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October 27, 2003

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, MD 20852.

Re: Docket 03N-0211, 30 July 2003: *Revisions to Labeling and Storage
Requirements for Blood and Blood Components, Including Source Plasma*

Dear Docket Officer:

The AABB appreciates the opportunity to provide comments to this
Proposed Rule in **support of the simplification and updating of
specific regulations that are applicable to container labeling and
instruction circulars.** Simplifying and updating labeling regulations
and consolidating them into one section of the Code of Federal
Regulations is welcomed and long overdue. Many of the proposed revisions
do in fact remove unnecessary or outdated requirements and are
consistent with current practice.

The American Association of Blood Banks (AABB) is the professional
society for over 8,000 individuals involved in blood banking and
transfusion medicine and represents approximately 2,000 institutional
members, including blood collection centers, hospital-based blood banks,
and transfusion services as they collect, process, distribute, and
transfuse blood and blood components and hematopoietic stem cells. Our
members are responsible for virtually all of the blood collected and
more than 80 percent of the blood transfused in this country. For over
fifty years, the AABB's highest priority has been to maintain and
enhance the safety and availability of the nation's blood supply.

**We applaud the changes that will facilitate the use of a labeling
system using machine-readable information that would be acceptable as a
replacement for the "ABC Codabar" system for labeling blood and blood
components.** AABB is a strong proponent of technologies, such as bar
coding, that are aimed at saving patient lives by reducing the risk of
human error (ensuring the right patient gets the right unit of blood).
ISBT 128 barcode symbology features greater security and flexibility in
coding that will facilitate the use of a uniform container label for
blood and blood components. The proposed changes to §606.121 to allow
use of facility identification numbers other than the registration
number, such as the ISBT facility code (which includes machine-readable
information) is enthusiastically supported by AABB.

**Other proposals in the document raise serious concerns** for the
members of our association, even though "the agency believes that these
requirements reflect current industry practice and do not impose an
additional burden." FDA proposes revisions to the current storage and
shipping temperatures for frozen noncellular blood components, both for
transfusion and for further manufacturing use, "to guard against
degradation of the heat labile clotting factors." Specifically, CFR
§610.53, §640.34, and §640.54 would be amended such that Fresh Frozen
Plasma (FFP) and Cryoprecipitated Antihemophiliac Factor (AHF) stored at
the current required temperatures of --18 C, or colder, would outdate at
the end of three months from the collection date of the source blood.
The Proposed Rule would require storage at --25 C, and would extend the
expiration date to two years.

# Current Practice

**The proposed amendments are not consistent with current practice in
the United States.** Current practice in the United States is defined by
well-established FDA requirements and/or Standards of the American
Association of Blood Banks. FFP and cryoprecipitate currently stored at
--18 C, or colder have an expiration date of one year. The AABB
Standards also permit storage at --65 C, or colder with a seven-year
expiration date. (This requires an approval from FDA in order to be a
licensed product, and AABB understands that FDA has approved such
licenses.) **The AABB is concerned that FDA believes the proposed
amendments in storage temperatures and expiration dates are current
practice in the United States.**

Blood establishments follow current requirements of the FDA and the AABB
in regard to quality control of Cryoprecipitated AHF to ensure that
adequate levels of fibrinogen and Factor VIII are available for
transfusion therapy. The products are stored in freezers that have
evidence of continuous monitoring of storage temperatures, or are stored
in a manner such that visual inspection will detect any occurrence of
unexpected thaw and refreeze. **The agency has not provided any clinical
studies to suggest that the current FDA licensed blood products, stored
at --18 C are providing inadequate levels of coagulation proteins**.

# Additional Burdens for Blood Establishments

**There are easily recognized "additional burdens" to hardware, software
and manpower resources that accompany the proposed amendments**.
Changing the temperature requirements to --25 C, or colder will require
significant alterations, as current freezers may not be able to maintain
these temperatures. Even if the freezers can maintain this temperature,
the freezer alarm systems are often pre-set at the factory, and are not
readily adjustable to monitor this new requirement. In many instances,
it will require additional compressors to be installed that could result
in necessary upgrades to electrical systems in some of the facilities.
Adding compressors to walk-in freezers will result in additional burden
to the drainage systems of the freezers. Most, if not all, blood
collection facilities have back-up generators for blood storage
equipment that will need to be re-evaluated and upgraded as necessary.

The Proposed Rule would require these frozen products to be shipped at
--25 C in order to maintain the original outdate of 24 months. Shipping
containers are validated for the current requirements of --18 C. These
containers will have to be re-validated and new systems purchased if the
current system is not capable of meeting the proposed requirements.

# Three Month Shelf-Life

**Shortening the expiration date to three months is problematic**. Most
blood establishments assign and track expiration dates through
information systems software. Upgrades and validation with the necessary
revisions to standard operating procedures and training will be
required. Blood suppliers may be capable of storing frozen plasma at
--25 C or colder, but transfusion services, especially the smaller ones,
may not be able to do so. It appears that transfusion services without
the necessary storage capabilities would need to re-label all the frozen
plasma products to be kept in the transfusion service inventory. The
AABB is concerned that such re-labeling is difficult to accomplish on
frozen products and may lead to increased errors and loss of components
due to improper labeling or exposure to inappropriate temperature during
an extended labeling process.

**AABB requests clarification of the following scenario**: FFP (or
cryoprecipitate) that has been stored at --25 C is shipped (at --25 C)
to a facility that must re-label due to inability to store the products
at --25 C, or colder. The products will be stored at --18 C. Does the
three-month shelf life begin at the date the product is no longer
maintained at

--25 C, or with the collection date of the source blood? (It is
understood that the re-assigned expiration date cannot exceed the
original assigned date.)

Due to the shortened shelf life of products stored at --18 C, the AABB
is concerned that transfusion facilities may be forced to keep smaller
inventories of FFP and cryoprecipitate on hand*.* This has the potential
to negatively impact patient safety*.* During the winter months of 2002
-- 2003, blood collection facilities were able to stockpile fresh frozen
plasma for use during the 2003 West Nile Virus 'season." **Decreasing
the shelf life of plasma products stored at --18 C to three months will
preclude the use of this valuable option in the future**.

# Heat Labile Clotting Factors

The Proposed Rule cites Krotitschke, R., "Stability of Fresh Frozen
Plasma: Results of 36-Month Storage at -20 C, -25 C, -30 C, and --40 C"
*Infusion Therapy and Transfusion Medicine,* 27:174-18, 2000, as the
basis for proposed changes that have far-reaching implications for blood
establishments. Yet, the conclusion of the study cited by FDA reads as
follows. **"The DGTI multicenter trial initiated by the Section 'Blood
Plasma Constituents' to determine the stability of FFP during 2 and 3
years of storage at 4 temperatures** **showed no detectable protein
changes in the FFP."** Also noted is the fact that the published study
does not emulate the FDA licensed products in the United States. The
study allowed for great variability in production and storage of the
products tested. The study did not report baseline coagulation factor
activity prior to freezing and did not use the same testing parameters
on all pools in the study.

Based on the stated conclusion of the indicated study, lack of any other
evidence to support the proposed amendment to 21 CFR §610.53, §640.34,
and §640.54, and the additional burden that would be imposed, the AABB
requests that this proposal for required storage at --25C and a
three-month outdate if stored at --18C be removed from the Final Rule.
The current storage temperature at --18 C for one year for licensed FFP
and cryoprecipitate should be maintained.

AABB would support an additional product storage temperature of --20 C
with a corresponding shelf life of 24-36 months.

The Proposed Rule would amend §640.70 (and re-designate it as §606.121
(e)(5)) so that Source Plasma must be stored at --30 C or colder, and
shipped at --15 C or colder. Again the agency has not provided any
evidence or clinical study conclusions to support this proposed
amendment. In June of 2003, the AABB submitted a proposal to FDA
requesting that recovered plasma become a regulated product called
Plasma for Manufacture. **AABB is concerned that if Plasma for
Manufacture is held to the same criteria as Source Plasma, then FFP
stored at --18 C, or --25 C could not be converted to Plasma for
Manufacture.**

# Labeling Regulations

The proposed amendments to §606.122(e) regarding the *Circular of
Information For The Use of Human blood and Blood Components* are
intended to make it "unnecessary to revise the labeling regulations as
testing requirements may be revised in the future." The agency indicates
in the proposed rule that the statement must include "the name of each
infectious agent for which the blood was tested, including all FDA
required tests." **AABB supports this change to §606.122(e) providing
our interpretation of "name each infectious agent" is correct.** AABB
interprets this proposal to "name each infectious agent" as requiring a
list such as

Human Immunodeficiency Virus (HIV) 1 and 2

Human T-cell Lymphotropic Virus (HTLV) I and II

Hepatitis B Virus (HBV)

Hepatitis C Virus (HCV)

Syphilis

The AABB does not believe it is necessary to name each type of test that
is performed for each infectious agent. For example, it is not necessary
to list both antibody testing and NAT testing

**The AABB proposes that FDA change wording in §606.121(c)(8)(ii)
regarding the Circular of Information (COI).** Current language is "See
Circular of Information for indications, contraindications, cautions,
and methods of infusion." While the COI does address these issues, as
well as other necessary items, the information is not organized
according to these specific headers. The AABB proposes that FDA use the
same language that is found in the AABB *Standards for Blood Banks and
Transfusion Services*: "See Circular of Information for the Use of Human
Blood and Blood Components." This language has appeared in the AABB
Standards since 1984.

Revised §606.121 (c) (11) will require a label statement "listing the
names and results of all the tests for communicable disease agents for
which the donation has been tested and found negative" if the product is
intended for further manufacturing use. This proposed requirement is in
contrast to the agency's stated goal of "limiting the number of times
establishments must revise container labels." Furthermore, FDA states
that "the requirement for the label to reflect updated testing
requirements, conform\[s\] to current industry practice and \[does\] not
impose an additional burden." There is no current industry practice that
requires all test results to be recorded on the label of a product
intended for further manufacture. Contracts with plasma fractionation
firms detail the manner in which a reactive or positive test result will
be reported, and it is generally reported on a required shipping form.
To require constant updating of product labels in order to report all
negative test results is counterproductive to the many positive aspects
of this Proposed Rule. There is no benefit to patient safety that will
offset the negative financial impact on blood establishments. **The AABB
requests that the proposed amendment to §606.121(c)(11) be removed from
the final rule.**

# Additional Comments

**The AABB has additional comments regarding §606.122 Instruction
Circular that are not related to the proposed changes.** The title of
the accepted Instruction Circular that has been accepted for years by
the FDA is "Circular of Information For the Use of Human Blood and Blood
Components." This title is more precise and descriptive than the current
generic title Instruction Circular, and is already used in §606.121.
**The AABB suggests changing the generic language to the more specific
title that is well recognized in the transfusion community.**

§606.122 (k)(1) references instructions to administer a suitable plasma
volume expander when Red Blood Cells are administered in the place of
Whole Blood. In today's medical environment, Whole Blood is very rarely
indicated, and physicians today are trained in the use of Red Blood
Cells. For the *Circular of Information For The Use of Human Blood and
Blood Components* to advise administration of a volume expander when
administration of a volume expander may be contraindicated is simply not
good medical practice. The possibility of fluid overload is a much more
likely occurrence and is known to create serious problems. **The AABB
requests that §606.122(k)(1) be removed**.

§606.122(k)(2) references a warning not to add Lactated Ringer's to Red
Blood Cells. **The AABB requests that the language in §606.122(k)(2) be
expanded to reflect current information** found in the *Circular of
Information for the Use of Human Blood and Blood Components* regarding
addition of medications and solutions.

**The AABB is uncertain what requirement is being addressed by
§606.122(l)(2) and requests that the language be clarified.** It appears
to reference the four-hour expiration time assigned to room temperature
products once the container has been entered.

**Likewise, the language in §606.122(m)(3) should be clarified**.
Current language contained in the current *Circular of Information for
the Use of Human Blood and Blood Components* could be used. "Transfusion
should be completed within four hours and prior to component
expiration."

In conclusion, the American Association of Blood Banks supports the
portions of the Proposed Rule that simplify and update specific
regulations that are applicable to container labeling and instruction
circulars, as well as those that facilitate the use of ISBT 128 labels,
and has made some additional proposals for updating these sections.
However, the proposed amendments to shorten the expiration date of
frozen noncellular blood components that are stored at the current
required temperature of --18 C do not appear to be based on sound
scientific or clinical evidence and will, therefore, impose apparently
unnecessary burdens on blood establishments.

AABB also notes that if the proposed amendments regarding storage of
frozen products at --25 C are included in the Final Rule, 180 days is
not sufficient time for blood establishments to make the necessary
changes and upgrades to hardware and software systems.

The American Association of Blood Banks is supportive of initiatives to
improve the safety of blood collection and safe transfusion of blood and
blood components to patients. The association stands ready to interact
with the Food and Drug Administration as necessary to ensure these goals
move forward.

Questions concerning these comments may be directed to M. Allene
Carr-Greer, Deputy Director, Regulatory Affairs, AABB
(<acarrgreer@aabb.org>).

Sincerely,

Karen Shoos Lipton, JD

Chief Executive Officer