[Federal Register Volume 67, Number 244 (Thursday, December 19, 2002)]
[Notices]
[Pages 77792-77793]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-31995]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 02N-0496]


Agency Information Collection Activities; Proposed Collection; 
Comment Request; Aluminum in Large and Small Volume Parenterals Used in 
Total Parenteral Nutrition

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Notice.

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SUMMARY:  The Food and Drug Administration (FDA) is announcing an 
opportunity for public comment on the proposed collection of certain 
information by the agency. Under the Paperwork Reduction Act of 1995 
(the PRA), Federal agencies are required to publish notice in the 
Federal Register concerning each proposed collection of information, 
including each proposed extension of an existing collection of 
information, and to allow 60 days for public comment in response to the 
notice. This notice solicits comments on the labeling requirements for 
aluminum content in large volume parenterals (LVPs), small volume 
parenterals (SVPs), and pharmacy bulk packages (PBPs) used in total 
parental nutrition (TPN).

DATES:  Submit written or electronic comments on the collection of 
information by February 18, 2003.

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

FOR FURTHER INFORMATION CONTACT: Karen L. Nelson, Office of Information 
Resources Management (HFA-250), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-1482.

SUPPLEMENTARY INFORMATION: Under the PRA (44 U.S.C. 3501-3520), Federal 
agencies must obtain approval from the Office of Management and Budget 
(OMB) for each collection of information they conduct or sponsor. 
``Collection of information'' is defined in 44 U.S.C. 3502(3) and 5 CFR 
1320.3(c) and includes agency requests or requirements that members of 
the public submit reports, keep records, or provide information to a 
third party. Section 3506(c)(2)(A) of the PRA (44 U.S.C. 3506(c)(2)(A)) 
requires Federal agencies to provide a 60-day notice in the Federal 
Register concerning each proposed collection of information, including 
each proposed extension of an existing collection of information, 
before submitting the collection to OMB for approval. To comply with 
this requirement, FDA is publishing notice of the proposed collection 
of information set forth in this document.
    With respect to the following collection of information, FDA 
invites comments on: (1) Whether the proposed collection of information 
is necessary for the proper performance of FDA's functions, including 
whether the information will have practical utility; (2) the accuracy 
of FDA's estimate of the burden of the proposed collection of 
information, including the validity of the methodology and assumptions 
used; (3) ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information on respondents, including through the use of 
automated collection techniques, when appropriate, and other forms of 
information technology.

Aluminum in Large and Small Volume Parenterals Used in Total Parenteral 
Nutrition--21 CFR 201.323 (OMB Control Number 0910-0439)--Extension

    FDA is requesting OMB approval under the PRA for the labeling 
requirements for aluminum content in LVPs, SVPs, and PBPs used in TPN. 
As explained in the final rule on aluminum content labeling 
requirements published in the Federal Register of January 26, 2000 (65 
FR 4103), aluminum content in parenteral drug products could result in 
a toxic accumulation of aluminum in the tissues of individuals 
receiving TPN therapy. Research indicates that neonates and patient 
populations with impaired kidney function may be at high risk of 
exposure to unsafe amounts of aluminum. Studies show that aluminum may 
accumulate in the bone, urine, and plasma of infants receiving TPN. 
Many drug products used routinely in parenteral therapy may contain 
levels of aluminum sufficiently high to cause clinical manifestations. 
Generally, when medication and nutrition are administered orally, the 
gastrointestinal tract acts as an efficient barrier to the absorption 
of aluminum, and relatively little ingested aluminum actually reaches 
body tissues. However, parenterally administered drug products 
containing aluminum bypass the protective mechanism of the 
gastrointestinal tract and aluminum circulates and is deposited in 
human tissues.
    Aluminum toxicity is difficult to identify in infants because few 
reliable techniques are available to evaluate bone metabolism in 
premature infants. Techniques used to evaluate the effects of aluminum 
on bone in adults cannot be used in premature infants. Although 
aluminum toxicity is not commonly detected clinically, it can be 
serious in selected patient populations, such as neonates, and may be 
more common than is recognized.
    FDA amended its regulations to add labeling requirements for 
aluminum content in LVPs, SVPs, and PBPs used in TPN. FDA specified an 
upper limit of aluminum permitted in LVPs and required applicants to 
submit to FDA validated assay methods for determining aluminum content 
in parenteral drug products. The agency added these requirements 
because of evidence linking the use of parenteral drug products 
containing aluminum to

[[Page 77793]]

morbidity and mortality among patients on TPN therapy, especially among 
premature neonates and patients with impaired kidney function.
    The information collection reporting requirements resulting from 
this rulemaking are as follows:
    21 CFR 201.323(b)--Requires that the package insert of all LVPs 
used in TPN therapy state that the drug product contains no more than 
25 micrograms per liter ([mu]g/L). This information must be contained 
in the ``Precautions'' section of the labeling of all LVPs used in TPN 
therapy.
    21 CFR 201.323(c)--Requires that the maximum level of aluminum 
present at expiry be stated on the immediate container label of all SVP 
drug products and PBPs used in the preparation of TPN solutions. The 
aluminum content must be stated as prescribed in the regulation. The 
immediate container label of all SVP drug products and PBPs that are 
lyophilized powders used in the preparation of TPN solutions must 
contain the statement prescribed in the regulation.
    21 CFR 201.323(d)--Requires that the package insert for all LVPs, 
SVPs, and PBPs used in TPN contain a warning statement, prescribed in 
the regulation, intended for patients with impaired kidney function and 
for neonates receiving TPN therapy. This information must be contained 
in the ``Warnings'' section of the labeling.
    21 CFR 201.323(e)--Requires that applicants and manufacturers must 
use validated assay methods to determine the aluminum content in 
parenteral drug products. The assay methods must comply with current 
good manufacturing practice requirements. Applicants must submit to FDA 
both validation of the method used and release data for several 
batches. Manufacturers of parenteral drug products not subject to an 
approved application must make assay methodology available to FDA 
during inspections. Holders of pending applications must submit an 
amendment to the application.
    Compliance with the information collection burdens under Sec.  
201.323(b), (c), and (d) (21 CFR 201.323(b), (c), and (d)) consists of 
submitting application supplements to FDA containing the revised 
labeling for each product. Based on data concerning the number of 
applications for LVPs, SVPs, and PBPs used in TPN received by the 
agency, FDA estimates that the labeling for approximately 200 products 
will be changed under Sec.  201.323(b), (c), and (d). FDA estimates 
that it will take approximately 14 hours to prepare and submit to FDA 
each labeling change. FDA estimates that approximately 65 respondents 
will each submit one validated assay method annually under Sec.  
201.323(e). FDA estimates that it will take approximately 14 hours to 
prepare and submit to FDA each validated assay.
    FDA estimates the burden of this collection of information as 
follows:

                                 Table 1.--Estimated Annual Reporting Burden\1\
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                                                      Annual
         21 CFR Section               No. of       Frequency per   Total Annual      Hours per      Total Hours
                                    Respondents      Response        Responses       Response
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201.323(b), (c), (d)                      200               1             200              14           2,800
201.323(e)                                 65               1              65              14             910
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  Total                                                                                                 3,710
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


    Dated: December 13, 2002.
Margaret M. Dotzel,
Assistant Commissioner for Policy.
[FR Doc. 02-31995 Filed 12-18-02; 8:45 am]
BILLING CODE 4160-01-S