[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