[Federal Register Volume 68, Number 146 (Wednesday, July 30, 2003)]
[Proposed Rules]
[Pages 44678-44688]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-19289]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 600, 606, 610, and 640
[Docket No. 2003N-0211]
Revisions to Labeling and Storage Requirements for Blood and
Blood Components, Including Source Plasma
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to revise
the labeling and storage requirements for certain human blood and blood
components, including Source Plasma, by combining, simplifying, and
updating specific regulations applicable to container labeling and
instruction circulars, and the shipping and storage temperatures for
frozen noncellular blood components. This proposed rule would
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. FDA is taking
this action as part of its ``Blood Initiative'' to comprehensively
review and, as necessary, revise its regulations, policies, guidances,
and procedures related to the licensing and regulation of blood
products. This proposed rule is intended to help ensure the continued
safety of the blood supply, and to help ensure consistency in container
labeling and storage temperatures.
DATES: Submit written or electronic comments on the proposed rule by
October 28, 2003. See section VIII of this document for the proposed
effective date of a final rule based on this document.
ADDRESSES: Submit written comments to the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
rm. 1061, Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.
FOR FURTHER INFORMATION CONTACT: Sharon A. Carayiannis, Center for
Biologics Evaluation and Research (HFM-17), Food and Drug
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, 301-827-
6210.
SUPPLEMENTARY INFORMATION:
I. Background
A. Development of the International Society for Blood Transfusion
(ISBT) 128
In the Federal Register of August 30, 1985 (50 FR 35472), FDA
published a notice of availability entitled ``Guideline for the Uniform
Labeling of Blood and Blood Components,'' which described the uniform
container label for blood and blood components. The standard labels for
blood and blood components recommended in the guideline incorporated
barcode symbology known as ``ABC Codabar.''
In August 1989, the ISBT, an organization established to promote
and maintain a high level of ethical, medical, and scientific standards
in blood transfusion medicine and science throughout the world,
recognized that ``ABC Codabar,'' the first barcoding system adopted by
the health care industry, was becoming outdated and initiated the
design of a new system using the barcode symbology known as Code 128
(identified hereafter as ISBT 128).
Currently, under Sec. 606.121(c)(13) (21 CFR 606.121(c)(13)), the
container label for blood and blood components may bear encoded
information in the form of machine-readable symbols approved for use by
the Director, Center for Biologics Evaluation and Research (CBER). On
March 23, 1995, FDA asked the Blood Products Advisory Committee (BPAC)
whether FDA should support conversion from the ``ABC Codabar'' system
to the ISBT 128 system. BPAC voted in favor of FDA supporting the
transition to the new barcoding system. The change to ISBT 128 was also
supported by the Department of Defense (DoD), and by the blood industry
including America's Blood Centers (ABC), American Association of Blood
Banks (AABB), and American National Red Cross (ARC). In December 1996,
the International Council for Commonality in Blood Bank Automation
(ICCBBA) held an ISBT 128 Consensus Conference in Washington, DC, to
provide an opportunity for dialogue among the affected industry groups
and FDA. Although consensus was obtained for use of ISBT 128, some
participants expressed concerns regarding implementation timeframes and
costs of implementation to hospital transfusion services. However, the
updated symbology used in ISBT 128 has numerous advantages over the
``ABC Codabar.'' In addition to other reasons, the conversion to ISBT
128 was supported because ISBT 128 is more secure, allows more
flexibility in coding highly variable information, uses double-density
coding to allow more information to be encoded in a limited space, and
can be interpreted by some of the barcode readers used with ``ABC
Codabar.''
The ICCBBA, including representatives from ABC, AABB, ARC, and DoD,
developed and submitted to FDA a draft document that recommended that
ISBT 128 replace the ``ABC'' Codabar system used on blood and blood
component labels in the United States. ICCBBA recommended that the
document entitled ``United States Industry Consensus Standard for the
Uniform Labeling of Blood and Blood Components Using ISBT 128,''
Version 1.2.0 (draft standard), serve as the basis for FDA guidance on
blood and blood component labeling. On November 21, 1998, FDA made a
copy of the draft standard available on its Web site for public
comment. In the Federal Register of November 27, 1998 (63 FR 65600),
FDA announced the availability of the draft standard and requested
public comment on both the use of ISBT 128 and timeframes for
implementation. The ICCBBA revised the draft standard in response to
public comment and submitted to FDA the revised document, ``United
States Industry Consensus Standard for the Uniform Labeling of Blood
and Blood Components Using ISBT 128,'' Version 1.2.0, dated November
1999 (the ``Version 1.2.0 Standard'').
FDA reviewed the draft standard, the comments received in response
to the Federal Register notice of November 27, 1998, and the ``Version
1.2.0 Standard,''
[[Page 44679]]
and concluded that conformance to the ``Version 1.2.0 Standard,''
prepared and revised by ICCBBA, would help facilitate the use of a
uniform container label for blood and blood components. In the Federal
Register of June 6, 2000 (65 FR 35944), FDA announced the availability
of a final guidance entitled ``Guidance for Industry: Recognition and
Use of a Standard for the Uniform Labeling of Blood and Blood
Components'' dated June 2000, which recognizes as acceptable, except
where inconsistent with the regulations, use of the ``Version 1.2.0
Standard'' prepared by ICCBBA, and the implementation of the ISBT 128
uniform labeling system. Although FDA finds the system acceptable, FDA
has identified two inconsistencies between the ``Version 1.2.0
Standard'' and the current requirements of Sec. 606.121(c)(2) and
(e)(1)(ii). This proposed rule would delete the current requirement of
Sec. 606.121(c)(2) to include the FDA assigned registration number on
blood and blood component labels. This revision is intended to provide
establishments flexibility in using the registration number or other
recognized donation facility identification numbers, such as the ISBT
facility code (which includes machine-readable information), as the
unique facility identifier. Additionally, this proposed rule would
delete the current requirement of Sec. 606.121(e)(1)(ii) that the
anticoagulant precede the proper name. However, until the date a final
rule resulting from this proposal becomes effective, if a manufacturer
intends to follow the ``Version 1.2.0 Standard'' in lieu of current
Sec. 606.121(c)(2) or (e)(1)(ii), a manufacturer would seek an
approval for exceptions or alternatives under Sec. 640.120 (21 CFR
640.120). Once the application for an alternative is approved, a
manufacturer may use the ``Version 1.2.0 Standard'' to produce labels
that meet FDA's labeling requirements.
B. Changes to Storage and Shipping Temperatures
FDA has reviewed data concerning the storage and shipping
temperatures of frozen noncellular blood components, e.g.,
Cryoprecipitated Antihemophilic Factor and Fresh Frozen Plasma. We have
determined that the current requirements for storage and shipping
temperatures should be updated to ensure potency of the blood
components over time and to provide more flexibility in inventory
management. Therefore, we are proposing to revise 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. The proposed changes
in shipping and storage temperatures are consistent with published data
and current industry practice (Ref. 1).
II. Highlights of the Proposed Rule
FDA is proposing to remove, simplify, or update specific labeling
regulations applicable to blood and blood components to be more
consistent with current practices and to remove any unnecessary or
outdated requirements. FDA is proposing to consolidate the labeling
requirements for blood and blood components intended for transfusion
and for blood and blood components intended for further manufacturing
use. FDA is proposing to revise specific regulations to facilitate the
use of a uniform container label for blood and blood components in the
United States and internationally and to remove any inconsistency
between the ``Version 1.2.0 Standard'' and the Federal regulations at
Sec. 606.121. The proposed rule would facilitate the use of a labeling
system using the ISBT 128 machine-readable data. In addition, the
proposal would facilitate the use of new labeling systems that may be
developed in the future.
The proposed changes would also simplify the regulations by
consolidating the regulations for labeling blood and blood components,
including Source Plasma, into one section, making it unnecessary for
blood establishments to refer to several sections of the regulations to
find applicable labeling standards.
In addition to moving certain regulations to Sec. 606.121, FDA is
also proposing to revise some of the labeling provisions regarding
storage and shipping temperatures for frozen noncellular blood
components in proposed Sec. 640.70(a)(3) and (b). FDA is proposing to
revise storage and shipping temperatures in current Sec. Sec. 600.15,
610.53, 640.34, 640.54, 640.69, and 640.76, (21 CFR 600.15, 610.53,
640.34, 640.54, 640.69, and 640.76) to help ensure the potency of the
frozen noncellular blood components and for consistency between the
labeling regulations and the regulations concerning shipping and
storage temperatures of frozen noncellular blood components. As part of
this rulemaking, FDA is proposing to update the temperature
requirements and address as many labeling changes as possible at one
time, thereby limiting the number of times establishments must revise
container labels. Also, we have replaced ``shall'' with ``must'' in all
places wherever it appears in the regulations.
A. Summary of Consolidation of Regulations in Sec. 606.121
FDA is proposing to consolidate regulations so blood establishments
may find all applicable labeling standards under one section of
regulations. The regulations for labeling all blood and blood
components would be moved from other sections of the regulations to
Sec. 606.121. The following table summarizes the regulations that
would be revised, consolidated, and redesignated under the proposal.
The table is intended to serve as a convenient reference for the
consolidation of regulations; all revisions to the regulations are
discussed later in this preamble. A current regulation listed in the
table remaining unchanged may not be discussed further in the preamble.
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Revisions
Would be Revised, and/or Discussed in
Current Section: Redesignated as: Section II of
this document:
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Sec. 606.121(a) The Introductory paragraph of B
Sec. 606.121, paragraph
(a) is reserved
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Sec. 606.121(b) Revised only B
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Sec. 606.121(c)(1) Revised only B
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Sec. 606.121(c)(2) Revised only C
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Sec. 606.121(c)(3) Revised only B
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[[Page 44680]]
Sec. 606.121(c)(4) Revised only B
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Sec. 606.121(c)(5) Sec. 606.121(c)(8)(v) B
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Sec. 606.121(c)(6) Sec. 606.121(c)(5) B
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Sec. 606.121(c)(7) Unchanged B
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Sec. 606.121(c)(8) Revised only B
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Sec. 606.121(c)(9) Sec. 606.121(c)(8)(iv) B
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Sec. 606.121(c)(10) Sec. 606.121(c)(6) B
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Sec. 606.121(c)(11) Sec. 606.121(c)(10) B
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Sec. 606.121(c)(12) Sec. 606.121(c)(9) B
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Sec. 606.121(c)(13) Unchanged C
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Sec. 606.121(d)(1) to Revised only B
(d)(3)
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Sec. 606.121(d)(4) Deleted B
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Sec. 606.121(d)(5) Sec. 606.121(d)(4) B
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Sec. 606.121(e)(1)(i) Sec. 606.121(e)(1)(ii) B
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Sec. Sec. 606.121(e)(1)(i) C
606.121(e)(1)(ii)
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Sec. Revised only B
606.121(e)(1)(iii)
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Sec. 606.121(e)(2) Unchanged B
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Sec. 606.121(e)(3) Deleted, see 606.121(c)(4) B
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Sec. 606.121(e)(4) Sec. 606.121(e)(3) B
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Sec. 606.121(e)(5)(i) Sec. 606.121(e)(4)(i) B
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Sec. Deleted, see 606.121(e)(5)(i) B
606.121(e)(5)(ii)
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Sec. Sec. 606.121(e)(4)(ii) B
606.121(e)(5)(iii)
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Sec. 606.121(f) Revised only B
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Sec. 606.121(g) Unchanged B
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Sec. 606.121(h) Revised only B
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Sec. 606.121(i)(1) to Revised only, paragraph E
(3) (i)(4) added
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Sec. 606.121(i)(4) Sec. 606.121(i)(5) E
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Sec. 606.121(i)(5) Sec. 606.121(i)(6) E
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Sec. 606.121(j) Revised only B
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Sec. 606.122(e), (f), Revised only E
and (m)
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Sec. 640.70(a), the Sec. 606.121(e)(5) B
introductory sentence
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Sec. 640.70(a)(1) Deleted, see Sec. B
606.121(c)(1)
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Sec. 640.70(a)(2) Sec. 606.121(c)(10) and B
Sec. 606.121(e)(5)(i)
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Sec. 640.70(a)(3) Sec. 606.121(e)(5)(ii) D
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Sec. 640.70(a)(4) Sec. 606.121(e)(5)(iii) B
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Sec. 640.70(a)(5) Deleted, see Sec. B
606.121(c)(3)
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Sec. 640.70(a)(6) The second sentence of Sec. B
606.121(c)(4)
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[[Page 44681]]
Sec. 640.70(a)(7) Sec. 606.121(e)(5)(vi) B
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Sec. 640.70(a)(8) Sec. 606.121(c)(11) E
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Sec. 640.70(a)(9) Sec. 606.121(e)(5)(iv) B
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Sec. 640.70(a)(10) see Sec. 606.121(c)(2) C
Deleted
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Sec. 640.70(a)(11) Sec. 606.121(c)(11) E
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Sec. 640.70(b) Sec. 606.121(e)(5)(v) D
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B. Proposed Revisions to Clarify and Consolidate Regulations, Including
Source Plasma Regulations
The following proposed revisions are intended to consolidate the
existing labeling regulations in Sec. 640.70 into Sec. 606.121. As
part of the consolidation, labeling regulations in Sec. 640.70 would
be moved to Sec. 606.121, and Sec. 640.70 would be removed from the
Code of Federal Regulations (CFR). This change would enable blood
establishments to find all the labeling requirements for blood and
blood components, including Source Plasma, in one section of the CFR
rather than having to consult different sections of the CFR when
manufacturing several products. Any redundant regulations have been
eliminated. FDA is proposing minor edits for clarity.
1. Proposed Revisions to Sec. 606.121(a)
FDA is proposing to amend Sec. 606.121(a), which describes the
container label requirements for blood and blood components, by
redesignating current paragraph (a) to create an introductory paragraph
under Sec. 606.121 and reserving paragraph (a). Under the proposal,
the first sentence of the introductory paragraph (current Sec.
606.121(a)) would be revised by deleting the phrase ``except Source
Plasma'' to provide that proposed Sec. 606.121 applies to all blood
and blood components, including Source Plasma.
2. Proposed Revisions to Sec. 606.121(b)
FDA is proposing to amend Sec. 606.121(b) by adding the phrase
``with any appropriate modifiers and attributes'' to clarify that the
label may be altered under specific circumstances to adequately
identify the contents of a container. Examples of appropriate modifiers
include ``washed,'' ``frozen,'' and ``liquid.'' Examples of attributes
include ``irradiated,'' and ``divided'' which indicate a process
change. For consistency, FDA is proposing conforming amendments to
Sec. 606.121(c)(1) and (d)(2).
3. Proposed Revisions to Sec. 606.121(c)
Because proposed Sec. 606.121(c)(1) applies to the container label
of all blood and blood components, including Source Plasma, FDA is
proposing to delete current Sec. 640.70(a)(1). The proposed revisions
to Sec. 606.121(c)(2) are discussed in section III.C.1 of this
document.
FDA is proposing to revise Sec. 606.121(c)(3) to require that
labels include all the donor numbers or a pool number that would enable
establishments to trace each individual unit in the pool to the donor.
Proposed Sec. 606.121(c)(3) includes the same requirements for
container labels for pooled products found in Sec. 640.70(a)(5);
therefore, FDA is proposing to delete Sec. 640.70(a)(5).
FDA is proposing to amend Sec. 606.121(c)(4) to clarify the
expiration date of pooled plasma and to delete Sec. 606.121(e)(3)
because it would be redundant with revised Sec. 606.121(c)(4). Under
the proposal, Sec. 640.70(a)(6) would be revised and redesignated as
the second sentence of Sec. 606.121(c)(4). If Source Plasma intended
for further manufacturing into noninjectable products is pooled, the
expiration date is determined from the collection date of the oldest
unit in the pool, and the pooling records must show the collection date
for each unit in the pool. The proposed changes would simplify the
regulations by moving the requirements for determining the expiration
date of Source Plasma to the section that specifies requirements for an
expiration date on the container label for blood and blood components.
Current Sec. 606.121(c)(5) is redesignated and revised, as
discussed in the following paragraph. FDA is proposing that current
Sec. 606.121(c)(6) remain unchanged and be redesignated as Sec.
606.121(c)(5). Under the proposal, current Sec. 606.121(c)(7) remains
unchanged.
FDA is proposing to simplify the wording of Sec. 606.121(c)(8)(i).
Paragraphs 606.121(c)(8)(ii) and (c)(8)(iii) remain unchanged. FDA is
proposing to redesignate Sec. 606.121(c)(9) as Sec. 606.121(c)(8)(iv)
and to revise redesignated Sec. 606.121(c)(8)(iv) by deleting the
redundant phrase ``The statement.'' FDA is proposing to redesignate
Sec. 606.121(c)(5) as Sec. 606.121(c)(8)(v) and to revise
redesignated Sec. 606.121(c)(8)(v) by deleting the redundant phrase
``If the product is intended for transfusion.''
FDA is proposing to redesignate current Sec. 606.121(c)(12) as
Sec. 606.121(c)(9). FDA is proposing to revise redesignated Sec.
606.121(c)(9) by adding a phrase to clarify that the labeling
requirements would apply to products intended for manufacturing use
when an ABO and/or Rh designation is appropriate. In addition, FDA is
proposing to update redesignated Sec. Sec. 606.121(c)(9)(ii) and
(c)(9)(iii) by using current terminology for a weak expression of the D
antigen on red blood cells. The revised section would read ``If the
test using Anti-D Blood Grouping Reagent is negative but the test for
weak D (formerly DU) is * * *''
Under the proposal, current Sec. 606.121(c)(10) is redesignated as
Sec. 606.121(c)(6).
FDA is proposing to combine current Sec. 606.121(c)(11) and part
of current Sec. 640.70(a)(2) and redesignate the combined regulations
as proposed Sec. 606.121(c)(10). FDA is proposing to revise
redesignated Sec. 606.121(c)(10) by adding a phrase to the first
sentence to clarify that blood and blood components intended for
further manufacturing use, and Source Plasma are subject to these
requirements. Additionally, FDA is proposing to revise redesignated
Sec. 606.121(c)(10) by adding an alternative warning statement and
provide for the use of ``other cautionary statements as approved by
CBER.'' These proposed changes and the alternative warning statement
reflect current industry practice. FDA is proposing to delete current
Sec. 606.121(e)(5)(ii) because it
[[Page 44682]]
would be redundant with redesignated Sec. 606.121(c)(10).
4. Proposed Revisions to Sec. 606.121(d)
FDA is proposing to amend Sec. 606.121(d) by deleting the phrase
``Except for recovered plasma intended for manufacturing use or'' and
revise the regulation to clarify that this paragraph applies to the
container labels for all blood and blood components. Additionally,
Sec. 606.121(d) is revised to remove an obsolete mail code and to
provide for the use of labels printed on materials other than paper.
FDA is proposing to amend Sec. 606.121(d)(1) to clarify the labeling
requirements that apply to the ABO and Rh blood grouping label. The
revised regulation remains consistent with current blood establishment
practice and the proposed changes are intended only to make the
regulations more descriptive and precise. In addition to the conforming
amendment previously discussed, proposed Sec. 606.121(d)(2) and (d)(3)
are revised to clarify the labeling requirements, as well as provide
for use of a variety of labeling color schemes.
FDA is proposing to delete current Sec. 606.121(d)(4) requiring
the use of ink colors that are a visual match to the specific color
samples designated by the Director, CBER, and to redesignate current
Sec. 606.121(d)(5) as Sec. 606.121(d)(4). As proposed, redesignated
Sec. 606.121(d)(4) (current Sec. 606.121(d)(5)) would also be revised
to update the regulations consistent with current industry practice, to
provide a consistent label appearance, and to facilitate the use of
black and white labels produced by on-demand printers while still
allowing for the use of color coded labels if blood establishments wish
to continue their use. FDA believes, consistent with current industry
practice, that the use of color coded labels with strict adherence to
specific color samples does not increase product safety, and that the
use of black and white or color coded labels without specific color
samples would not have an adverse affect on identification of the ABO
blood group.
5. Proposed Revisions to Sec. 606.121(e)
FDA is proposing to redesignate current Sec. 606.121(e)(1)(i) as
Sec. 606.121(e)(1)(ii). FDA is proposing to redesignate current Sec.
606.121(e)(1)(ii) as Sec. 606.121(e)(1)(i) and to amend redesignated
Sec. 606.121(e)(1)(i) as discussed in section II.C.2 of this document.
FDA is proposing to revise Sec. 606.121(e)(1)(iii) by changing
``shall'' to ``must.'' Section 606.121(e)(2) remains unchanged.
FDA is proposing to delete current Sec. 606.121(e)(3) because it
is redundant with proposed Sec. 606.121(c)(4) and redesignate current
Sec. 606.121(e)(4) as Sec. 606.121(e)(3) and current Sec.
606.121(e)(5) as Sec. 606.121(e)(4). Additionally, a conforming
amendment is proposed to current Sec. 606.121(j) because it refers to
the current Sec. 606.121(e)(4). FDA is proposing to update
redesignated Sec. 606.121(e)(3) (current Sec. 606.121(e)(4)) by
changing ``shall'' to ``must.''
As proposed, redesignated Sec. 606.121(e)(4)(i) and (e)(4)(ii)
(current Sec. Sec. 606.121(e)(5)(i) and (e)(5)(iii), respectively)
remain unchanged. Consistent with current industry practice, FDA is
proposing to add Sec. 606.121(e)(4)(iii) to require establishments to
state on the container label the type of anticoagulant from which the
recovered plasma was prepared.
FDA is proposing to add new Sec. 606.121(e)(5) to include the
provisions in the introductory sentence of current Sec. 640.70(a),
part of Sec. 640.70(a)(2), and Sec. Sec. 640.70(a)(3), (a)(4),
(a)(7), (a)(9), and (b). Proposed Sec. 606.121(e)(5) would clarify and
consolidate in Sec. 606.121 labeling requirements specific for Source
Plasma. As proposed, redesignated Sec. 606.121(e)(5)(i) (part of
current Sec. 640.70(a)(2)) would be updated, consistent with proposed
Sec. 606.121(c)(10), to provide flexibility in the use of upper and
lowercase types in cautionary statements. Additional revisions to
redesignated Sec. Sec. 606.121(e)(5)(ii) (current Sec. 640.70(a)(3))
and 606.121(e)(5)(v) (current Sec. Sec. 640.70(a)(3) and (b),
respectively) are discussed in section II.D of this docoument. FDA is
proposing to redesignate current Sec. 640.70(a)(7) as Sec.
606.121(e)(5)(vi). Under the proposal, FDA would update redesignated
Sec. 606.121(e)(5)(vi) (current Sec. 640.70(a)(7)) to broaden the
labeling requirements to include collections from donors who are not
immunized but are in specific collection programs, such as disease
associated collections from donors who have antibodies to
cytomegalovirus. FDA is proposing to redesignate current Sec.
640.70(a)(4) as Sec. 606.121(e)(5)(iii) and current Sec. 640.70(a)(9)
as Sec. 606.121(e)(5)(iv).
6. Proposed Revisions to Sec. Sec. 606.121(f) and (h)
FDA is proposing to amend Sec. 606.121(f) by revising the last
sentence. The proposed change would clarify that all blood and blood
components intended solely for further manufacturing, including
recovered plasma and Source Plasma, do not need to be labeled ``NOT FOR
TRANSFUSION'' because their intended use for further manufacturing is
clearly stated on the label. Section 606.121(g) remains unchanged.
Under the proposal, Sec. 606.121(h) would be revised by changing
``shall'' to ``must'', and ``640.2(f)'' to read ``Sec. 610.40(g)''.
7. Summary of Consolidation of Regulations in Sec. 640.70 into Sec.
606.121
As previously discussed in this section, FDA is proposing to
consolidate the existing labeling regulations in Sec. 640.70 into
Sec. 606.121. As part of the consolidation, regulations that currently
exist in both sections would be found only in Sec. 606.121 as follows:
[sbull] Sec. 640.70(a)(1) is deleted because it is redundant with
proposed Sec. 606.121(c)(1).
[sbull] Sec. 640.70(a)(2) is revised and redesignated as proposed
Sec. 606.121(c)(10) and as proposed Sec. 606.121(e)(5)(i).
[sbull] Sec. 640.70(a)(4) is revised and redesignated as Sec.
606.121(e)(5)(iii).
[sbull] Sec. 640.70(a)(5) is removed because it is redundant with
proposed Sec. 606.121(c)(3).
[sbull] Sec. 640.70(a)(6) is revised and redesignated as the
second sentence of proposed Sec. 606.121(c)(4).
[sbull] Sec. 640.70(a)(7) is revised and redesignated as Sec.
606.121(e)(5)(vi).
[sbull] Sec. 640.70(a)(9) is revised and redesignated as Sec.
606.121(e)(5)(iv).
C. Proposed Revisions to Clarify and Consolidate Regulations Related to
Use of a Labeling System Using Machine-Readable Information
The proposed revisions discussed in this section of this document
are primarily intended to allow for the use of a machine-readable
encoded information system, such as ISBT 128. Those changes would allow
manufacturers of blood, blood components, and Source Plasma to submit
product specific labeling that is consistent with approved labeling
formats, such as ISBT 128, to the Director, CBER, for approval without
requesting a variance under Sec. 640.120. Under this proposal, Sec.
606.121(c)(13) would remain unchanged. In the Federal Register of March
14, 2003 (68 FR 12499) FDA issued a proposed rule entitled ``Bar Code
Label Requirements for Human Drug Products and Blood'' (proposed Bar
Code Rule), that would amend Sec. 606.121(c)(13) to require certain
human drug and biological product labels to bear bar codes and also
would require the use of machine-readable information on container
labels for blood and blood components intended for transfusion. The
proposed
[[Page 44683]]
Bar Code Rule specifically invites comment on whether FDA should
require the use of ISBT 128, or require ``machine-readable
information'' as approved by the Director, CBER, or some other standard
or symbology. If you are interested in commenting on the use of bar
codes on container labels for blood and blood components for
transfusion, please refer to the proposed Bar Code Rule and submit your
comments (see 68 FR 12499).
1. Proposed revisions to Sec. 606.121(c)(2)
FDA is proposing to amend Sec. 606.121(c)(2) by replacing
``registration number'' with ``unique facility identifier.'' This
change would remove the requirement to include the FDA assigned
registration number on blood and blood component labels. Although the
FDA assigned registration number is acceptable as a ``unique facility
identifier,'' the proposal would also provide for the use of other
recognized donation facility identification numbers, such as the ISBT
facility code (which includes machine-readable information). Consistent
with the general provisions for licensing in 21 CFR part 601,
establishments collecting Source Plasma may use their registration
number or other recognized donation facility identification number as
the unique facility identifier which would aid in identifying the
location where the product was collected. Under the proposal, current
Sec. 640.70(a)(10) would be removed because the requirements of Sec.
640.70(a)(10) for ``name, address, and license number'' on the Source
Plasma label are included in proposed Sec. 606.121(c)(2).
2. Proposed Revisions to Sec. 606.121(e)(1)(i)
As previously discussed in section II.B of this document, FDA is
proposing to amend redesignated Sec. 606.121(e)(1)(i) (current Sec.
606.121(e)(1)(ii)). This revision is intended to facilitate the use of
a labeling system using machine-readable information, such as ISBT 128,
by providing more flexibility in labeling. Specifically, this revision
would remove the labeling requirements regarding the placement and
prominence of the anticoagulant.
D. Proposed Revisions Related to Temperature Requirements
FDA is proposing revisions to update temperature requirements for
storage and shipment of blood and blood components. The proposed
changes described in this section are intended to provide consistency
with data published in Europe and to help ensure the potency of blood
and blood components by guarding against the degradation of heat labile
clotting factors during storage and shipment (Ref. 1). Because these
storage and shipping temperatures may be reflected in the product
labeling, FDA is proposing to update the temperature requirements in
this rulemaking to address as many labeling changes as possible as part
of this rulemaking and enable establishments to make a number of
revisions to labels for blood products at one time. This revision would
simplify labeling of blood and blood components. Additionally, this
approach is intended to reduce the burden on industry by minimizing the
number of times blood container labels must be revised and reordered.
1. Proposed Revisions to Sec. Sec. 610.53, 640.34, and 640.54
FDA is proposing to revise Sec. Sec. 610.53, and 640.34(b) by
changing ``shall'' to ``must'', and by changing the storage and
shipping temperatures for Cryoprecipitated Antihemophiliac Factor (AHF)
and for Fresh Frozen Plasma to -25 [deg]C or colder if stored for 24
months after the date of collection, and -18 to -25 [deg]C if stored
for 3 months after the date of collection. FDA is proposing changes to
Sec. 640.54 for consistency with the proposed changes in shipping and
storage temperatures for Cryoprecipitated AHF.
2. Proposed Revisions to Sec. Sec. 640.69, 640.70, and 640.76
As previously mentioned, FDA is proposing to redesignate current
Sec. 640.70(a)(3) as Sec. 606.121(e)(5)(ii). FDA is proposing to
revise redesignated Sec. 606.121(e)(5)(ii) (current Sec. Sec.
640.70(a)(3)), 640.69(c), and 640.76(a) and (b) by changing the storage
and shipping temperatures for Source Plasma to -30 [deg]C and -15
[deg]C, respectively, or colder. FDA is proposing to redesignate
current Sec. 640.70(b) as Sec. 606.121(e)(5)(v), and to revise
redesignated Sec. 606.121(e)(5)(v) by changing the storage and
shipping temperatures for Source Plasma diverted for Source Plasma
Salvaged to -30 [deg]C and -15 [deg]C, respectively, or colder.
3. Proposed Revisions to Sec. 640.34
FDA is proposing to revise Sec. 640.34(g)(2) to clarify that
frozen plasma must be stored at appropriate temperatures to ensure
product potency.
E. Proposed Changes to Clarify and Consolidate Regulations Related to
Communicable Disease Testing, and Autologous Donations
The proposed revisions discussed in this section of this document
would require labels for blood, blood components, and Source Plasma to
include the results of the communicable disease tests performed on a
sample of the donor's blood obtained at the time of the blood donation.
The proposed regulations would require establishments to include on
product labels the results of all communicable disease testing
performed as required in Sec. 610.40. Currently in Sec. Sec. 606.121
and 640.70, only the results of tests for Hepatitis B surface antigen
(HBsAg) and antibody to Human Immunodeficiency Virus (anti-HIV) are
required on the label. In the Federal Register of June 11, 2001 (66 FR
31146), FDA published a related rulemaking entitled ``Requirements for
Testing Human Blood Donors for Evidence of Infection Due to
Communicable Disease Agents'' (the testing final rule). The proposed
revisions are consistent with the requirements of the testing final
rule.
1. Proposed Revisions to Redesignated Sec. 606.121(c)(11)
FDA is proposing to redesignate current Sec. Sec. 640.70(a)(8) and
(a)(11) as Sec. 606.121(c)(11) and to revise redesignated Sec.
606.121(c)(11) to require labeling statements based on communicable
disease test results. The proposed change provides that the labeling
requirements apply to Source Plasma and would require establishments to
label products for further manufacture with the results of all required
communicable disease testing performed in accordance with Sec. 610.40.
2. Proposed Addition to Sec. 606.121(c)(12)
As previously described in this section, FDA is proposing to
redesignate current Sec. 606.121(c)(12) as Sec. 606.121(c)(9), and to
add new Sec. 606.121(c)(12). Proposed Sec. 606.121(c)(12) is intended
to clarify that blood establishments would be permitted under certain
circumstances to use blood or blood components which test repeatedly
reactive for communicable disease agents, provided the units are
appropriately labeled to indicate all test results. This labeling
change is consistent with the labeling requirements of Sec. 610.40 of
the testing final rule described in the previous paragraph.
[[Page 44684]]
3. Proposed Revisions to Sec. 606.121(i)
FDA is proposing to revise Sec. 606.121(i) by using more
descriptive and precise terms, by replacing the word ``shall'' with
``must'' and by replacing ``Whole Blood or Red Blood Cells'' with
``blood or blood components.'' Section 606.121(i)(1) would be revised
consistent with industry practice by adding ``date of birth'' to the
list of examples of information that may be used to help ensure correct
identification of the autologous transfusion recipient. In addition,
FDA is proposing to delete the words ``blood group'' from the list of
information that may identify an autologous transfusion recipient in
Sec. 606.121(i)(1). No revision is proposed for Sec. 606.121(i)(2).
FDA is proposing to revise Sec. 606.121(i)(3) to simplify the
requirements and to provide consistency with current industry practice
and with the requirements for appropriate donor classification proposed
in redesignated Sec. 606.121(c)(8)(v). FDA is proposing to add new
paragraph (i)(4) to clarify and update the existing requirements.
Accordingly, FDA is proposing to redesignate current Sec. Sec.
606.121(i)(4) and (i)(5) as Sec. 606.121(i)(5) and (i)(6),
respectively.
FDA is proposing to revise redesignated Sec. 606.121(i)(5)
(current Sec. 606.121(i)(4)) to provide that the label for blood or
blood components intended for autologous transfusion must be labeled as
``FOR AUTOLOGOUS USE ONLY'' if obtained from a donor who is reactive to
one or more tests for evidence of infection due to communicable disease
agents. Current Sec. 606.121(i)(4) is specific for the tests currently
required in the regulations. Consistent with the testing final rule,
the proposed revision to redesignated Sec. 606.121(i)(5) (current
Sec. 606.121(i)(4)) would provide for appropriate labeling regardless
of how testing standards may change in the future. FDA is proposing to
update redesignated Sec. 606.121(i)(6) (current Sec. 606.121(i)(5)),
revising it by replacing ``homologous'' with ``allogeneic.''
4. Proposed Revisions to Sec. 606.122
FDA is proposing to amend Sec. 606.122 Instruction circular by
revising the introductory paragraph and paragraphs (e), (f), and (m).
Section 606.122 requires that an instruction circular must be available
for distribution if the product is intended for transfusion. The
introductory paragraph would be revised to replace ``shall'' with
``must''. Current Sec. 606.122(e) requires that the instruction
circular contain statements that the product was prepared from blood
that was negative when tested for antibody to human immunodeficiency
virus (HIV), was nonreactive for hepatitis B surface antigen by FDA
required tests and nonreactive when tested by a serological test for
syphilis. Proposed Sec. 606.122(e) would clarify that the instruction
circular must contain statements regarding the results of all required
infectious agent testing. By making this change, it would become
unnecessary to revise the labeling regulations as testing requirements
may be revised in the future. FDA is proposing to amend Sec.
606.122(f) by updating the warning statement, which currently refers
only to the hazard of transmitting hepatitis, to reflect the risk
associated with the communicable disease agents for which testing is
currently performed.
Note that the terms ``infectious agent testing'' and ``communicable
disease testing'' (used interchangeably in this proposed rule and in
guidance documents) refer to the same testing performed in accordance
with Sec. 610.40. The term ``infectious agent'' is used rather than
``communicable disease agent'' for consistency with the ``Version 1.2.0
Standard.''
FDA is proposing to amend the introductory phrase in Sec.
606.122(m), and paragraphs (m)(2), (m)(3), and (m)(5) to update the
information required in the instruction circular for plasma. In the
introductory sentence of Sec. 606.122(m), FDA is proposing to update
the regulations by replacing the word ``shall'' with ``must.'' Section
606.122(m)(1) would remain unchanged. FDA is proposing to revise Sec.
606.122(m)(2) and (m)(3) to clarify that the instruction circular must
contain instructions to thaw the frozen product at a temperature
``appropriate for the product'' and, when applicable, instructions to
begin administration of the product within ``a specified time'' after
thawing, respectively. The proposed changes would provide greater
flexibility in the instruction circular, and would provide for various
new thawing methods and procedures for administration that might be
used in the future without requiring additional changes to the
regulation.
FDA is proposing to amend Sec. 606.122(m)(5), consistent with the
changes in proposed redesignated Sec. 606.122(e), to update the
information in the instruction circular regarding the transfusion of
plasma to warn of the risk of transmission of many communicable disease
agents, rather than refer only to the hazard of transmitting hepatitis.
III. Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612, and
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). Section 202(a) of the
Unfunded Mandates Reform Act of 1995 requires that agencies prepare a
written statement of anticipated costs and benefits before proposing
any rule that may result in an expenditure by State, local, and tribal
governments, in the aggregate, or by the private sector, of $100
million in any one year (adjusted annually for inflation). Under the
Regulatory Flexibility Act, unless an agency certifies that a rule will
not have a significant economic impact on a substantial number of small
entities, the agency must analyze regulatory options that would
minimize any significant impact of a rule on small entities.
The agency has reviewed this proposed rule and believes that it is
consistent with the regulatory philosophy and principles identified in
the Executive order and these two statutes. The proposed rule is not a
significant regulatory action as defined by the Executive order and so
is not subject to review under the Executive order. No further analysis
is required under the Regulatory Flexibility Act because the agency has
determined that these proposed rule amendments have no compliance costs
and will not have a significant effect on a substantial number of small
entities. This proposed rule also does not trigger the requirements for
a written statement under section 202(a) of the Unfunded Mandates
Reform Act because it does not impose a mandate that results in
expenditure of $100 million or more by State, local, and tribal
governments in the aggregate, or by the private sector in any one year.
The purpose of the proposed rule amendments is to simplify and
unify the existing labeling standards. Labeling standards are currently
found in multiple sections of the regulations and these amendments
would move these standards to one section of the regulations. By
revising, consolidating, and redesignating these regulations, parties
wishing to understand the labeling requirements will be able to
[[Page 44685]]
refer to a single source. The proposed rule amendments also include
provisions that add flexibility to the regulations that should lower
the cost of compliance.
Some aspects of the proposed rule amendments do establish new label
requirements and provisions. One such requirement is that the label
must reflect updated testing requirements. The agency believes these
requirements, including the requirement for the label to reflect
updated testing requirements, conform to current industry practice and
do not impose an additional burden.
The proposed rule requires a change in the instruction circular to
reflect current testing practices. Existing labeling regulations do not
allow the circular to reflect current required testing or to adjust to
future changes in required testing or plasma thawing procedures. The
agency believes the instruction circular would already be in compliance
with the proposed rule amendments and reflect current requirements and
practices if compliance were permitted by existing regulations. By
adding flexibility to the rules regarding the instruction circular, the
proposed rule lowers the overall cost of compliance. Moreover, as the
instruction circular is updated regularly, the agency believes any
required changes can be made in the ordinary revision cycle and that
this rule will not impose an additional burden.
The proposed rule amendments also update the temperature
requirements for storage and shipping of blood and blood components.
The agency believes that these requirements reflect current industry
practice and do not impose an additional burden.
In general, the agency believes the proposed rule will have no
compliance costs, because any requirements are either industry practice
or would be industry practice absent existing prohibitions. Because the
agency believes these proposed rule amendments have no compliance
costs, the agency certifies they will not have a significant economic
impact on a substantial number of small entities.
IV. The Paperwork Reduction Act of 1995
This proposed rule contains information collection provisions that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). As
previously described, FDA is proposing to consolidate regulations so
blood establishments may find all applicable labeling standards under
one section of regulations. The regulations for labeling of all blood
and blood components would be moved from other sections of the
regulations to Sec. 606.121. Since the agency believes the proposed
rule amendments conform to current industry practice, FDA is not
estimating the burden of the proposed rule. The information collection
requirements under Sec. Sec. 606.121 and 606.122 are approved under
OMB control number 0910-0116.
V. Environmental Impact
The agency has determined under 21 CFR 25.30(j) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
VI. Federalism
FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the rule does not contain policies that have substantial direct effects
on the States, on the relationship between the National Government and
the States, or on the distribution of power and responsibilities among
the various levels of government. Accordingly, the agency has concluded
that the rule does not contain policies that have federalism
implications as defined in the Executive order and, consequently, a
federalism summary impact statement is not required.
VII. Request for Comments
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments regarding this proposed
rule. Submit a single copy of electronic comments or two paper copies
of any mailed comments, except that individuals may submit one paper
copy. Comments are to be identified with the docket number found in
brackets in the heading of this document. Received comments may be seen
in the Division of Dockets Management between 9 a.m. and 4 p.m., Monday
through Friday.
VIII. Proposed Effective Date
The agency is proposing that any final rule that may issue based
upon this proposed rule become effective 180 days after its date of
publication in the Federal Register.
IX. Reference
The following reference has been placed on display in the Division
of Dockets Management (see ADDRESSES) and may be seen by interested
persons between 9 a.m. and 4 p.m., Monday through Friday.
1. Krotitschke, R., ``Stability of Fresh Frozen Plasma: Results of
36-Month Storage at -20 [deg]C, -25 [deg]C, -30 [deg]C, and -40
[deg]C,'' Infusion Therapy and Transfusion Medicine, 27:174-180, 2000.
List of Subjects
21 CFR Part 600
Biologics, Reporting and recordkeeping requirements.
21 CFR Part 606
Blood, Labeling, Laboratories, Reporting and recordkeeping
requirements.
21 CFR Part 610
Biologics, Labeling, Reporting and recordkeeping requirements.
21 CFR Part 640
Blood, Labeling, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act, and the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, it is proposed that 21 CFR parts 600,
610, 606, and 640 be amended as follows:
PART 600--BIOLOGICAL PRODUCTS: GENERAL
1. The authority citation for 21 CFR part 600 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 360i, 371,
374; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.
2. Section 600.15 is amended in the table in paragraph (a) by
revising the entries for Cryoprecipitated AHF, Fresh Frozen Plasma, and
Source Plasma to read as follows:
Sec. 600.15 Temperatures during shipment.
* * * * *
(a) Products.
----------------------------------------------------------------------------------------------------------------
Product Temperature
----------------------------------------------------------------------------------------------------------------
Cryoprecipitated AHF........... -25 [deg]C or colder if expiration is 24 months or
-18 to -25 [deg]C if expiration is 3 months.
* * * * * * *
[[Page 44686]]
Fresh Frozen Plasma............ -25 [deg]C or colder if expiration is 24 months or
-18 to -25 [deg]C if expiration is 3 months.
* * * * * * *...................................................................................................
Source Plasma.................. -15 [deg]C or colder.
* * * * * * *...................................................................................................
----------------------------------------------------------------------------------------------------------------
* * * * *
PART 606--CURRENT GOOD MANUFACTURING PRACTICE FOR BLOOD AND BLOOD
COMPONENTS
3. The authority citation for 21 CFR part 606 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360j, 371,
374; 42 U.S.C. 216, 262, 263a, 264.
4. Section 606.121 is revised to read as follows:
Sec. 606.121 Container label.
The container label requirements are designed to facilitate the use
of a uniform container label for blood and blood components, including
Source Plasma, by all blood establishments.
(a) [Reserved]
(b) The label provided by the collecting facility and the initial
processing facility must not be removed, altered, or obscured, except
that the label may be altered to indicate the proper name, with any
appropriate modifiers and attributes, and other information required to
identify accurately the contents of a container after blood components
have been prepared.
(c) The container label must include the following information, as
well as other specialized information as required in this section for
specific products:
(1) The proper name of the product in a prominent position, with
any appropriate modifiers and attributes;
(2) The name, address, unique facility identifier, and, if a
licensed product, the license number of each manufacturer;
(3) The donor or lot number relating the unit to the donor. If
pooled, all donor numbers, all donation numbers, or a pool number that
is traceable to each individual unit comprising the pool;
(4) The expiration date, including the day, month, and year, and,
if the dating period for the product is 72 hours or less, including any
product prepared in a system that might compromise sterility, the hour
of expiration. If Source Plasma intended for manufacturing into
noninjectable products is pooled, the expiration date is determined
from the collection date of the oldest unit in the pool, and the
pooling records must show the collection date for each unit in the
pool.
(5) For Whole Blood, Plasma, Platelets, and partial units of Red
Blood Cells, the volume of the product, accurate to within +/-10
percent; or optionally for Platelets, the volume range within
reasonable limits.
(6) Where applicable, the name and volume of source material.
(7) The recommended storage temperature (in degrees Celsius).
(8) If the product is intended for transfusion, the statements:
(i) ``Rx only.''
(ii) ``See Circular of Information for indications,
contraindications, cautions, and methods of infusion.''
(iii) ``Properly identify intended recipient.''
(iv) ``This product may transmit infectious agents.''
(v) The appropriate donor classification statement, i.e., ``paid
donor'' or ``volunteer donor,'' in no less prominence than the proper
name of the product.
(A) A paid donor is a person who receives monetary payment for a
blood donation.
(B) A volunteer donor is a person who does not receive monetary
payment for a blood donation.
(C) Benefits, such as time off from work, membership in blood
assurance programs, and cancellation of nonreplacement fees that are
not readily convertible to cash, do not constitute monetary payment
within the meaning of this paragraph.
(9) If the product is intended for transfusion or as is otherwise
appropriate, the ABO group and Rh type of the donor must be designated
conspicuously. For Cryoprecipitated Antihemophiliac Factor (AHF), the
Rh type may be omitted. The Rh type must be designated as follows:
(i) If the test using Anti-D Blood Grouping Reagent is positive,
the product must be labeled: ``Rh positive.''
(ii) If the test using Anti-D Blood Grouping Reagent is negative
but the test for weak D (formerly Du) is positive, the product must be
labeled: ``Rh positive.''
(iii) If the test using Anti-D Blood Grouping Reagent is negative
and the test for weak D (formerly Du) is negative, the product must be
labeled: ``Rh negative.''
(10) If the product is not intended for transfusion, a statement as
applicable: ``Caution: For Manufacturing Use Only,'' or ``Caution: For
Use in Manufacturing Noninjectable Products Only,'' or other cautionary
statement as approved by the Director, Center for Biologics Evaluation
and Research (CBER).
(11) If the product is intended for further manufacturing use, a
statement listing the names and results of all the tests for
communicable disease agents for which the donation has been tested and
found negative.
(12) The blood and blood components must be labeled in accordance
with Sec. 610.40, when the donation is tested and demonstrates
evidence of infection due to a communicable disease agent(s).
(13) The container label may bear encoded information in the form
of machine-readable symbols approved for use by the Director, Center
for Biologics Evaluation and Research (HFB-1).
(d) Unless otherwise approved by the Director, CBER, the container
label must be white and print must be solid black, with the following
additional exceptions:
(1) The ABO and Rh blood groups must be printed as follows:
(i) Rh positive: Use black print on white background and use solid
black or other solid color for ABO.
(ii) Rh negative: Use white print on black background for Rh and
use black outline for ABO.
(2) The proper name of the product, with any appropriate modifiers
and attributes, the donor classification statement, and the statement
``properly identify intended recipient'' may be printed in solid red or
in solid black.
(3) The following color scheme may be used for differentiating ABO
Blood groups:
------------------------------------------------------------------------
Blood group Color of label
------------------------------------------------------------------------
O Blue
------------------------------------------------------------------------
A Yellow
------------------------------------------------------------------------
B Pink
------------------------------------------------------------------------
AB White
------------------------------------------------------------------------
(4) Special labels, such as those described in paragraphs (h) and
(i) of this section, may be color coded.
[[Page 44687]]
(e) Container label requirements for particular products or groups
of products.
(1) Whole Blood labels must include:
(i) The name of the applicable anticoagulant approved for use by
the Director, CBER.
(ii) The volume of anticoagulant.
(iii) If tests for unexpected antibodies are positive, blood
intended for transfusion must be labeled: ``Contains (name of
antibody).''
(2) Except for frozen, deglycerolized, or washed Red Blood Cell
products, red blood cell labels must include:
(i) The volume of Whole Blood, and the type of anticoagulant with
which the product was prepared.
(ii) If tests for unexpected antibodies are positive and the
product is intended for transfusion, the statement: ``Contains (name of
antibody).''
(3) If tests for unexpected antibodies are positive, Plasma
intended for transfusion must be labeled: ``Contains (name of
antibody).''
(4) Recovered plasma labels must include:
(i) In lieu of an expiration date, the date of collection of the
oldest material in the container.
(ii) For recovered plasma not meeting the requirements for
manufacture into licensable products, the statement: ``Not for Use in
Products Subject to License Under Section 351 of the Public Health
Service Act.''
(iii) The type of anticoagulant with which the product was
prepared.
(5) Source Plasma labels must include the following information:
(i) The cautionary statement, as specified in Sec. 606.121(c)(10),
must follow the proper name with any appropriate modifiers and
attributes and be of similar prominence as the proper name.
(ii) The statement ``Store at -30 [deg]C or colder'': Provided,
That where plasma is intended for manufacturing into noninjectable
products, this statement may be replaced by a statement of the
temperature appropriate for manufacture of the final product to be
prepared from the plasma.
(iii) The total volume or weight of plasma and total quantity and
type of anticoagulant used.
(iv) When plasma collected from a donor is reactive for a serologic
test for syphilis, a statement that the plasma is reactive and must be
used only for the manufacturing of positive control reagents for the
serologic test for syphilis.
(v) Source Plasma diverted for Source Plasma Salvaged must be
relabeled ``Source Plasma Salvaged'' as prescribed in Sec. 640.76 of
this chapter. Immediately following the proper name of the product,
with any appropriate modifiers and attributes, the labeling must
conspicuously state as applicable, ``STORAGE TEMPERATURE EXCEEDED -30
[deg]C'' or ``SHIPPING TEMPERATURE EXCEEDED -15 [deg]C''.
(vi) A statement as to whether the plasma was collected from
nonimmunized donors, or from donors in specific collection programs
approved by the Director, CBER. In the case of specific collection
programs the label must state the defining characteristics of the
plasma.
(f) Blood and blood components determined to be unsuitable for
transfusion must be prominently labeled: ``NOT FOR TRANSFUSION,'' and
the label must state the reason the unit is considered unsuitable. The
provision does not apply to blood and blood components intended solely
for further manufacturing.
(g) [Reserved]
(h) The following additional information must appear on the label
for blood or blood components shipped in an emergency prior to
completion of required tests, in accordance with Sec. 610.40(g) of
this chapter:
(1) The statement: ``FOR EMERGENCY USE ONLY BY ----------.''
(2) Results of any tests prescribed under Sec. Sec. 610.40 and
640.5(a), (b), or (c) of this chapter completed before shipment.
(3) Indication of any tests prescribed under Sec. Sec. 610.40 and
640.5(a), (b), or (c) of this chapter not completed before shipment.
(i) The following additional information must appear on the label
for blood or blood components intended for autologous transfusion:
(1) Information adequately identifying the patient e.g., name, date
of birth, hospital, and identification number.
(2) Date of donation.
(3) The statement: `` AUTOLOGOUS DONOR.''
(4) The ABO and Rh blood group and type, unless exempt under Sec.
606.121(c)(9).
(5) In place of the allogeneic blood group label, each container of
blood intended for autologous use and obtained from a donor who fails
to meet any of the donor suitability requirements under Sec. 640.3 of
this chapter or who is reactive to or positive for one or more tests
for evidence of infection due to communicable disease agents must be
prominently and permanently labeled: ``FOR AUTOLOGOUS USE ONLY.''
(6) Units of blood originally intended for autologous use, except
those labeled as prescribed under paragraph (i)(5) of this section, may
be issued for allogeneic transfusion provided the container label
complies with all applicable provisions of paragraphs (b) through (e)
of this section. In such case, the special label required under
paragraphs (i)(1), (i)(2), and (i)(3) of this section must be removed
or otherwise obscured.
(j) A tie-tag attached to the container may be used for providing
the information required by paragraphs (e)(1)(iii), (e)(2)(ii), and
(e)(3), (h), or (i)(1), (i)(2), and (i)(3) of this section.
5. Section 606.122 is amended by revising the introductory
paragraph, and paragraphs (e), (f), (m)(2), (m)(3), and (m)(5) to read
as follows:
Sec. 606.122 Instruction circular.
An instruction circular must be available for distribution if the
product is intended for transfusion. The instruction circular must
provide adequate directions for use, including the following
information:
* * * * *
(e) A statement that the product was prepared from blood that was
tested and found negative for evidence of infection due to the
infectious agents (include the name of each infectious agent for which
the blood was tested, including all FDA required tests).
(f) The statement: ``Warning: The risk of communicable disease
agents is present. Careful donor selection and available laboratory
tests do not eliminate the hazard.''
* * * * *
(m) For Plasma, the instruction circular must contain:
(1) * * *
(2) Instructions to thaw the frozen product at a temperature
appropriate for the product.
(3) When applicable, instructions to begin administration of the
product within a specified time after thawing.
(4) * * *
(5) A statement that this product has the same risk of transmitting
communicable disease agents as Whole Blood; other plasma volume
expanders without this risk are available for treating hypovolemia.
* * * * *
PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS
6. The authority citation for 21 CFR part 610 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c,
360d, 360h, 360i, 371, 372, 374, 381; 42 U.S.C. 216, 262, 263, 263a,
264.
7. Section 610.53 is amended by revising paragraph (c) in the table
for
[[Page 44688]]
Cryoprecipitated AHF, and Plasma products for the item Fresh Frozen
Plasma to read as follows:
Sec. 610.53 Dating periods for licensed biological products.
* * * * *
(c) * * *
------------------------------------------------------------------------
A B C D
------------------------------------------------------------------------
Dating period
Manufacturer's after leaving
Manufacturer's storage period 0 manufacturer's
storage period 1 [deg]C or colder storage when
Product to 5 [deg]C (unless stored at 2 to 8
(unless otherwise otherwise [deg]C (unless
stated) stated) otherwise
stated)
------------------------------------------------------------------------
* * * * *
------------------------------------------------------------------------
Cryoprecipitated do do 24 months from
AHF the date of
collection of
source blood
providing
labeling
recommends
storage at -25
[deg]C or
colder or
3 months from
the date of
collection of
source blood
providing
labeling
recommends
storage between
-18 to -25
[deg]C.
------------------------------------------------------------------------
* * * * *
------------------------------------------------------------------------
Plasma products Not applicable do 24 months from
1. Fresh Frozen the date of
Plasma collection of
source blood
providing
labeling
recommends
storage at -25
[deg]C or
colder or
3 months from
the date of
collection of
source blood
providing
labeling
recommends
storage between
-18 to -25
[deg]C.
------------------------------------------------------------------------
* * * * *
PART 640--ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS
8. The authority citation for 21 CFR part 640 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42
U.S.C. 216, 262, 263, 263a, 264.
9. Section 640.34 is amended by revising paragraphs (b) and (g)(2)
to read as follows:
Sec. 640.34 Processing.
(a) * * *
(b) Fresh Frozen Plasma. Fresh Frozen Plasma must be prepared from
blood collected by uninterrupted venipuncture with minimal damage to
and minimal manipulation of the donor's tissue. The plasma must be
separated from the red blood cells, and placed in a freezer within 8
hours or within the timeframe specified in the directions for use for
the blood collecting, processing, and storage system. The plasma must
be stored at -25 [deg]C or colder if the expiration is 24 months; and
at -18 to -25 [deg]C if the expiration is 3 months.
* * * * *
(g) * * *
(2) With the exception of Platelet Rich Plasma and Liquid Plasma
the final product must be inspected for evidence of thawing or breakage
at the time of issuance. The containers need not be stored in a manner
that shows evidence of thawing if records of continuous monitoring can
establish that the appropriate storage temperature recommended on the
labeling for the product was maintained throughout the storage period.
If continuous monitoring of the product is not available, the final
product must be stored in a manner that will show evidence of thawing
and must not be issued if there is any evidence of thawing.
* * * * *
10. Section 640.54 is amended by revising paragraph (a)(3) to read
as follows:
Sec. 640.54 Processing.
(a) * * *
(3) Immediately after separation and freezing of the plasma, the
plasma must be stored and maintained at the appropriate storage
temperature recommended on the labeling for the product until thawing
of the plasma for further processing to remove the Cryoprecipitated
AHF.
* * * * *
11. Section 640.69 is amended by revising paragraph (c) to read as
follows:
Sec. 640.69 General requirements.
* * * * *
(c) Inspection. Source Plasma intended for further manufacturing
into injectable products must be inspected for evidence of thawing at
the time of issuance, except that inspection of individual plasma
containers need not be made if the records of continuous monitoring of
the storage temperature establish that the temperature remained at -30
[deg]C or colder. If there is evidence that the storage temperature has
not been maintained at -30 [deg]C or colder, the plasma may be
relabeled and issued as provided in Sec. 640.76(a) of this chapter.
* * * * *
Sec. 640.70 [Removed]
12. Section 640.70 Labeling is removed.
Sec. 640.76 [Amended]
13. Section 640.76 Products stored or shipped at unacceptable
temperatures is amended as follows:
a. In paragraphs (a)(1) and (a)(2) by removing ``-20 [deg]C'' and
adding in its place ``-30 [deg]C'' wherever it appears;
b. In paragraphs (a)(1), (a)(2), and (b) by removing ``shall'' and
adding in its place ``must'' wherever it appears;
c. In paragraphs (a)(2) and (b) by removing ``-5 [deg]C'' and
adding in its place ``-15 [deg]C'' wherever it appears.
Dated: July 12, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-19289 Filed 7-29-03; 8:45 am]
BILLING CODE 4160-01-S