[Federal Register: June 3, 2003 (Volume 68, Number 106)]
[Rules and Regulations]
[Page 32979-32981]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr03jn03-6]
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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