The FDA mandate on aluminum exposure and labeling for TPN formulas becomes effective July 26, 2004.1 In light of these pending requirements, caregivers involved in the delivery of TPN must have an in-depth understanding of the principles associated with the safe administration of these formulas.
TPN admixtures have been successfully used for more than three decades for patients with nonfunctioning and inaccessible gastrointestinal tracts. These formulas are extremely complex and contain more than 40 components, including amino acids, dextrose, lipids, water, electrolytes, trace elements, and vitamins.2
Because variable amounts of aluminum are present in many of the raw materials used in TPN or are produced during the manufacturing process, traces of aluminum exist in TPN formulas. And aluminum content alone should not be the prime consideration in TPN decisions; products that are selected for lower aluminum content must also be carefully evaluated for their effect on compatibility within the TPN formulation.3
Prior to this FDA regulation, pharmacists and other healthcare professionals were not always made aware of how much aluminum a TPN product contained because there was no mandate requiring a labeling of aluminum content.2
Health Risks of Aluminum
Concern over aluminum toxicity is nothing new.5 Aluminum is one of the most abundant elements in the earth’s crust, but there is no known physiologic requirement for it and the body has evolved to protect itself from excessive ingestion.4 When aluminum is ingested, the gastrointestinal tract can act as a barrier to prevent it from being absorbed into the body’s tissues.8
However, when drugs are administered parenterally, the aluminum they contain can be deposited in tissues, potentially at toxic amounts.8 Because TPN bypasses the intestinal tract and, therefore, the body's natural barriers to foreign substances in the bloodstream, aluminum toxicity is an issue with TPN.
Aluminum toxicity presents serious health risks and has been associated with metabolic bone disease, neurodegenerative disease, dialysis encephalopathy, PN cholestasis, and microcytic anemia.5 Aluminum also accumulates in the parathyroid glands and may interfere with the secretion of parathyroid hormone (PTH), which may contribute to the low bone-turnover state seen in patients with aluminum toxicity.4
Patients who pose the highest risk for aluminum toxicity are pediatric and geriatric patients, as well as patients with renal failure. In order to minimize aluminum exposure, health care providers should monitor their patients' daily aluminum intake and seek TPN infusions with the lowest aluminum content.9
The first bone disorder symptom reported by TPN consumers was spinal pain, and a number of studies were performed in the mid-1980s to investigate the source. In 1991, the Journal of Parenteral and Enteral Nutrition identified aluminum accumulations as a continuing problem for TPN consumers, noting that such accumulations had been linked to bone disorders.9
About the Mandate
Compliance with the FDA mandate was originally scheduled to become effective on January 26, 2001, but the date has been extended several times, most recently to July 26, 2004, in order to allow manufacturers more time to comply with the ruling.5 It is important to note that aaiPharma’s M.V.I.® products already meet all rules and regulations set forth in the FDA mandate and published in the Federal Register.6
The mandate requires the following:7
- An upper limit of 25 mcg/L of aluminum for large-volume parenterals (LVP)
- The maximum level of aluminum at expiry for small-volume parenterals (SVP) and pharmacy bulk packages (PBP) must be placed on actual product labels
- A warning statement must 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."10
Healthcare professionals who deliver TPN products will now be responsible for:
- Choosing the lowest aluminum contents for TPN solutions2
- Calculating the aluminum load for each component and for the solution as a whole2
- Informing physicians if a calculation exceeds 5 mcg/kg per day5
The ruling also provides for consistency of aluminum concentration between batches. It mandates certain analytical methods to which all manufacturers involved in the production of TPN admixtures or components used in TPN must adhere:2
- Validated methods must be used to determine aluminum content and must comply with current good manufacturing practices
- 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
The FDA rule was designed to protect patients from the known toxicities of aluminum overload. Caregivers must remain vigilant in order to be aware of the amount of aluminum their TPN patients may be receiving.4
References:
1. Driscoll DF. Aluminum Contamination And Total Parenteral Nutrition Admixtures. Newslines, December 2003. Available at: http://www.imakenews.com/mvius/e_article000210964.cfm. Accessed February 2004 .
2. Perry L. Improving safety of TPNs: Applying new FDA rules. Drug Topics 2003;2:HSE14.
3. Rollins C. FDA Effective Date for Aluminum Labeling Approaching. Newsflash, January 2003. Available at: http://www.imakenews.com/mvius/e_article000120632.cfm. Accessed February 2004.
4. Kline, GL. Aluminum Toxicity and Its Control in Patient Receiving Total Parenteral Nutrition. Newslines, January 2003. Available at: http://www.imakenews.com/mvius/index000026037.cfm. Accessed February 2004 .
5. Perry L. FDA delays mandate on aluminum labeling in TPNs. Drug Topics Jan. 26, 2004;148:HSE6
6. aaiPharma’s MVI Web site, Product Information section. Available at: http://www.mvi-us.com/product_info/product_info.html. Accessed February 2004.
7. Amendment of Regulations on Aluminum in Large and Small Volume Parenterals Used in Total Parenteral Nutrition; Delay of Effective Date.Federal Register 21CFR Part 201, Vol.68,No.106,June 3,2003.
8. FDA Issues Rule on Aluminum in Parenteral Packaging. Pharmaceutical and Medical Packaging News, April 2000. Avaiable at: http://www.devicelink.com/pmpn/archive/00/04/011.html. Accessed February 2004 .
9. Schaffner R. Understanding Metabolic Bone Disease. The Oley Foundation’s In the News column. Available at: http://www.c4isr.com/oley/lifeline/95-010.htm. Accessed February 2004 .
10. Department of Health and Human Services. Food and Drug Administration. Aluminum in large and small volume parenterals used in total parenteral nutrition. Federal Register- Proposed Rules 2000; (17):4103-4111.
