(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 ([micro]g/L).
(b) The package insert of LVP's used in TPN therapy must state that the drug product contains no more than 25 [micro]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) Except as provided in paragraph (d) of this section, 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. The aluminum content must be stated as follows: "Contains no more than __ [micro]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 __ [micro]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 July 26, 2004.
(d) If the maximum level of aluminum is 25 [micro]g/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 [micro]g/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 [micro]g/L".
(e) 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 [micro]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.
(f) 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 314.60 or 314.96 of this chapter.