[Federal Register Volume 67, Number 155 (Monday, August 12, 2002)]
[Proposed Rules]
[Pages 52429-52431]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-20300]



 ========================================================================
 Proposed Rules
                                                 Federal Register
 ________________________________________________________________________
 
 This section of the FEDERAL REGISTER contains notices to the public of 
 the proposed issuance of rules and regulations. The purpose of these 
 notices is to give interested persons an opportunity to participate in 
 the rule making prior to the adoption of the final rules.
 
 ========================================================================
 

  Federal Register / Vol. 67, No. 155 / Monday, August 12, 2002 / 
Proposed Rules  

[[Page 52429]]



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

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) proposes to amend 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). FDA proposes that the immediate 
container labels of SVPs and PBPs containing 25 micrograms per liter 
(mcg/L) or less of aluminum may state: ``Contains no more than 25 
mcg/L of aluminum'' instead of stating the exact amount of aluminum 
they contain. FDA is taking this action in response to a request from 
industry.

DATES: Submit written or electronic comments by October 28, 2002.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Submit electronic comments at http://www.fda.gov/dockets/ecomments. All comments should be identified with the docket 
number found in brackets in the heading of this document.

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 Federal Register of January 26, 2000 (65 FR 4103), FDA 
published a final rule amending 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 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 extending the effective date to January 26, 2003.
    Current Sec. 201.323(c) requires 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 statement 
on the immediate container label currently must read as follows: 
``Contains no more than __ mcg/L of aluminum.'' For those SVPs and 
PBPs that are lyophilized powders used in the preparation of TPN 
solutions, the maximum level of aluminum at expiry must 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 __ mcg/L.'' The maximum level of 
aluminum must 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. The labeling requirement applies to all 
SVPs and PBPs used in the preparation of TPN solutions, including, but 
not limited to: Parenteral electrolyte solutions, such as calcium 
chloride, calcium gluceptate, calcium gluconate, magnesium sulfate, 
potassium acetate, potassium chloride, potassium phosphate, sodium 
acetate, sodium lactate, and sodium phosphate; multiple electrolyte 
additive solutions; parenteral multivitamin solutions; single-entity 
parenteral vitamin solutions, such as vitamin K injection, folic acid, 
cyanocobalamin, and thiamine; and trace mineral solutions, such as 
chromium, copper, iron, manganese, selenium, and zinc.
    On June 1, 2000, the agency met with the Health Industry 
Manufacturers Association (HIMA, now called AdvaMed). HIMA requested 
that FDA permit SVPs and PBPs containing less than 25 mcg/L to be 
labeled ``Contains no more than 25 mcg/L of aluminum'' rather than 
requiring such products to be labeled with the exact amount of aluminum 
as required by Sec. 201.323(copyright) (Ref. 1). In support of this 
proposal, participants made the following points: (1) 25 mcg/L of 
aluminum is a safe level of aluminum for SVPs because the agency has 
already determined that amount of aluminum to be safe for LVPs; (2) it 
would make no clinical difference to know the precise amount less than 
25 mcg/L that an SVP contained; and (3) permitting the label to 
state ``Contains no more than 25 mcg/L'' rather than the exact 
amount of aluminum would avoid the need for labels to be reprinted in 
the future with the exact amounts of aluminum at expiry.
    One comment to the proposed rule had asked FDA to set a minimum 
level below which the amount of aluminum in SVPs and PBPs would not 
have to be declared. In the final rule, the agency responded that it 
was important for health care practitioners to know as much as possible 
about aluminum levels so that practitioners could calculate the total 
aluminum exposure from multiple sources and would be able to prepare 
low-aluminum parenteral solutions for patients in high risk groups.
    HIMA's request has caused the agency to reconsider its position on 
whether it is appropriate to set a minimum level of aluminum in SVPs 
and PBPs that would not have to be declared. While the comment to the 
proposed rule did not suggest a particular minimum level, HIMA has now 
proposed a specific level, 25 mcg/L of aluminum. FDA has already 
determined that 25 mcg/L is a safe upper limit for manufacturers to 
include in LVPs and believes that it is similarly appropriate for SVPs 
and PBPs.
    An important factor for the agency when reconsidering its position 
was that if an SVP or PBP that contains 25 mcg/L of aluminum is 
added to a TPN solution that contains 25 mcg/L of aluminum, the 
concentration of aluminum in the mixture will still be 25 mcg/L. 
Consistent with its approach to LVPs (to which SVPs and PBPs are added) 
that are permitted to contain 25 mcg/L, FDA believes health care 
practitioners will be provided with sufficient information on the 
aluminum

[[Page 52430]]

content of SVPs and PBPs if the label states that the product contains 
no more than 25 mcg/L of aluminum. For this reason, the agency does 
not believe it is necessary for SVPs and PBPs that contain 25 mcg/L 
or less of aluminum to be labeled with the precise concentration of 
aluminum. Therefore, the agency proposes to modify the required 
labeling as requested.

II. Description of the Proposed Rule

    The proposed rule would add new Sec. 201.323(d) to permit SVPs and 
PBPs that contain 25 mcg/L or less of aluminum to be labeled 
``Contains no more than 25 mcg/L'' rather than requiring such 
products to state the exact amount of aluminum.

III. Proposed Implementation Plan

    FDA proposes that the effective date of any final rule that may 
issue based on this proposed rule coincide with the effective date of 
the aluminum final rule that published in the Federal Register of 
January 26, 2000 (66 FR 7864). As discussed in section I of this 
document, the agency has extended this effective date to January 26, 
2003. The agency intends to further extend this effective date as 
necessary to provide time for this proposed rule to be finalized.

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 tentatively concludes that this proposed 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 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). The agency believes that 
this proposed rule is consistent with the regulatory philosophy and 
principles identified in the Executive order.
    The proposed rule would relax the requirements of the final rule 
for labeling aluminum content in SVPs and PBPs used in TPN. 
Specifically, manufacturers would be allowed 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 mcg/L of 
aluminum. Thus, the proposed rule is not a significant action as 
defined by the Executive order.
    In the Analysis of Impacts section of the final rule published on 
January 26, 2000, 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 mcg/L of aluminum use the added 
flexibility in labeling this proposal provides, the compliance burden 
cited above could be reduced.
    Because this proposed rule could slightly decrease current 
compliance costs for the affected industry without imposing any 
additional costs, FDA has determined that the proposed rule is not a 
significant action as defined by the Executive order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options to minimize any significant impact on a substantial 
number of small entities. FDA made the determination for the final rule 
published January 26, 2000, 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 proposed rule could slightly lessen the economic impact 
of the final rule published on January 26, 2000. Accordingly, FDA 
certifies that this proposed rule would 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 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 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 proposed 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 proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed 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 proposed 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.

VIII. Request for Comments

    Interested persons may submit to the Dockets Management Branch (see 
ADDRESSES) written or electronic comments regarding this proposal. Two 
copies of any comments are to be submitted, except that individuals may 
submit one 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 Dockets Management Branch between 9 a.m. and 4 p.m., 
Monday through Friday.

IX. Reference

    The following reference has been placed on display in the Dockets 
Management Branch (see ADDRESSES) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Minutes of June 1, 2000, HIMA meeting, slide 10.

List of Subjects in 21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

PART 201--LABELING

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

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


[[Page 52431]]


    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.

    2. Section 201.323 is amended by revising the first two sentences 
of the introductory text of paragraph (c); 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) 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. Except as provided in paragraph (d) of this section, 
the aluminum content must be stated as follows: ``Contains no more than 
__ mcg/L of aluminum.'' * * *
    (d) If the maximum level of aluminum is 25 mcg/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 mcg/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 mcg/L.''
* * * * *

    Dated: July 17, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-20300 Filed 8-9-02; 8:45 am]
BILLING CODE 4160-01-S