Section

[Code of Federal Regulations]
[Title 21, Volume 4]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR201.323]

[Page 70-72]

TITLE 21--FOOD AND DRUGS

CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES

PART 201--LABELING--Table of Contents

Subpart G--Specific Labeling Requirements for Specific Drug Products

Sec. 201.323 Aluminum in large and small volume parenterals used in total parenteral nutrition.

(a) The aluminum content of large volume parenteral (LVP) drug
products used in total parenteral nutrition (TPN) therapy must not
exceed 25 micrograms per liter (g/L).
(b) The package insert of LVP's used in TPN therapy must state that
the drug product contains no more than 25 g/L of aluminum. This
information must be contained in the ``Precautions'' section of the
labeling of all large volume parenterals used in TPN therapy.
(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 (PBP's) used in the preparation
of TPN solutions. The aluminum content must be stated as follows:
``Contains no more than __ g/L of aluminum.'' The immediate
container label of all SVP's and PBP's that are lyophilized powders used
in the preparation of TPN solutions must contain the following
statement: ``When reconstituted in accordance with the package insert
instructions, the concentration of aluminum will be no more than __
g/L.'' This 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 January 26, 2001.
(d) The package insert for all LVP's, all SVP's, and PBP's used in
TPN must contain a warning statement. This warning must be contained in
the ``Warnings'' section of the labeling. The warning must state:

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.

(e) 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 the Food and Drug Administration
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
under Sec. 314.60 or Sec. 314.96 of this chapter.

[65 FR 4110, Jan. 26, 2000]

[[Page 71]]

Effective Date Note: At 65 FR 4110, Jan. 26, 2000, Sec. 201.323 was
added, effective Jan. 26, 2001. At 66 FR 7864, Jan. 26, 2001, the
effective date was delayed until Jan. 26, 2003.

Appendix A to Part 201--Examples of Graphic Enhancements Used by FDA

I. Section 201.66 Standard Labeling Format

A. Overall

1. The ``Drug Facts'' labeling is set off in a box or similar
enclosure by the use of a barline with all black type printed on a
white, color contrasting background.

B. Typeface and size

1. ``Drug Facts'' is set in 14 point Helvetica Bold Italic, left
justified.
2. ``Drug Facts (continued)'' is set in 8 point Helvetica Bold
Italic for the words ``Drug Facts'' and 8 point Helvetica Regular for
the word ``(continued)'' and is left justified.
3. The headings (e.g., ``Directions'') are set in 8 point Helvetica
Bold Italic, left justified.
4. The subheadings (e.g., ``Ask a doctor or pharmacist before use if
you are'') are set in 6 point Helvetica Bold, left justified.
5. The information is set in 6 point Helvetica Regular with 6.5
point leading, left justified.
6. The heading ``Purpose'' is right justified.
7. The bullet is a 5-point solid square.
8. Two em spacing separates bullets when more than one bullet is on
the same line.
9. A table format is used for 3 or more dosage directions.
10. A graphic appears at the bottom of the first panel leading the
reader to the next panel.

C. Barlines and hairlines

1. A 2.5-point horizontal barline extends to each end of the ``Drug
Facts'' box (or similar enclosure), providing separation between each of
the headings.
2. A 0.5-point horizontal hairline extends within 2 spaces on either
side of the ``Drug Facts'' box (or similar enclosure), immediately
following the title and immediately preceding the subheadings.
3. A 0.5-point horizontal hairline follows the title, immediately
preceding the heading, when a heading appears on a subsequent panel
immediately after the ``Drug Facts (continued)'' title.

D. Box or Enclosure

1. All information is enclosed by a 2.5-point barline.

II. Section 201.66 Modified Labeling Format

A. Overall

1. The ``Drug Facts'' labeling is presented in all black type
printed on a white color contrasting background.

B. Typeface and size

1. ``Drug Facts'' is set in 9 point Helvetica Bold Italic, left
justified.
2. The headings (e.g., ``Directions'') are set in 8 point Helvetica
Bold Italic, left justified.
3. The subheadings (e.g., ``Ask a doctor or pharmacist before use if
you are'') are set in 6 point Helvetica Bold, left justified.
4. The information is set in 6 point Helvetica Regular with 6.5
point leading, left justified.
5. The heading ``Purpose'' is right justified.
6. The bullet is a 5-point solid square.
7. Bulleted information may start on same line as headings (except
for the ``Warnings'' heading) and subheadings, with 2 em spacing
separating bullets, and need not be vertically aligned.

C. Barlines and hairlines

D. Box or Enclosure

1. All information is set off by color contrast. No barline is used.

III. Examples of Sec. 201.66 Standard Labeling and Modified Labeling
Formats

[[Page 72]]

A. Section 201.66 Standard Labeling Format
[GRAPHIC] [TIFF OMITTED] TR17MR99.007

B. Section 201.66 Modified Labeling Format
[GRAPHIC] [TIFF OMITTED] TR17MR99.008