able to provide the information
about transfusion. It is not reasonable to make assumptions about
whether a donor was transfused or not, based on the type of surgery when
this information is available to the donor from their medical record.
Operationally, "major surgery" would have to be defined in the blood
center's standard operating procedures, and likely would not be defined
in the same way by different blood centers. Since surgery is not an
independent risk factor for transfusion-transmitted infections, there is
no need to add a less specific question to the DHQ about surgery, when
the more specific question about blood transfusion and other possible
blood exposure are already asked. Travel to areas endemic for a TTI --
Please see our response elsewhere in this document to 630.3(k) where we
recommend that "the definition of transfusion-transmitted infection
(TTI) and all references to it should be deleted." In the event that a
particular TTI poses a threat to blood safety in the US, FDA can rapidly
establish donor deferral policies through the guidance mechanism. This
proposal defines a donor as ineligible if he or she has traveled to or
has resided in an area endemic for a TTI. However, the proposed
definition of TTI is too imprecise to be codified in regulations. With
regard to donor deferral, there are many examples of transfusion
transmitted infections that have not risen to a high enough level of
concern to warrant a travel or residency deferral: current examples are
Dengue, Chikungunya, and Leishmania (with the exception of the unusual
circumstances in Iraq). The appropriate policy for each such agent can
be established through public forums (such as the Blood Products
Advisory Committee) where all stakeholders can advance their points of
view which can then be taken under advisement by FDA, followed by
guidance when warranted. If broad language requiring travel deferrals
for TTIs is codified in the CFR, there is a risk that the opportunity
for informed decision-making on an agent-by-agent basis will be reduced.
Also, a blanket application of the rule to all TTIs might result in
deferral for a very large percentage of travel and, in this increasingly
mobile society, might jeopardize blood availability without providing
any material safety benefits. Issuance of guidance on a case-by-case
basis is effective, as documented by the travel deferrals implemented
during the SARS epidemic. Xenotransplantation -- While we agree that
individuals who have undergone xenotransplantation should not be
eligible as blood donors, we strongly object to the addition of
questions to identify the vanishingly small number of such recipients.
It is extremely unlikely that a xenotransplant recipient would become a
blood donor due to the strong recommendation for deferral of
xenotransplant recipients made in the "Guidance for Industry: Source
Animal, Product, Preclinical and Clinical Issues Concerning the Use of
Xenotransplantation Products in Humans" issued in April 2003. Section J
of this document contains a recommendation that recipients of
xenotransplants be counseled not to donate blood or tissues during the
informed consent process. In addition, the DHQ already asks donors about
transplants in the last 12 months; donors who have undergone
xenotransplantation are likely to provide this history even if their
transplant occurred over 12 months ago. Consequently, most blood centers
will defer donors who report a history of xenotransplantation through
already established procedures. There is no need for the addition of
unwarranted and incomprehensible questions to an already extensive and
exhaustive DHQ. Xenotransplantation products are subject to regulation
by the FDA (e.g., under section 351 of the Public Health Service Act and
the Federal Food, Drug, and Cosmetic Act). In accordance with the
statutory provisions governing premarket development,
xenotransplantation products are subject to FDA review and approval.
Investigators of such products need to obtain FDA review of proposed
xenotransplantation clinical trials before proceeding. Consequently, FDA
is in the ideal position to make sure that investigators of
xenotransplantation products advise recipients not to donate blood
because of the potential risk of infection with both recognized and
unrecognized infectious agents. This certainly will be a more effective
strategy than searching for the rare individual at theoretical risk
among the millions of individuals who volunteer to donate blood. We
believe these queries will not only be ineffective, but may also divert
the donor's attention from questions that address real risks to blood
recipients (i.e., donors in the window of seroconversion for hepatitis
and HIV). Additionally, we are concerned that deferral of intimate
contacts of xenotransplantation recipients casts too broad a net and
could defer perfectly safe blood donors. It is important to note that a
major factor in the transmission of zoonotic pathogens to xenotransplant
recipients is that the immunosuppression required to prevent rejection
will render them uniquely susceptible to infection. In contrast,
immunosuppression is not an issue in contacts who would be qualified as
eligible blood donors. There is currently a moratorium on
xenotransplantation that effectively renders the issue moot for now, and
further erodes the efficacy of a requirement for donor history
questions. If and when the moratorium is lifted, guidance based on the
state-of-the-art can be used without enshrining a requirement in CFR
now. Exposure to a released TTI -- The potential for accidental or
intentional release of a biological, chemical or nuclear agent capable
of causing or potentially causing disease that could affect the safety,
purity or potency of a blood product is speculative. Since it is unknown
when or if such an event will occur, it is not possible to assess their
potential effect on a routine basis. When these events have occurred in
the past, for example the anthrax attacks of 2001 and SARS, the industry
worked in conjunction with the FDA, CDC and other public health entities
to determine the potential impact on donors and products. Industry and
regulators have proven their ability to respond to such incidents
rapidly and effectively on a case-by-case basis. We believe it is best
to deal with such situations through guidance as they occur rather than
codify them in the CFR. This proposal does not enhance the safety of
blood products and should be deleted from the final rule. Unreliable
answers -- While, we agree with the deferral of donors who appear to be
under the influence of drugs or alcohol, or due to any other reason
affecting the reliability of the donor's answers, we believe this should
be managed by each institution's standard operating procedures. The AABB
DHQ does include attention questions that would likely identify donors
who are not able to provide reliable answers for various reasons. This
proposal does not enhance the safety of blood products and should be
deleted from the final rule.

> **Recommendation -- 21 CFR Section 630.10(g)(1) -- We recommend that
> the phrase "or dental" be deleted. 21 CFR Section 630.10(g)(2) --
> should be reworded for clarity: (2) Medication, as indicated by FDA
> guidance; We recommend that 21 CFR Sections 630.10(g)(3), (4), (5),
> (6), and (8) be deleted from the final rule.**

**21 CFR Section 630.10(h)** -- *How do you perform a physical
assessment of the donor? You must determine that the donor is in good
health based on the following, at a minimum: (1)Temperature ...*

*(2) Blood pressure. The donor\'s systolic blood pressure must not
measure above 180 millimeters of mercury or below 90 millimeters of
mercury, and the diastolic blood pressure must not measure above 100
millimeters of mercury or below 50 millimeters of mercury. A donor with
measurements outside these limits may be permitted 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.*

*(3) Hemoglobin or hematocrit determination for allogeneic donation.*

*(i) 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; and*

*(ii) An allogeneic donor must have a hemoglobin level no less than 12.5
grams per deciliter of blood, or a hematocrit value no less than 38
percent. An autologous donor must have a hemoglobin level no less than
11.0 grams per deciliter of blood, or a hematocrit value no less than 33
percent.*

*(4) Pulse. The donor\'s pulse rate must be regular and between 50 and
100 beats per minute. A donor with an irregular pulse rate or
measurements outside these limits may be permitted to donate only when
the responsible physician has examined the donor and determines that the
health of the donor would not be adversely affected.*

*(5) Weight. The donor must weigh a minimum of 50 kilograms (110 pounds)
and must not have had an unexplained loss of greater than 10 percent of
body weight within the past 6 months; and (6)Skin examination ....*

**Preamble, Section H. 2. Assessment of the Donor's Eligibility to
Donate, b. The donor's medical history** *Blood pressure (Proposed§
630.10(h)(2)) --- For the purpose of this rulemaking, we would require
under proposed paragraph (h)(2) that the collecting establishment
determine not to be eligible a donor whose blood pressure measures above
180 mm of mercury or below 90 mm of mercury for the systolic value, and
above 100 mm of mercury or below 50 mm of mercury for the diastolic
value. These limits are currently an industry standard in use by many
blood establishments. We are soliciting comments with supporting
scientific data on the need for such limits on systolic and diastolic
values, adverse events associated with donation that have been
attributed to blood pressure. In particular, we are seeking comments
with supporting scientific data on the necessity, or lack of necessity,
of specific upper or lower blood pressure limits in blood donation, and
any adverse events attributed to blood pressure and associated with
donation. **....** We are also seeking comments on the accuracy and
interpretation of blood pressure measurements taken in the setting of
blood and plasma donation. Hemoglobin r hematocrit determination
(Proposed § 630.10(h)(3)).---"We are specifically soliciting comments
and supporting data on the following: • Changing the minimum acceptable
hemoglobin level to 12.0 grams per deciliter of blood or a hematocrit
value of 36 percent as acceptable minimal values for female allogeneic
donors; • The possibility of adverse effects caused by the collection of
blood and blood components from Allogeneic donors with such minimum
hemoglobin level of 12.5 grams per deciliter of blood or a hematocrit
value of 38 percent for males, and hemoglobin level of 12.0 grams per
deciliter of blood or a hematocrit value of 36 percent for females,
which are considered below normal by medical criteria; or if such
decisions should be left to the discretion of the medical director of
the collecting establishment on a case-by-case basis; • Establishing a
more stringent interdonation interval; and • The use of copper sulfate
solution based methods as an appropriate method to determine Acceptable
hemoglobin levels.*

**Background/Discussion:**

[Blood Pressure]{.underline} **--** Current FDA regulations state that
blood pressure should be normal but do not specify the actual values.
While the proposed values are ones commonly used by some blood
collection facilities, the practice is not universal. Some facilities
use similar but different criteria. In the UK blood pressure is not even
measured at the time of whole blood donation. There is simply no data to
indicate that the measurement of blood pressure, yet alone specific
criteria, is useful in terms of donor safety. A single measure of blood
pressure, especially in the setting of an anticipated blood donation,
would never be used clinically to determine a donor's true blood
pressure. Inaccurate determinations occur under stress, mismatch of the
subject's weight and the cuff size used, ingestion of caffeine or
decongestants, recent exercise, smoking, food intake, etc. The suggested
values for the upper limit of blood pressure, 180/100, whether commonly
used or not, is entirely arbitrary. There is no evidence that otherwise
healthy donors with elevated systolic blood pressures would be harmed by
blood donation. There is little data on the effect of lower blood
pressures. Some reports in the older literature suggest that the
incidence of vasovagal reactions may be higher in donors with lower
blood pressure levels. Ogata et al (Transfusion 1980;20:679) state that
donors with lower diastolic blood pressure were more prone to reaction.
Kasprisin et al (Transfusion 1992;32:23) reported that donors with
systolic pressure of 80-100 had a higher incidence of vasovagal
reactions than did donors with systolic pressures of 120-140. However,
other studies (Zervou et al, Transfusion Medicine 2005;15:389) found no
relationship between either blood pressure or pulse and the incidence of
vasovagal reactions. Even if it were true that donors with lower blood
pressures had a slightly higher vasovagal reaction rate, it does not
necessarily follow that they should be deferred from donation. There are
many categories of donors well known to have somewhat higher reaction
rates than others (e.g. first time donors, females, lower weight donors,
younger donors) yet we do not hesitate to accept them for donation.

[Pulse]{.underline} -- Currently there are no FDA regulations concerning
measurement of pulse in blood donors. Although AABB Standards do
currently state that the pulse should be between 50 and 100 beats per
minute, there are no data to indicate that this is appropriate. It is
common for healthy people to have pulse rates below 50 beats per minute.
It is also not universal practice to measure the pulse. Pulse is not
determined in the UK. Health Canada has authorized Hema-Quebec to
abandon the use of pulse in donor qualification based on data provided
by Dr. Gilles Delage (personal communication Dr. Delage). In Dr.
Delage's study, 106 autologous donors were accepted for donation in
spite of a pulse that did not meet the standard acceptance criteria, no
adverse effects were seen. The rate of moderate and severe adverse
reactions was no different in a series of over 300,000 donors drawn when
pulse measurement was not part of the qualifying criteria (1995-1996)
than it was in a series of over 600,000 donors drawn with such criteria
in place. Finally, these investigators followed 2005 donors who were
deferred for failing pulse criteria for 2-3 years and compared them to
2005 donors who donated on the same day but passed the pulse criteria.
There was no significant difference in the incidence of cardiac events.
Thus there is no evidence that the measurement of pulse, let along
specific criteria, is useful in terms of donor safety. The suggested
requirement that the pulse be "regular" is even more problematic. It is
common for normal donors to have sinus arrhythmia (a perfectly normal
rhythm) or occasional extra systoles, and deferring such donors would be
entirely inappropriate. Even with more complicated rhythms, there is no
evidence that drawing a unit of blood would result in harm to a donor
who is otherwise healthy. We feel that the criteria for acceptability of
donors with an irregular pulse (if the pulse is even measured) should be
determined by the policies of the collection facility, under the
guidance of the facility's medical director. [Unexplained weight
loss]{.underline} -- The medical/scientific rationale for the
unexplained weight loss recommendation is not stated nor is it obvious.
Weight in some individuals can fluctuate dramatically. Weight loss is
not a very specific sign of a medical illness that could pose a safety
threat to either the donor or the recipient. Medical conditions that
might require donor deferrals are better identified though the use of
other questions on the donor questionnaire. There are also a number of
practical problems with the proposed criterion for unexplained weight
loss. Firstly, the proposed rule assumes that a donor will have
accurately recorded their weight on multiple occasions in recent months.
Secondly, it is unlikely that the individual donor will be able to
easily compute whether their weight loss was less than or greater than
10%. For example, proper application of this proposed rule would require
that a 150 pound donor who lost 15 pounds be deferred whereas a 160
pound donor with the same weight loss would be accepted. Given the
variation in education level among donors, it is unrealistic to expect
each donor to reliably make this determination themselves. In practice,
the donor screener would need to 1) ask about the absolute amount of
weight loss; 2) ascertain the donor's previous baseline weight at
various times during the previous six months and then 3) perform a
calculation to determine the percentage weight loss. Even after this
determination, a further assessment would need to be made about whether
this weight loss was explained or unexplained; this is clearly a
subjective evaluation. A situation could arise where the weight loss was
explainable according to the donor's thinking, but was interpreted as
unexplainable by the donor screener.

> **Recommendation -- 21 CFR Section 630.10(h)(2) and (4) -- We
> recommend that the requirements for upper and lower limits for blood
> pressure and pulse requirements be deleted from the proposed rule.
> There is no evidence to support their inclusion and paucity of
> evidence is not a justification for mandating common practice that is
> not based on evidence. We feel that it is inappropriate for the FDA to
> enshrine criteria that are based on nothing but tradition. If upper
> and lower limits of blood pressure and pulse must be established, we
> urge that it be set by the establishment's medical director. 21 CFR
> Section 630.10(h)(5) -- ABC recommends that the criterion for
> deferring a donor for an unexplained weight loss of greater than 10
> percent of body weight within the past 6 months be deleted from the
> proposed rule.**
>
> **Request for Comment on acceptable hemoglobin levels -- The issue of
> changing the acceptable hemoglobin/hematocrit levels for males or
> females is controversial and requires further investigation. It is
> anticipated that some relevant data will become available from the
> REDS II study and should inform any subsequent guidance. The study
> aims to evaluate the effects of blood donation on iron and hemoglobin
> levels among donors. It also will help identify the optimal measures
> for predicting iron and hemoglobin depletions that lead to blood donor
> deferrals. Until the results of the REDS II study are published, we
> believe that it would be premature to specify changes to hemoglobin or
> hematocrit requirements in the final rule.**

**21 CFR Section 630.10(i)** -- *What additional requirements must you
complete before determining the eligibility of the donor? Immediately
before donation, you must obtain the following:*

*(1) Proof of identity and mailing address. You must obtain proof of
identity of the donor and an address where the donor may be contacted
for 8 weeks after donation; and*

*(2) Donor\'s written statement of understanding. You must provide a
written statement of understanding to be read and signed by the donor.
You must establish procedures in accordance with Sec. 606.100 of this
chapter to provide assistance to those unable to read the written
statement of understanding. You must design those procedures to assure
that the donor understands fully the material in the donor\'s written
statement of understanding, and provide for a signature or acceptable
substitute for a signature to indicate that understanding. The written
statement of understanding 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. The statement must clearly state the following:*

*(i) The donor has reviewed the provided educational material required
by Sec. 630.10(b) regarding relevant transfusion-transmitted infections,
including the fact that relevant transfusion-transmitted infections
present potential risks to the safety, purity, or potency of the blood
supply;*

*(ii) The donor agrees not to donate if the donation could result in a
potential risk to the safety, purity, or potency of the blood supply as
described in the educational material;*

*(iii) A sample of the donor\'s blood will be tested for specified
relevant transfusion transmitted infections required in Sec. 610.40(a)
of this chapter and for syphilis.*

*(iv) If any of the tests required in Sec. 610.40(a) of this chapter are
reactive, the sample of blood will be tested further, as required in
Sec. 610.40(e) of this chapter;*

*(v) 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 must identify the donor as ineligible
to donate and the donor must be notified under Sec. 630.40 of the basis
for the deferral and the period of deferral;*

*(vi) The hazards and risks of the donation procedure or of
hyperimmunization, if applicable; and(vii) the donor has the opportunity
to ask questions and withdraw consent at any time.*

**Background/Discussion;**

[Mailing address]{.underline} -- According to the US Census Bureau, more
than 40 million of 282 million people move annually in the US, for a
total of 14.19 percent each year. From a blood availability perspective,
if 3-5 percent of these individuals were blood donors (per national
donation estimates), a cohort of at least 123,000-204,000 donors would
be expected to move each year, some of whom will move in the 8 weeks
following a blood donation. US Census Bureau data also show that most
moves are by individuals within the 18-34 year age group. This would
comprise students, young families, and many military personnel. From a
donor recruitment and retention perspective, this is the most critical
age group to retain and grow because of the aging of the donor
population. Even a temporary decrease in donations by this group --
because they cannot produce their expected new address on the day of
donation -- will not only reduce overall annual blood donations, but
will also make it more difficult to maintain and increase the blood
donor base as current donors, who are generally middle age, become
ineligible to donate. The impact of this requirement on spring blood
drive activity on college campuses is especially troublesome due to mass
movement of college students to other addresses for the summer. This can
have a critical impact on blood availability during the summer months.
It is assumed that the reason for this regulation is a concern about the
ability to notify donors who have reactive infectious disease tests.
According to the US Postal Service, which collects data for the National
Change of Address file, most individuals who move do leave a forwarding
address, and donors can be contacted through this mechanism. Also,
although standard mail delivery has historically been the predominant
means of contacting people, we believe that this is increasingly being
replaced by newer communication technologies such as email and cell
phones, and these can be used for notification purposes when necessary.

[Donor's written statement of understanding]{.underline} -- Although
blood establishments have traditionally obtained donor signatures as
part of the donation process, in the past there has never been a
requirement to do so for whole blood or plateletpheresis donors. Many
blood collection facilities are moving to computerized donor
registration and screening processes. The reasons for doing this are
twofold. First, to eliminate errors due to donor and staff failure to
complete elements of the donor record (the computer system will not
allow the process to advance until all requirements are completed);
second, to move to a paperless system. Requiring a written signature
defeats the purpose on both counts and will impede implementation of
optimal error reduction strategies by blood establishments. Some of the
computerized systems have already received FDA approval to proceed
without either actual or electronic donor signatures. The consent that
donors traditionally have signed is an affirmation that the donor has
read the informational materials, has answered the questions truthfully,
understands that infectious disease testing will be done, and agrees to
donate. In our modern era, these sorts of affirmations are commonly
handled electronically and no written signature is involved. The same
approach should suffice for blood donation. As noted above, there has
not previously been a regulatory requirement for a written signature for
whole blood collection or for plateletpheresis donation. Although it is
required under the current 21 CFR 640.61 for plasmapheresis donors, the
regulation applies only to manual apheresis procedures that are not now
routinely used for plasma collection. The informed consent referred to
in part 640.61 is more than the affirmation of understanding at issue in
the present discussion; it represents consent to undergo a risky
procedure. It is important to note that the requirement for a written
signature was deleted from the AABB Standards a number of years ago in
recognition that it was not necessary and that a paperless system would
be desirable. We firmly believe that it is important to progress to
paperless systems. Adding a requirement for a written signature to this
process would not allow this to occur, it would provide no additional
benefit, unnecessarily complicate the process, and insert an additional
opportunity for error. We encourage the FDA to champion this forward
thinking approach by clarifying that the donor's understanding can be
documented in a number of ways, including the electronic methods
described above.

> **Recommendation -- We strongly recommend that the requirement to
> obtain an address where the donor may be contacted for 8 weeks after
> donation be deleted. ABC agrees that donors should be adequately
> informed about the blood donation process and that there should be
> documentation that the donor has been so informed. However, we do not
> believe that this documentation requires the donor's written
> signature. We recommend that the guidance document that will be issued
> to provide recommendations for compliance with the rule clarify that
> electronic records are an acceptable method for documenting a donor\'s
> statement of understanding.**

**21 CFR Section 630.15(a)** -- *What additional donor eligibility
requirements are specific to Whole Blood?*

*(1) Donation frequency. Whole Blood must not be collected from a donor
more than once in 8 weeks if the donor participates in a single unit
collection program; or more than once in16 weeks if the donor
participates in a double unit collection program, unless the donor is
examined and certified to be in good health by a responsible physician
at the time of donation and one of the following three conditions
exist:*

*(i) An individual presents a physician\'s prescription for therapeutic
phlebotomy for medical reasons; or*

*(ii) The donation is for autologous use; or (iii) The donation is a
dedicated donation based on the intended recipient\'s documented medical
need.*

*(2) Therapeutic phlebotomy. When a donor who is determined to be
eligible under Sec. 630.10(d) undergoes a therapeutic phlebotomy to
promote the health of the donor, the container label must conspicuously
state the disease of the donor that necessitated phlebotomy. However, no
disease labeling is required under this section for a donation collected
from a donor who meets all eligibility criteria and undergoes a
therapeutic phlebotomy as ordered by a physician treating the donor for
Hereditary Hemochromatosis, provided that you perform without charge
therapeutic phlebotomies for all individuals with Hereditary
Hemochromatosis.*

> **Request for Clarification -- This section discusses the continuation
> of the requirement that establishments collect a single unit of whole
> blood no more than once in 8 weeks or 16 weeks if two units of red
> blood cells are collected by an automated method. FDA is also
> proposing that a donor may donate sooner if the collecting
> establishment's physician examines the donor and certifies the donor
> to be in good health. We request clarification in the regulation that
> hemachromatosis is an exception to the 8 week or 16 week requirement.
> In addition, we request clarification in the regulations that
> hemachromatosis patients can be collected more frequently without a
> variance.**

**21 CFR Section 630.15(b)** -- *What additional donor eligibility
requirements are specific to Plasma collected by plasmapheresis?*

*(1) Physical examination and informed consent.*

*(i) In addition to the physical assessment required in Sec. 630.10(d),
the responsible physician must examine the donor for medical conditions
that would place the donor at risk during plasmapheresis. If the donor
is determined to be at risk, you must defer the donor from donating. In
a program of repeat plasmapheresis, i.e., collections occur more than
once every 28 days, the donor must be examined on the day of the first
donation or no more than 1 week before the first donation and at
subsequent intervals of no more than 1 year.*

*(ii) When conducting the physical examination, the responsible
physician must explain the 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 hazards
involved if the donor is hyperimmunized. The explanation must be made in
such a manner that the donor may give informed consent and has a clear
opportunity to refuse the procedure as required under Sec.
630.10(i)(2).*

*(2) Weight. You must weigh a donor at each donation.*

*(3) Total protein level. Before each plasmapheresis procedure, a 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 of plasma sample or
the comparable level for a serum sample.*

*(4) Examination before immunization...*

*(5) Deferral due to red blood cell loss. You must defer a donor from
donating plasma for a period of 8 weeks after any of the following
events...*

*(6) Exceptions to deferral due to red blood cell loss...*

*(7) Malaria. Freedom from risk of malaria is not required for a donor
of Source Plasma.*

**Background/Discussion:**

[Informed consent]{.underline} -- The proposed rule eliminates 21 CFR
640.61 Informed Consent, and proposed section 630.10 (i)(2) requires
that donors sign a statement of understanding that includes a statement
that the donor has been informed of and understands the collection
procedure and the educational material. This would appear to replace the
informed consent, however, proposed section 630.15 (b)(1)(ii) requires
that the responsible physician explain the hazards of the procedure to
the donor, and that the explanation must be made in such a manner that
the donor may give *informed consent*. For plasmapheresis donors, the
distinction between the statement of understanding and the informed
consent should be clarified. Donor weight -- As addressed in our
response to 21 CFR Section 630.10(h)(5) weight should not be used as an
indicator of good health. Donors are asked at each donation if they are
in good health and other questions to elicit specific information about
the donor's health that might disqualify the donor from donating.
Tracking donor weight for eligibility does not add valuable information
beyond the donor history questions and medical screening. While weight
is essential for the plasmapheresis volume nomograms, in contrast, whole
blood donations should not be required to have the donor's weight
recorded.

[Total Protein]{.underline} -- FDA proposes to continue to require a
measurement of total protein and have a value of no less than 6.0 g/dL
or no more than 9.0 g/dL. The basis for the upper limit is not clear.
The basis for the lower limit is presumably to assure adequate protein
levels in the blood prior to donation and that these levels are not
seriously lowered by plasmapheresis. We agree with the concept that
there should be laboratory measurements to assure that the donor is not
adversely affected by serial donation and has adequate levels of certain
essential proteins such as albumin and immunoglobulins. However, it is
not clear that the 6.0 and 9.0 values are necessarily the correct ones
by all measurement systems. In Europe, for example, IgG levels are
measured. Malaria and other comparable pathogens -- The exclusion of
Source Plasma donors from malaria endemic deferral permits by logical
extension, that this science-based approach could also be made
applicable to syphilis and other similar pathogens which hold no
relevance to the final products made from Source Plasma. Because malaria
and a host of other pathogens do not impact plasma products or are
removed by the processing, we suggest that a consistent approach be
applied with the following guiding principles: an awareness of the
distinctions between materials collected for direct transfusion and
those of further manufacture, and the intended final use of the
products. Anything that could be removed by filtration should not be a
deferrable criterion.

> **Request for Clarification -- 21 CFR Section 630.15(b)(1) -- For
> plasmapheresis donors, the distinction between the statement of
> understanding (21 CFR 630.10(i)(2)) and the informed consent stated in
> this section should be clarified.**
>
> **Recommendation -- Some of the donor eligibility requirements for
> plasmapheresis provide no additional safety to the donor or recipient
> and should be removed from the final rule. 21 CFR Section 630.15(b)(2)
> -- The requirement that the donor's weight be determined at each
> plasmaphersis donation is necessary for the plasma volume nomograms;
> however weight should not be used as an indicator of general health.
> 21 CFR Section 630.15(b)(3) -- The requirement for total protein
> should be reworded: (3) Each firm shall have a plan acceptable to FDA
> to measure serum proteins and immunoglobulins by methods and frequency
> that assure that the donor's health will not be seriously impacted by
> reduction in essential serum proteins. In the absence of a firm's
> submission of specific proposal to FDA the use of serum or plasma
> protein measured at each donation and every four months along with a
> serum or plasma electrophoresis will be required. For the donor to
> donate, the total plasma or serum protein shall have a value of no
> less than 6.0 grams per deciliter. The acceptable upper limit may be
> established by the firm based on applicable statistical analysis of
> test results on their donors. Values outside of these limits would
> require deferral until the donor's protein level is at an acceptable
> range.**
>
> **Comment -- 21 CFR Section 630.15(b)(7) We agree with excluding
> Source Plasma donors from malaria-endemic deferral. We would also
> suggest that this approach be adopted for other parasitic diseases,
> which, due to the nature of Source Plasma donation and the
> manufacturing process, have no impact on product quality or safety**

**21 CFR Section 630.20** -- *You may collect blood and blood components
from a donor who is determined to be not eligible to donate under Sec.
630.10(d) and 630.15, or deferred under Sec. 610.41 of this chapter only
if:*

*(a) The responsible physician examines the donor and certifies in
writing that the donor\'s health permits the collection procedure;*

*(b) The collection is performed under the supervision of the
responsible physician who is aware of the donor\'s health status; and*

*(c) At least one of the following is met:*

*(1) The donation is for autologous use as prescribed by the donor\'s
physician, and is not for allogeneic transfusion or for further
manufacturing use;*

*(2) The donor is participating in a plasmapheresis program that
collects plasma for further manufacturing use into products for which
there are no alternative sources, and the collection program has
received prior approval from the Director, Center for Biologics
Evaluation and Research; or*

*(3) The donation is restricted for use solely by a specific recipient
based on documented*

*medical need and the responsible physician determines that the donation
presents no undue*

*medical risk to the recipient.*

**Background/Discussion:** The requirement that a physician examines the
donor and certifies in writing that the donor is healthy enough to
donate is not only unnecessary, but would severely disrupt the ability
to provide patient care, especially for plasma therapy where there is
not an alternative source or in the case of a donation restricted for
use (directed donation) solely by a specific recipient based on
documented medical need. With regard to directed donations the most
common scenario in which this occurs is a platelet donor who has been
selected on the basis of HLA type to donate for a specific patient. At
presentation the donor's hematocrit is 37%. It is perfectly reasonable
under this circumstance for the physician to approve the platelet
collection, and it serves no useful purpose to require that the
physician to examine the patient. We thus feel that the proposed
requirements are too restrictive when it comes to medical determinations
by the collection facility physicians. Autologous donors who do not meet
allogeneic criteria are quite common; it is simply not practical for a
blood center physician to examine all of these donors, some of whom are
drawn at sites some distance from the central facility, or to be aware
of the specifics of the reason for their allogeneic ineligibility. An
autologous donor/patient's health has already been assessed by their
personal physician. These issues are properly and adequately handled by
the facility's policies and procedures which spell out the specific
circumstances under which the facility's physicians should become
involved.

> **Recommendation -- We recommend that the language throughout this
> section refer to "responsible physician or physician substitute." In
> addition, the proposed requirement that a physician examines the donor
> and certifies in writing that the donor's health permits the
> collection procedure, and supervises the collection procedure, should
> be deleted**

**21 CFR Section 630.25** -- *You are not required to perform a physical
examination of the donor for medical conditions under Sec. 630.15(b)(1),
to perform a test for total protein under Sec. 630.15(b)(3), to
determine the immunoglobulin composition of the serum or plasma under
Sec. 640.65(b)(1)(i) of this chapter, or to review the laboratory data
as required in Sec. 640.65(b)(2)(i) of this chapter, if:*

*(a) The donor has not donated Whole Blood in the preceding 8 weeks,
Plasma by plasmapheresis in the preceding 4 weeks, or participated in a
double Red Blood Cells unit collection program within the preceding 16
weeks;*

*(b) The donor has not donated more than 12.0 liters of plasma (14.4
liters of plasma for donors weighing more than 175 lbs.) in the past
year;*

*(c) The donor is determined by the responsible physician to be in good
health under Sec .630.10(d); and*

*(d) The donor is not participating in an immunization program for the
production of high-titer*

*plasma.*

> **Request for Clarification --The intervals allowed between an
> infrequent plasma donation and whole blood, plasmapheresis and double
> red cells are defined. We request clarification on the interval
> allowed between an infrequent plasma donation and a platelet donation
> by apheresis.**

**21 CFR Section 630.30(a)(5) --** *When is a donation suitable? A
donation is suitable when: (5) For platelet components, you have taken
adequate steps to assure that the donation is tested for bacterial
contamination and found negative; and*

.

**Background/Discussion:** The language is ambiguous in that a
culture-based bacterial test is not negative until completion of its
incubation, a duration that is arbitrary and currently extends to the
outdate of the product. This extended incubation allows an attempt at
withdrawal of distributed, nontransfused platelets when a positive
culture occurs late in storage. If applied as the proposed language
suggests, it would be impossible to distribute a platelet before
outdate. In current practice, cultured platelets are released as
'negative to date' while incubation is continued. The duration of
incubation of a culture-based test before release will always be
somewhat arbitrary, balancing adequate time to detect clinically
significant bacterial contamination with the need to make platelets
available for transfusion. This language should be deleted and the CFR
should remain silent on this issue. The language proposed in
630.30(a)(5) would include platelets derived from whole blood donations,
that are not currently addressed in professional standards, and are not
generally subjected to bacterial testing until surrogate methods are
applied near or at release in the transfusion service. Systems exist
that allow pooling of whole blood derived platelets before storage and
testing with culture-based methods early in storage, as are used for
apheresis platelets. These systems have not been enthusiastically
embraced by collection facilities as they are operationally poorly
suited to most collection facility component laboratories. The proposed
language would operationally prohibit the use of platelets derived from
whole blood and pooled immediately prior to transfusion. These account
for around 25% of platelet doses transfused in the US. It is
inappropriate for FDA to require the implementation of these systems via
the CFR without extensive public discussion of the issue.

> **Recommendation -- The proposal to obtain a negative test result
> prior to determining a platelet donation to be suitable should be
> deleted. An appropriate requirement is for a** "**negative to date"
> test result at the time of distribution of the platelet, while the
> incubation continues.**

**Preamble Section D, 3. Testing for bacterial contamination for
platelets and other transfusible blood components --** *In some
instances, specific bacteria identified as contaminants in a blood
component could indicate an underlying bacteremia or serious illness in
the donor. Therefore, we are also soliciting comments on: (1) Whether to
require, in the context of testing of platelet components prior to
release, the identification of the species of the bacterial contaminant
and (2) whether to require donor deferral and notification when
identification of the contaminant indicates possible endogenous
bacteremia, and not contamination during collection and processing.
Additionally, we are also considering whether to extend, to other blood
components for transfusion, the requirement for testing for bacterial
contamination, and donor deferral and notification based on the
results.*

**Background/Discussion:** No definition of endogenous bacteremia is
provided, and we are aware of no bright line dividing an endogenous
bacteremia from contamination, since the organisms involved overlap
significantly. While the presence of a pathogen, e.g. listeria, is a
clear cut indication for referral for evaluation of a donor, and the
association of *Streptococcus bovis* with intrinsic colon pathology is
well recognized and has resulted in early diagnosis of colonic lesions
in platelet donors, these are the exceptions. On the other hand, both
coagulase negative staphylococci and *Staphylococcus aureus* are well
recognized as causes of native valve endocarditis in otherwise well
individuals and could be considered endogenous. However, when it is
accepted in the setting of platelet cultures, they are almost always
contaminants from the skin. Are oral streptococci that commonly cause
transient bacteremia and community-acquired endocarditis endogenous? A
requirement for deferral, notification and referral for such an
ill-defined spectrum of organisms can result in unneeded medical
evaluation and stigmatization of donors for what we are certain is
minimal return. These decisions should not be prescribed in CFR, but
left to medical directors who can exercise reasonable clinical judgment.
Additionally, the agency is considering whether to extend, to other
blood components for transfusion, the requirement for testing for
bacterial contamination, and donor deferral and notification based on
the results. It is not appropriate to extend requirements for bacterial
detection to other components. In the BaCON study (Kuehnert et al.
Transfusion 2001;41:1493), the ratio of sepsis associated with RBC
transfusion to that from apheresis platelets was approximately 1:50
(.2/million RBC vs. 10/million apheresis platelets). This is most
probably due to the inhibitory effects of storage of RBCs at 4oC, rather
than room temperature for platelets, on the growth of the contaminating
bacterial inoculum. In the 2005 National Blood Collection and
Utilization Survey, there were 1,527,000 apheresis platelet collections
and 15,288,000 RBC collections (including RBC apheresis, autologous and
directed). If one assumes the same culture approach, generally an
aerobic and anaerobic bottle, extension of culturing to whole blood
would require at least 10 times the investment in culture materials,
incubators, computer interfaces, personnel, etc. as required for
platelets to detect .02 times the risk. It is not appropriate to extend
requirements for bacterial detection to other components.

> **Response to request for comment -- We consider both of these issues
> to fall within the purview of the collection facility's medical
> director as the practice of medicine. 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.**

**Current CFR language 640.3(c**) -- *Additional qualifications of
donor; viral hepatitis. No individual shall be used as a source of Whole
Blood if he has\--*

*(1) A history of viral hepatitis after the 11th birthday;*

*(2) A history of close contact within 12 months of donation with an
individual having viral hepatitis;*

*(3) A history of having received within 12 months of donation, human
blood or any derivative of human blood which the Food and Drug
Administration has advised the blood establishment is a possible source
of viral hepatitis.*

**Background/Discussion:** A number of countries (for example, England
and Australia) now require only a one-year deferral period for a history
of viral hepatitis. There does not appear to be a good rationale for
maintaining an indefinite deferral, given the properties of the relevant
viruses, use of multiple screening tests for HBV and HCV and the absence
of any chronic form of infection with HAV or HEV (with the exception of
patients undergoing transplantation who may develop chronic HEV disease,
but would not be eligible donors). Further, there no longer appears to
be any evidence for residual transfusion-associated hepatitis with an
infectious etiology. Finally, the putative "hepatitis viruses" GBV/C or
HGV and TTV/SEN-V have not been found to be associated with clinical
hepatitis.

> **Recommendation -- We recommend removal of the current requirement
> for indefinite deferral of presenting donors with a history of viral
> hepatitis after the 11th birthday**.

**21 CFR 640.21(a)(2)** - *Under Sec. 630.10(i)(2)(vi) of this chapter,
the statement of understanding must include a statement that the
long-term effects of frequent apheresis are unknown.*

**Background/Discussion:** In its response to "Draft Guidance for
Industry and FDA Review Staff on Collection of Platelets by Automated
Methods" (Docket No. 2005D-0330, 03 October 2005) AABB noted that no
long term adverse effects have been reported to frequent apheresis, and
that they do not believe it is necessary to include this statement with
information provided to the donor. However, if a statement must be
included, it is more accurate to indicate that there are no data to
indicate any harmful effects. Discussions in the literature that address
the possibility of long term adverse effects raise this as a speculative
concern rather than a firm conclusion. The subsequently released
"Guidance for Industry and FDA Review Staff on Collection of Platelets
by Automated Methods" dated December 2007, makes no mention of a
requirement to include the above statement. Furthermore, the statement
is not required for donors of plasma or red cells by apheresis or for
whole blood donation, all of which share similar small unknown risks.

> **Recommendation -- Delete section 640.21 (a)(2) to be consistent with
> the "Guidance for Industry and FDA Review Staff on Collection of
> Platelets by Automated Methods" dated December 2007 and to be
> consistent with practice for all other donated components.**

**21 CFR 640.21(b)** - *A donor must not serve as a source of platelets
for transfusion if the donor has recently ingested drugs that adversely
affect platelet function.*

**Background/Discussion:** A donor of apheresis platelets who has
ingested drugs that inhibit platelet function should be deferred as
described in "Guidance for Industry and FDA Review Staff on Collection
of Platelets by Automated Methods" dated December 2007. However, donors
of whole-blood-derived (wbd) platelets do not need to be deferred. A wbd
platelet component from a donor who has ingested platelet inhibitory
drugs would not be given as a single unit dose

> **Recommendation -- The language should be rewritten:**
>
> **(b) -- A donor must not serve as the sole source of platelets for
> transfusion if the donor has recently ingested drugs that adversely
> affect platelet function.**

**21 CFR Section 640.21(c)** -- *A plateletpheresis donor may donate at
intervals shorter than 8*

*weeks provided:*

*(1) The establishment performs a platelet count before starting the
initial plateletpheresis*

*procedure and before each subsequent procedure;*

*(2) The platelet count required in paragraph (c)(1) of this section is
greater than*

*150,000/microL;*

*(3) The donor\'s post-donation platelet count is no less than 100,000
platelets/microL; and*

*(4) The donor donates the following...*

**Background/Discussion:** ABC believes the regulation should be less
prescriptive in defining requirements for when platelet counts are taken
but still require establishments to adequately monitor donors to be sure
that they are within appropriate levels before and after donation. We
agree that the platelet counts of donors before and after collection are
important to donor health. In fact, the stated platelet counts of
greater than 150,000/μL pre-donation and not less than 100,000/μL post
donation are appropriate. However, various blood centers, and various
collection devices used, approach the assurance of these targets
differently. "Guidance for Industry and FDA Review Staff on Collection
of Platelets by Automated Methods" dated December 2007 recognizes that
platelet counts are not always known. However, it does recommend that
action be taken when the collecting establishment becomes aware of
decreases in platelet count below 100,000/μL. Assurance that
pre-donation platelet counts above 150,000/μL is also recommended. As we
discussed previously in our comments to the "Draft Guidance for Industry
and FDA Review Staff on Collection of Platelets by Automated Methods",
it is not usually a platelet count immediately before the collection
that is completed, but a pre-collection sample that is drawn. "A
pre-donation platelet count is only one of the ways recommended by the
manufacturer and approved by FDA to set the target yield parameters.
Other options include:

• Average of the last three venous platelet counts;

• Utilize the platelet count obtained from a pre-collection venous blood
sample from the donor's previous donations;

• Utilize average donor pre-platelet count for local donor populations;
and

• Use the default count for the collection equipment being used."

In addition, many establishments validate and regularly re-qualify
devices to assure that target levels are within correct boundaries.

> **Recommendation -- We recommend that the language be reworded:**
>
> **(c) -- A plateletpheresis donor may donate at intervals shorter than
> 8 weeks provided:**
>
> **(1) The establishment performs a platelet count before starting the
> initial plateletpheresis procedure;**
>
> **(2) The platelet count required in paragraph (c)(1) of this section
> is greater than 150,000/microL;**
>
> **(3) The establishment has procedures in place that assure that
> donors will have a platelet count equivalent to or above
> 150,000/microL before collection and no less than 100,000/microL after
> the collection; and**
>
> **(4) The donor donates the following...**

**21 CFR Section 640.21(c)(4)** -- *A plateletpheresis donor may donate
at intervals shorter than 8 weeks provided:*

*(iii) For a double or triple component collection procedure, no more
than one procedure*

*within a 7 calendar day period.*

**Background/Discussion:** There is no evidence to support a regulatory
requirement for a 7 day donation interval following collection of a
double or triple product. As outlined in our response to the "Draft
Guidance for Industry and FDA Review Staff on Collection of Platelets by
Automated Methods" (Docket No. 2005D-0330, 03 October 2005), ABC is not
aware of any evidence to support a position that donor safety is
compromised under current donation policy that restricts donations to 24
times each year, requires a pre-donation count of \>150,000 and an
interval of 2 days between platelet donations. Adherence to these
policies and to the device manufacturer's instructions to ensure that
there is not excessive plasma loss will provide adequate safeguards for
donor safety and will preclude donation at an excessive frequency. From
an operational standpoint it will be exceedingly difficult, if not
impossible, to track complicated donor eligibility algorithms using
currently approved blood establishment computer software according to
whether a double or triple product was collected. The "Guidance for
Industry and FDA Review Staff on Collection of Platelets by Automated
Methods" dated December 2007, includes language which creates a
non-binding recommendation that "the interval between collection of a
double or triple Platelets, Pheresis and any subsequent collection of
Platelets, Pheresis should be at least 7 days." Given the lack of
scientific basis for this recommendation, it would be unwise to
incorporate a 7 day restriction into the CFR. The Guidance process would
allow blood collectors to more readily gain approval of a different
protocol by validating the safety of more frequent donations.

> **Recommendation -- Delete 640.21 (c) (4)(iii) in order to reduce the
> regulatory burden on blood collectors created by a restriction that is
> not evidence based.**

**Direct Final Rule/Proposed Rule: Revisions to the Requirements
Applicable to Blood, Blood Components and Source Plasma**, Docket
2007N-0264 , August 2007. Definition of Plasma (21 CFR Section
640.30(a)(2)) amended. *(2) The fluid portion of human blood intended
for intravenous use which is prepared by apheresis methods as specified
in the directions for use for the blood collecting, processing, and
storage system including closed and open systems.*

**Background/Discussion:** We believe this modification of the
definition for plasma facilitates interoperability for blood centers to
assign plasma collected by apheresis to use for either transfusion or
further manufacturing as needed. The modified definition is compatible
with the AABB Interorganizational Plasma Task Force recommendation that
FDA recognize a new product, Component Plasma. Comments to 21 CFR
Section 640.34 (see below) provides a more in-depth discussion of this
issue

> **Recommendation -- In comments to the August 2007 docket the AABB
> Interorganizational Plasma Task Force proposed that the definition
> should be further amended to include further manufacturing use:**
>
> **(2) The fluid portion of human blood intended for intravenous use
> *or further manufacturing use* which is prepared by apheresis methods
> as specified in the directions for use for the blood collecting,
> processing, and storage system including closed and open systems.**

**\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

**21 CFR Section 640.34 Component Processing**

**Background/Discussion:** The AABB Interorganizational Plasma Task
Force has had several communications with the Office of Blood Research
and Review regarding proposed licensure requirements for a product
called Component Plasma. Excerpts are provided here as background. April
2007 "...the issue of the use of infrequent plasmapheresis and
concurrent plasma as an option for further manufacturing is a critical
consideration today as blood centers seek to maximize the use of
life-saving blood donations, whether the components are for transfusion
or for the manufacture of plasma-derived therapies. The issue of
maximizing blood donations is of utmost importance as blood centers seek
to identify ways to minimize the likelihood of TRALI...The Task Force
has also considered the different options available as the organizing
point for the product and believe that donor criteria is an appropriate
organizing point...Use of the totality of donor qualifications,
frequency of collection, collection volumes and other donor oversight
provisions appear the most reasonable approach to differentiating
Component Plasma from Source Plasma." June 2007 "...Recent discussions
at the HHS Advisory Committee on Blood Safety and Availability
reiterated the importance of increasing the supply of plasma available
for therapeutic use. Concurrent collection of recovered plasma (that, in
fact, is the same quality as FFP) to be used for fractionation could
have a positive impact on this issue. Fractionators report they
currently see difficulty on the part of recovered plasma suppliers to
meet obligations for recovered plasma due to the shift to automated
platforms. We believe that there must be a pathway available that will
allow concurrent FFP to be converted to recovered plasma (plasma for
fractionation) when it is not needed for transfusion inventories. Blood
establishments view this as an ethical issue and again ask for
assistance from FDA in establishing this pathway. It is vitally
important that the pathway recognize the donor suitability requirements
and donation frequencies used in blood centers and allow
interchangeability at the blood center level between plasma for
transfusion and plasma for fractionation based on need. We view that
this can best be accomplished by modifying the definition of Plasma in
Title 21, Code of Federal Regulations (21 CFR), Subpart D, to include
plasma for fractionation as well as plasma for transfusion. With
increased dependence on automated collection platforms to meet the
ever-present demand for blood products, blood centers need the same
flexibility in managing plasma inventories for transfusion and for
manufacturing that they have with manual collections. These processes
should not be limited based on intent at time of collection. Serious
consideration should be given to plasma availability for both
transfusion recipients and for recipients of therapeutics proteins to
avoid shortages of such life-saving products. The task force
respectfully requests that FDA initiate the process for updating
existing regulations to reflect the current technology of blood
collection. In the interim, we ask for assistance in obtaining a product
name and corresponding code for Source Plasma collected in an
*infrequent* program, and consideration of an exception to 21 CFR 640.30
under 21 CFR 640.120 to include the option of collecting plasma to be
used for fractionation. These issues have very high priority to our
community. Timing is critical as blood establishments are currently
taking measures to mitigate TRALI in transfusion recipients and continue
their move toward blood collection utilizing automated methods." Data
submitted with the June 2007 letter -- "As noted in the 2005 AABB
Nationwide Blood Collection and Utilization Survey Report (2004 data),
approximately 824,000 units of red cells were produced using automated
methods. Since the volume of red cells collected did not Significantly
change, each red cell manufactured by automation displaced one whole
blood collection. Demand for FFP and cryo-poor plasma for transfusion
remained relatively stable during this period and was satisfied by
approximately 29% of whole blood collected. The remaining plasma was
available for further manufacturing. Recent data (2006) from a subset of
US blood collectors (BCA member centers representing 30% of the supply)
show red cell automation rates at 18%, representing an absolute amount
equal to that seen for the entire blood collection system in 2004. It is
thought that the entire market is capable of reaching red cell
automation levels of 20% in the near future. When this occurs, 3 million
units of whole blood will be replaced, leading to a loss of
approximately 825,000 liters (3 million x 275mL) that would be available
for further manufacturing. Further data in the AABB report document the
increased reliance on apheresis platelets collected by automation to
meet current demand. But, from the more than 1 million plateletpheresis
procedures performed in 2004, only about 25% collected a concurrent
plasma because this product can only be used for transfusion and not
further manufacturing. It is estimated that nearly 70% of these
procedures could, in theory, produce an additional unit of concurrent
plasma, resulting in over 250,000 liters of plasma for further
manufacturing."

> **Recommendation -- Include requirements for Component Plasma
> previously submitted to the Office of Blood Research and Review, April
> 2007, and to docket 2007N-0264 "Direct Final Rule/Proposed Rule:
> Revisions to the Requirements Applicable to Blood, Blood Components
> and Source Plasma", October 2007, and attached to this document.**

**21 CFR Section 640.65(b)(1)(i) --** *Except as provided under Sec.
630.25 of this chapter, a sample of blood must be drawn from each donor
on the day of the initial physical examination or plasmapheresis,
whichever comes first, and at least every 4 months thereafter. A
serological test for syphilis, a total plasma or serum protein
determination, and electrophoresis or quantitative immuno-diffusion test
or an equivalent test to determine immunoglobulin composition of the
plasma or serum, must be performed on the sample.*

> **Recommendation -- We believe that the regulations should allow
> flexibility in protein monitoring. See comments elsewhere in this
> document regarding proposed 21 CFR Section 630.15(b)(3).**

**21 CFR Section 640.72(a)(3) --** *The original or a clear copy of the
donor\'s written statement of understanding for participation in the
plasmapheresis program or for immunization.*

> **Recommendation -- Guidance material should provide recommendations
> for use of electronic records to satisfy this requirement. Such a
> recommendation will be in agreement with proposed 21 CFR Section
> 630.10(i)(2) that allows for a "signature or acceptable substitute for
> a signature to indicate that understanding".**

**21 CFR Section 640.72(a)(4) --** *Documentation by the responsible
physician that the donor is in good health under 630.10 and 630.15 of
this chapter on the day of examination; such documentation must address
the eligibility of the donor as a plasmapheresis donor and, when
applicable, an immunized donor.*

> **Recommendation -- Guidance material should clarify that trained
> personnel, including the physician substitute, are appropriate to make
> this determination. See comments elsewhere in this document to 21 CFR
> Section 630.5(a)-(d).**

**21 CFR Section 640.73(a) --** *If a donor has a fatal reaction which,
in any way, may be associated with plasmapheresis, you must notify the
Director of the Center for Biologics Evaluation and Research by
telephone as soon as possible.*

**Background/Discussion:** The proposed regulatory language is too broad
and would greatly increase the reports that must be submitted. To
require a report of a fatality that "in any way" can be associated with
plasmapheresis is extremely burdensome and provides no benefit beyond
the current requirements of 640.73(a) to report complications of
donation that are confirmed to be fatal.

> **Recommendation -- We recommend that the language reflect what is
> currently in 21 CFR Section 606.170(b). Proposed 21 CFR Section
> 640.73(a) should be reworded: (a) -- If a complication of donation is
> confirmed to be fatal, you must notify the Director of the Center for
> Biologics Evaluation and Research by telephone as soon as possible.**

**21 CFR Section 640.73(b) --** *If a donor enrolled in an immunization
program for the collection of Source Plasma under this subpart has an
adverse experience related to your administration of the immunizing
agent, you must report the event to FDA:*

*(1) By telephone, facsimile, express mail, or electronic mail as soon
as possible, if the adverse experience is a serious or life threatening
adverse experience, as described in Sec. 600.80(a) of this chapter; or*

*(2) In an annual report, if the adverse experience is neither serious
nor life threatening. Such a report is due to FDA on the anniversary of
FDA\'s approval of your immunization program.*

*(c) You must follow up the initial report required under paragraphs (a)
and (b)(1) of this section by submitting a written report of the
investigation to the Director, Office of Compliance and Biologics
Quality, Center for Biologics Evaluation and Research, within 7 days of
your first learning of the donor's reaction. (See § 600.2 of this
chapter.)*

**Preamble, Q. Reporting of Donor Reactions (Proposed Sec. 640.73)** --
*Because manufacturers of blood and blood components are currently
exempt from the safety reporting requirements under Sec. 600.80, we do
not receive adequate information to monitor and assess safety-related
information (other than fatalities) concerning donors enrolled in
immunization programs and the collection of Source Plasma by
plasmapheresis. Such information is essential for evaluating our
scientific and regulatory policies and for monitoring industry practices
and their implications on donor and blood safety.*

**Background/Discussion:** We believe that industry data will become
available that will support current observations that reactions are
infrequent and generally mild.

> **Recommendation -- We recommend that this requirement not be included
> in the Final Rule on the basis that no valuable data will be
> forthcoming under the proposed reporting of adverse events for
> immunizing agents such as red cells or vaccines. Vaccine events are
> already reported to the Vaccine Adverse Event Reporting System (VAERS)
> and as necessary to the manufacturer as required in 21 CFR § 600.80.
> Currently, red cells are exempt from the requirement. In view of the
> low risk of adverse events and the ability of FDA investigators to
> access these reports on inspections, we believe that exemption should
> be continued.**

**21 CFR Section 640.120(b) --** *In a public health emergency, the
Director may issue an exception or alternative to any requirement in
subchapters C and 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
to respond to an unanticipated immediate need for blood, blood
components, or blood products.*

**Background/Discussion:** We acknowledge that the FDA has responded in
the recent past with guidance to the blood community during public
health emergencies. However, if specific variances to current
regulations were known in advance, establishments could plan
appropriately. This would enable a blood establishment to further
prepare by modifying BECS configurations and testing, modifications to
standard operating procedures, and the necessary training, all within an
acceptable cGMP environment. ABC strongly supports initiatives that
improve the safety of patients and donors and stand ready to interact
with FDA as necessary. ABC requests that FDA carefully consider product
availability and safety issues when evaluating the requirements put
forth in this final rule.

> **Recommendation -- We believe that this proposed section should
> include areas in which the FDA is willing to grant a variance. We
> recommend the section be modified as follows:**
>
> **(b) .... Several examples of variances that would be considered
> are:**
>
> **(1) Decreased interdonation interval provided the donor meets other
> criteria as specified in section 630.10**
>
> **(2) Allogeneic donation hemoglobin/hematocrit level of ≥11 g/dL /
> 33% provided the donor meets other criteria as specified in section
> 630.10.**