Aluminum levels in total parenteral nutrition therapy products have triggered a proposed requirement.
Concerned over studies linking aluminum in parenteral drug products to mortality among patients on total parenteral nutrition (TPN) therapy—especially premature infants and patients with impaired kidney function—FDA has proposed sweeping changes to the labeling of both large-volume parenterals (LVPs) and small-volume parenterals (SVPs).
Under the proposal, FDA would establish a maximum permissible level of aluminum in LVPs, and that level would be printed on package inserts. In addition, the maximum level of aluminum at expiry would be required on the immediate container label of SVPs and on pharmacy bulk packages used in the preparation of TPN solutions.
The proposed regulation also calls for warning statements about aluminum toxicity in patients with impaired kidneys and neonates receiving TPN therapy on the package insert of all LVPs and SVPs, including pharmacy bulk packages. Finally, TPN therapy manufacturers would be asked to develop validated assay methods for determining the aluminum content in parenteral drug products and submit them to FDA for approval.
The proposed regulation appeared in the January 5, 1998, edition of the Federal Register (vol 63, no. 2, pp 176–185).
Section 201.323(b) would require that the package insert for all LVPs used in TPN therapy state that the product contains no more than 25 mg/L of aluminum. This statement would be included in the precautions section of the labeling.
Section 201.323(c) would require that SVPs and pharmacy bulk packages used in the preparation of TPN solutions state the product's maximum level of aluminum at expiry on the immediate container label. Those SVPs and pharmacy bulk products packaged as lyophilized powders for use in the preparation of TPN solutions would be required to have the following statement on the immediate container label: "When reconstituted in accordance with the package insert instructions, the concentration of aluminum will be no more than 25 mg/L." The maximum level of aluminum may be expressed as whichever of the following is greatest: (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 rule takes effect.
Section 201.323(d) would require that the package insert for all LVPs and SVPs, including pharmacy bulk packages, contain the following in the warning section of the label: "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."
Aluminum finds its way into TPN therapy products in a number of ways. According to FDA, aluminum is commonly found in coloring agents and excipients. It is also found in parenteral drugs as a contaminant in the protein source. And, it leaches from glass containers and closures during autoclaving and storage.
FDA received comments that suggested substituting plastic for glass in the packaging of TPN therapies. The agency decided not to require parenterals to be packaged only in plastic because not all products used for TPN therapy are available in plastic, and it was beyond the scope of the proposed rule to require plastic containers.
Other comments pointed out the difficulty of measuring aluminum leached from packaging during the entire shelf life of the product. FDA felt that the proposed label statement should stand since the amount of aluminum scavenged from various sources is generally very small compared with the aluminum contamination already present in the solution.
The comment period ends April 6, 1998. Address comments to Docket No. 90N-0056. FDA is also seeking comments on whether another warning is appropriate, namely, "Patients should receive no more than 4 to 5 mg/kg/day of aluminum," and whether a 4- to 5-mg/kg/day level is reasonable and adequate. One year after the final rule is published—publication will probably be this fall—the regulation will go into effect.