[Federal Register Volume 66, Number 18 (Friday, January 26, 2001)]
[Rules and Regulations]
[Pages 7864-7865]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-2125]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 201

[Docket No. 90N-0056]
RIN 0910-AA74


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 delaying until 
January 26, 2003, the effective date of a final rule published in the 
Federal Register of January 26, 2000 (65 FR 4103), and originally 
scheduled to become effective on January 26, 2001. The final rule 
amends FDA's regulations to add certain labeling requirements for 
aluminum content in large volume parenterals (LVP's), small volume 
parenterals (SVP's), and pharmacy bulk packages (PBP's) used in total 
parenteral nutrition (TPN). The rule also specifies an upper limit of 
aluminum permitted in LVP's and requires applicants to submit to FDA 
validated assay methods for determining aluminum content in parenteral 
drug products. FDA is delaying the effective date of this rule to 
address concerns raised by affected parties about the possible 
inability to meet the requirements of the rule by the current effective 
date.

DATES: The effective date for Sec. 201.323 (21 CFR 201.323), added at 
65 FR 4103, January 26, 2000, is delayed until January 26, 2003. Submit 
written comments by April 26, 2001.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20857. 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

    On January 26, 2000, the agency published final regulations at 
Sec. 201.323 (21 CFR 201.323) enacting certain requirements regarding 
aluminum levels in SVP's, LVP's, and PBP's used in TPN. The new 
regulations added to part 201 (21 CFR part 201) at Sec. 201.323(a) 
limit the aluminum content for all LVP's used in TPN therapy to 25 
micrograms per liter (g/L). This requirement applies to all 
LVP's used in TPN therapy, including, but not limited to, parenteral 
amino acid solutions, highly concentrated dextrose solutions, 
parenteral lipid emulsions, saline and electrolyte solutions, and 
sterile water for injection.
    New Sec. 201.323(b) requires the package insert for all LVP's used 
in TPN therapy to state that the drug product contains no more than 25 
g/L of aluminum. This statement must be included in the 
``Precautions'' section of the labeling.
    New Sec. 201.323(c) requires the product's maximum level of 
aluminum at expiry to be stated on the immediate container label of 
SVP's and PBP's used in the preparation of TPN solutions. The statement 
on the immediate container label must read as follows: ``Contains more 
than ____ g/L of aluminum.'' For those SVP's and PBP's 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 ____ g/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 SVP's and 
PBP's 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.
    New Sec. 201.323(d) requires the package insert for all LVP's, 
SVP's, and PBP's used in TPN to contain a warning statement. The 
warning statement must be included in the ``Warnings'' section of the 
labeling. The warning must contain the following language:

    WARNING: This product contains aluminum that may be toxic. 
Aluminum may reach toxic levels with prolonged parenteral 
administration if kidney function is impaired. Premature neonates 
are particularly at risk because their kidneys are immature, and 
they require large amounts of calcium and phosphate solutions, which 
contain aluminum.
    Research indicates that patients with impaired kidney function, 
including premature neonates, who receive parenteral levels of 
aluminum at greater than 4 to 5 g/kg/day accumulate 
aluminum at levels associated with central nervous system and bone 
toxicity. Tissue loading may occur at even lower rates of 
administration.

    New Sec. 201.323(e) requires applicants and manufacturers to use 
validated assay methods to determine the aluminum content in parenteral 
drug products used in TPN therapy. The assay methods must comply with 
current good manufacturing practice regulations under part 211 (21 CFR 
part 211) (see Sec. 211.194(a)). Holders of approved applications for 
LVP's, SVP's, and PBP's used in TPN therapy are required to submit a 
supplement to FDA under 21 CFR 314.70(c); see also 21 U.S.C. 356a(b) 
describing the assay method used for determining the aluminum content. 
Applicants must submit the validation method used and the release data 
for several batches. In addition, manufacturers of parenteral drug 
products not subject to an approved application must make assay 
methodology available to FDA during inspections (see Secs. 211.160 and 
211.180(c)).
    New Sec. 201.323 applies to all human drug LVP's, SVP's, and PBP's 
used in TPN. Licensed biological products are not covered by this rule.

II. Description and Rationale for a Delay of the Effective Date of 
the Final Rule

    Since publication of the final rule, the agency has received 
letters and has had other communications with industry and industry 
trade associations in which industry has stated the need for additional 
time to meet the requirements of the rule. In early June 2000, the 
agency met with representatives from industry and an industry 
association. The meeting participants discussed their concerns with the 
following issues: (1) Inadequate

[[Page 7865]]

time for final rule implementation; (2) insufficient space on immediate 
container label of SVP's to state aluminum levels; (3) LVP's that will 
not meet the 25 g/L limit without reformulation or 
repackaging; (4) unavailability of release data required for submission 
for low production products; (5) labeling SVP's and PBP's with less 
than 25 g/L of aluminum; (6) the need for a uniform approach 
to aluminum testing during stability studies so that the sampling time 
points for the tests are the same for all products; and (7) 
clarification that the final rule applies only to LVP, SVP, and PBP 
drug products used in TPN and not to devices.
    Industry and the industry association stated at this meeting that 
additional time is necessary for moving methods validation from 
research and development to production, to order and install equipment, 
and to reduce aluminum levels in raw materials. They also noted that a 
number of LVP's are in the 50 g/L of aluminum range rather 
than the 25 g/L range; therefore, these products will require 
repackaging or reformulation to meet the limit.
    FDA has included in docket number 90N-0056 a copy of the meeting 
minutes. As part of the meeting, FDA confirmed the following: (1) That 
submission of historical batch release or stability data after 
completion of production of several batches is consistent with the 
final rule as it exists; (2) that stability testing at time zero and 
annually thereafter is consistent with the final rule as it exists; (3) 
that the final rule applies only to LVP, SVP, and PBP drugs used in 
TPN; and (4) that when a PBP is divided into aliquots of LVP's, the LVP 
aliquots must meet the 25 g/L aluminum limit required for all 
LVP's.
    After the meeting, FDA confirmed that Sec. 201.10(i) permits a 
small package exemption that applies to SVP's with insufficient space 
on the immediate container label to state aluminum levels.
    FDA is issuing this notice to delay the effective date of the rule 
to address the concerns raised by industry regarding the inability to 
meet certain requirements of the rule within 1 year.

III. Comment on the Extension of the Effective Date

    FDA placed minutes from the meeting described in Section II of this 
document in Docket No. 90N-0056 shortly after the meeting in June 2000. 
Those minutes and the memoranda of associated telephone calls set forth 
in detail the reasons a stay of the effective date for the aluminum 
rule until January 26, 2003, would be in the public interest. In 
particular, the agency is concerned that some products unable to 
reformulate by the existing effective date are medically necessary and 
without alternatives thus potentially putting certain patients at great 
risk. Since the agency is extending the effective date of the aluminum 
final rule based on the information submitted to it and the safety 
concerns associated with the potential unavailability of certain 
medically necessary products it finds, for good cause, that this 
extension of the effective date of the final rule does not require 
further notice and comment procedures (5 U.S.C. 553(b); 21 CFR 
10.40(e)(1)). More than 6 months have passed since the agency placed 
supporting information in Docket No. 90N-0056, and the agency has 
received no adverse correspondence or comments with respect to the 
request to delay the extension date. In addition, FDA has received 
several telephone inquiries from other affected parties requesting a 
delay of the effective date. Therefore, the agency is now extending the 
effective date of the final rule. However, in accordance with 21 CFR 
10.40(e)(1), the agency will accept comment on this extension for a 
period of 90 days.

    Dated: January 18, 2001.
Ann M. Witt,
Acting Associate Commissioner for Policy.
[FR Doc. 01-2125 Filed 1-25-01; 8:45 am]
BILLING CODE 4160-01-F