Improving safety of TPNs: Applying new FDA rules

In a step toward making the administration of total parenteral nutrition (TPN) formulations safer, the Food & Drug Administration has published new labeling requirements mandating that manufacturers include information regarding aluminum content present in large volume parenterals (LVPs), small volume parenterals (SVPs), and pharmacy bulk packages (PBPs). The final regulations become effective Jan. 26, 2004.

The key message for pharmacists is to "be aware that many of these products are contaminated with aluminum," and to become actively involved in ensuring that they are administered safely within their facilities, said Gordon S. Sacks, Pharm.D., BCNSP, clinical associate professor, pharmacy practice division at the University of Wisconsin in Madison.

In light of this new ruling, pharmacists involved in the delivery of TPN must have an in-depth understanding of the principles associated with the safe administration of these formulations, explained Gordon L. Klein, a professor of pediatrics and preventive medicine at the University of Texas Medical Branch in Galveston, who interpreted the new ruling for pharmacists at the ASHP 37th Annual Midyear Clinical meeting in Atlanta last month.

Specific mandates of the ruling include the following:

• The aluminum content of LVP drug products used in the production of TPNs must not exceed 25 micrograms per liter (µg/L), which must be stated in the package insert of all LVPs used in TPN therapy in the "Precautions" section.
• The maximum level of aluminum present at expiry must be stated on the immediate container labels of all SVP drug products and PBPs used in the preparation of TPN solutions. The aluminum content must be stated as follows: "Contains no more than µg/L of aluminum."
• For SVPs and PBPs that are powders, the statement must read: "When reconstituted in accordance with the package insert instructions, the concentration of aluminum will be no more than µg/L."

A warning statement must also be included in all LVP, SVP, and PBP package inserts to read: "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 µg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration."

Pharmacists who deliver TPN products will now be responsible for:

• choosing the lowest aluminum contents for TPN solutions
• calculating the aluminum load for each component and for the solution as whole
• informing physicians whether the aluminum content is safe, unsafe, or toxic

The ruling also mandates certain analytic methods to which all manufacturers involved in the production of TPNs or components used in TPNs must adhere: 

• Validated methods must be used to determine aluminum content and must comply with current good manufacturing practices (GMPs).
• Supplement must be submitted to the FDA describing assay method, validation of method, and release data for several batches.
• Assay methodology must be made available to the FDA during inspections.

TPN admixtures have been successfully used in healthcare settings for more than 30 years to treat patients with nonfunctioning and inaccessible gastrointestinal tracts. Despite much success with their usage, adverse events continue to occur. These formulas are extremely complex and contain more than 40 components, including amino acids, dextrose, lipids, water, electrolytes, trace elements, and vitamins.

Because variable amounts of aluminum are present in many of the raw materials used to make TPNs or are intrinsically produced during the manufacturing process, it is impossible to eliminate all traces of the product from TPN formulas, explained Sacks. Furthermore, physicochemical incompatibilities can result from improper admixture practices and cause the administration of unsafe TPN formulations.

Contamination of TPN components with microorganisms has been associated with patient infections. A study also linked prolonged intravenous feeding of solutions containing aluminum to impaired neurological development in preterm infants.

Prior to this regulation, pharmacists were not routinely made aware of how much aluminum a TPN product contained because "there was no mandate requiring a labeling of aluminum content, but now there are enough data showing that it can be harmful," explained Sacks, who moderated a session on improving TPN safety at ASHP. Therefore, "we at least need these guidelines to limit the amount [of aluminum] that patients receive."

Jan. 20, 2003
Leah E. Perry
The author is a healthcare writer based in Atlanta.