[Federal Register Volume 68, Number 51 (Monday, March 17, 2003)]
[Notices]
[Pages 12701-12702]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-6227]


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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 02N-0496]


Agency Information Collection Activities; Submission for OMB 
Review; Comment Request; Aluminum in Large and Small Volume Parenterals 
Used in Total Parenteral Nutrition

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Notice.

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

SUMMARY:  The Food and Drug Administration (FDA) is announcing that the 
proposed collection of information listed below has been submitted to 
the Office of Management and Budget (OMB) for review and clearance 
under the Paperwork Reduction Act of 1995 (the PRA).

DATES: Fax written comments on the information collection provisions by 
April 16, 2003.

ADDRESSES:  Fax written comments on the information collection 
provisions to the Office of Information and Regulatory Affairs, OMB, 
Attn: Stuart Shapiro, Desk Officer for FDA, FAX 202-395-6974, or 
electronically mail comments to [email protected].

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: In compliance with 44 U.S.C. 3507, FDA has 
submitted the following proposed collection of information to OMB for 
review and clearance.

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 (44 U.S.C. 3501--3520) 
for the labeling requirements for aluminum content in large volume 
parenterals (LVPs), small volume parenterals (SVPs), and pharmacy bulk 
packages (PBPs) used in total parenteral nutrition (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 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

[[Page 12702]]

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 1 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.
    In the Federal Register of December 19, 2002 (67 FR 77792), the 
agency requested comments on the proposed collection of information. No 
comments were received.
    The burdens can be charted as follows:

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


    Dated: March 10, 2003.
William K. Hubbard,
Associate Commissioner for Policy and Planning.
[FR Doc. 03-6227 Filed 3-14-03; 8:45 am]
BILLING CODE 4160-01-S