[Federal Register Volume 68, Number 106 (Tuesday, June 3, 2003)]
[Rules and Regulations]
[Pages 32979-32981]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-13752]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 201

[Docket No. 02N-0241]


Amendment of Regulations on Aluminum in Large and Small Volume 
Parenterals Used in Total Parenteral Nutrition; Delay of Effective Date

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule; delay of effective date.

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SUMMARY: The Food and Drug Administration (FDA) is amending its 
regulations to change the labeling requirements concerning aluminum in 
small volume parenterals (SVPs) and pharmacy bulk packages (PBPs) used 
in total parenteral nutrition (TPN). The immediate container labels of 
SVPs and PBPs containing 25 micrograms per liter ([mu]g/L) or less of 
aluminum may state: ``Contains no more than 25 [mu]g/L of aluminum'' 
instead of stating the exact amount of aluminum they contain. In 
addition, the final rule revises the aluminum regulations to reflect 
the fact that the effective date of the final rule published in the 
Federal Register of January 26, 2000 (65 FR 4103) (the January 2000 
final rule) is delayed until July 26, 2004. The agency is taking these 
actions in response to a request from industry.

DATES: This final rule is effective July 26, 2004. The effective date 
for Sec.  201.323, added at 65 FR 4103, January 26, 2000, is delayed 
until July 26, 2004.

FOR FURTHER INFORMATION CONTACT: Christine F. Rogers, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

    In the January 2000 final rule, FDA amended its regulations in 
Sec.  201.323 (21 CFR 201.323) to enact certain requirements regarding 
aluminum levels in large volume parenterals (LVPs), SVPs, and PBPs used 
in TPN. The January 2000 final rule was originally scheduled to become 
effective on January 26, 2001. In the Federal Register of January 26, 
2001 (66 FR 7864), the agency published a document delaying the 
effective date to January 26, 2003. In the Federal Register of November 
26, 2002 (67 FR 70691), the agency published a document further 
delaying the effective date to January 26, 2004.
    Section 201.323(c) of the January 2000 final rule required the 
product's maximum level of aluminum at expiry to be stated on the 
immediate container label of SVPs and PBPs used in the preparation of 
TPN solutions. The January 2000 final rule required that the statement 
on the immediate container label read as follows: ``Contains no more 
than -- [mu]g/L of aluminum.'' For those SVPs and PBPs that are 
lyophilized powders used in the preparation of TPN solutions, the 
January 2000 final rule required that the maximum level of aluminum at 
expiry be printed on the immediate container label as follows: ``When 
reconstituted in accordance with the package insert instructions, the 
concentration of aluminum will be no more than -- [mu]g/L.'' The 
January 2000 final rule also required that the maximum level of 
aluminum be stated as the highest of: (1) The highest level for the 
batches produced during the last 3 years, (2) the highest level for the 
latest five batches, or (3) the maximum historical level, but only 
until completion of production of the first five batches after the 
effective date of the rule.
    In the Federal Register of August 12, 2002 (67 FR 52429), FDA 
proposed to amend Sec.  201.323 to permit the immediate container 
labels of SVPs and PBPs containing 25 [mu]g/L or less of aluminum to 
state: ``Contains no more than 25 [mu]g/L of aluminum'' instead of 
stating the exact amount of aluminum they contain (the 2002 proposed 
rule). The proposed amendment was prompted by a request from the Health 
Industry Manufacturers Association (HIMA, now called AdvaMed). A 
complete discussion of HIMA's arguments in support of the revision can 
be found in the 2002 proposed rule.
    The agency agreed with HIMA's request for the following reasons. 
FDA has already determined that 25 [mu]g/L is a safe upper limit for 
manufacturers to include in LVPs and believes that it is similarly 
appropriate for SVPs and PBPs. If an SVP or PBP that contains 25 [mu]g/
L of aluminum is added to a TPN solution that contains 25 [mu]g/L of 
aluminum, the concentration of aluminum in the mixture will still be 25 
[mu]g/L. Consistent with its approach to LVPs (to which SVPs and PBPs 
are added) that are permitted to contain 25 [mu]g/L, FDA believes 
health care practitioners will be provided with sufficient information 
on the aluminum content of SVPs and PBPs if the label states that the 
product contains no more than 25 [mu]g/L of aluminum.
    In the 2002 proposed rule, the agency also announced its intent to 
extend the effective date for Sec.  201.323 as necessary to provide 
time for the proposal to be finalized.

II. Comments on the Proposed Rule

    The agency received one comment on the 2002 proposed rule. The 
comment agreed with the proposal. The comment supported the agency's 
plan to extend the effective date of Sec.  201.323 until the proposed 
rule could be finalized. The comment asked that the effective date be 
extended at least 18 months after January 26, 2003, to give industry 
sufficient time to comply with Sec.  201.323. The comment also asked 
FDA to clarify that a delay of the effective date would apply to all 
products subject to Sec.  201.323.
    In response to this comment, the agency is delaying the effective 
date of

[[Page 32980]]

Sec.  201.323 until July 26, 2004. This delay applies to all products 
subject to Sec.  201.323.

III. Changes From the Proposed Rule

    The final rule delays the effective date of Sec.  201.323 to July 
26, 2004. The final rule also changes Sec.  201.323(c)(3) to reflect 
the fact that the effective date has been delayed. Section 
201.323(c)(3) provides that a manufacturer may state the maximum level 
of aluminum in terms of historical levels, but only until completion of 
production of the first five batches after the effective date of the 
January 2000 final rule. That effective date is the date by which 
manufacturers are to submit supplements describing the validated assay 
method used to determine aluminum content. Because manufacturers now 
have until July 26, 2004, to submit supplements, the final rule changes 
the date in Sec.  201.323(c)(3) to July 26, 2004. The final rule also 
slightly modifies the introductory language in Sec.  201.323(c) to 
clarify that the language ``except as provided in paragraph (d) of this 
section'' applies to both the second and third sentences in Sec.  
201.323(c). That is, the ``exception'' language applies generally to 
SVPs and PBPs used in the preparation of TPN and also to SVPs and PBPs 
that are lyophilized powders that are reconsituted and used in the 
preparation of TPN.

IV. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

V. Paperwork Reduction Act of 1995

    FDA concludes that this final rule contains no collections of 
information. Therefore, clearance by the Office of Management and 
Budget under the Paperwork Reduction Act of 1995 is not required.

VI. Analysis of Impacts

    FDA has examined the impacts of this amendment to Sec.  201.323 
under Executive Order 12866, the Regulatory Flexibility Act (5 U.S.C. 
601-612), and the Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1501 
et seq.). 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). 
The agency believes that this final rule is consistent with the 
regulatory philosophy and principles identified in the Executive order 
and in these two statutes.
    The purpose of this final rule is to relax the requirements of the 
January 2000 final rule for labeling aluminum content in SVPs and PBPs 
used in TPN. Specifically, this final rule allows manufacturers to use 
a standard statement of quantity of aluminum content in place of the 
exact amount for affected products that contain no more than 25 [mu]g/L 
of aluminum. FDA determined that the proposed rule would not be a 
significant action as defined by the Executive order. FDA received one 
comment to the proposed rule, but the comment did not address the 
Analysis of Impacts section of the proposed rule.
    In the Analysis of Impacts section of the January 2000 final rule, 
the agency relied on the Eastern Research Group (ERG) report entitled 
``Addendum to Compliance Cost Analysis for a Regulation for Parenteral 
Drug Products Containing Aluminum.'' In that report, ERG calculated the 
total relabeling costs for SVPs and PBPs to be about $523,000, or about 
$3,500 per product (equivalent to annualized costs totaling $128,000, 
or about $850 per product, discounted at 7 percent over 5 years). To 
the extent that manufacturers of SVPs and PBPs containing no more than 
25 [mu]g/L of aluminum use the added flexibility in labeling that this 
final rule provides, the compliance burden cited above could be 
reduced.
    The single comment to the proposed rule requested that an 
additional 18 months be added to the effective date of Sec.  201.323. 
FDA has complied with this request. Since this additional time would 
allow for more flexibility in implementing the compliance methods for 
all parts of Sec.  201.323, it could further reduce the compliance 
burden.
    Because this final rule could slightly decrease current compliance 
costs for the affected industry without imposing any additional costs, 
FDA has determined that the final rule is not a significant regulatory 
action as defined by the Executive order and thus is not subject to 
review under the Executive order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. FDA made the determination for the January 2000 
final rule that very few small firms, if any, would be significantly 
impacted. Thus, the agency certified that the final rule would not have 
a significant impact on a substantial number of small entities. This 
final rule could slightly lessen the economic impact of the January 
2000 final rule. Accordingly, FDA certifies that this final rule will 
not have a significant economic impact on a substantial number of small 
entities. No further analysis is required under the Regulatory 
Flexibility Act (as amended).
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 (Public 
Law 104-4) requires that agencies prepare a written statement of 
anticipated costs and benefits before finalizing 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 or more in any 
one year (adjusted annually for inflation).
    The Unfunded Mandates Reform Act does not require FDA to prepare a 
statement of costs and benefits for the final rule because the rule is 
not expected to result in any 1-year expenditure that would exceed $100 
million adjusted for inflation. The current inflation-adjusted 
statutory threshold is $110 million.

VII. Federalism

    FDA has analyzed this final 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.

List of Subjects in 21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
201 is amended as follows:

PART 201--LABELING

0
1. The authority citation for 21 CFR part 201 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360, 
360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.

[[Page 32981]]


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2. Section 201.323 is amended by revising the first sentence of the 
introductory text of paragraph (c); by removing from paragraph (c)(3) 
the word ``January'' and adding in its place the word ``July''; by 
redesignating paragraphs (d) and (e) as paragraphs (e) and (f), 
respectively; and by adding new paragraph (d) to read as follows:


Sec.  201.323  Aluminum in large and small volume parenterals used in 
total parenteral nutrition.

* * * * *
    (c) Except as provided in paragraph (d) of this section, the 
maximum level of aluminum present at expiry must be stated on the 
immediate container label of all small volume parenteral (SVP) drug 
products and pharmacy bulk packages (PBPs) used in the preparation of 
TPN solutions.* * *
    (d) If the maximum level of aluminum is 25 [mu]g/L or less, instead 
of stating the exact amount of aluminum as required in paragraph (c) of 
this section, the immediate container label may state: ``Contains no 
more than 25 [mu]g/L of aluminum.'' If the SVP or PBP is a lyophilized 
powder, the immediate container label may state: ``When reconstituted 
in accordance with the package insert instructions, the concentration 
of aluminum will be no more than 25 [mu]g/L''.
* * * * *

    Dated: May 22, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-13752 Filed 6-2-03; 8:45 am]
BILLING CODE 4160-01-S