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Executive Summary

PARENTERAL DRUG LABEL REQUIREMENTS SPECIFYING ALUMINUM CONTENT might be waived for drug products with an aluminum content less than a designated concentration, FDA Surgical-Dental Div. Supervisory Chemist Charles Hoiberg, PhD, commented at a Nov. 6 public workshop on aluminum in parenterals. Hoiberg said FDA has not yet issued labeling requirements for parenterals because a standardized assay to measure aluminum does not currently exist. He added that the possibility of waiving label requirements is one of the related issues FDA may also consider. FDA's workshop served as a forum for gathering information on the origins and clinical effects of aluminum loading and current methodology to determine trace aluminum. The meeting followed a March 3-4 Endocrinologic and Metabolic Drugs Advisory Committee meeting that addressed the issue of aluminum contamination of parenterals. The advisory committee made three recommendations to FDA at its March meeting: (1) a daily delivery of 30 micrograms of parenteral aluminum to adults and adolescents with normal renal function appears to be safe; (2) there should be a single aluminum content limit for each parenteral product based on the most restrictive use contemplated; and (3) parenteral products intended for repeated use in patients with renal failure or normal renal function should be labeled to indicate aluminum content. FDA has decided to implement the committee's recommendation on labeling of aluminum content. Hoiberg said FDA will also consider whether aluminum content at date of manufacture should be declared on the label for each lot or an upper limit be set; whether one method of analysis should be used or each applicant be allowed to develop their own validated method; and whether other contaminants known to be in parenterals, such as heavy metals, should also be investigated. Several methods of determining aluminum content were described by workshop panelists. Both Ted Rains, PhD, National Bureau of Standards, and John Savory, MD, University of Virginia Medical Center, stated that electrothermal atomic absorption spectrometry is the most sensitive and reliable means of measuring aluminum. Other methods include neutron activation analysis, graphite furnace atomic absorption, flame emission spectrometry with repetitive optical scanning and inductively coupled plasma atomic emission spectrometry. Hoiberg suggested that until FDA makes a final decision about how to measure aluminum content "it might be prudent . . . that drug companies would make the sort of commitment to try to reduce the aluminum as feasible and to practical levels." Summarizing workshop discussions, FDAer Gloria Troendle, MD, stated that amino acids and dextrose "are not considered sources of much aluminum, but the small volume parenterals, particularly calcium salts, phosphate, and albumin contribute large amounts of aluminum to patients." Regarding the issue of aluminum monitoring, Troendle said "there is some concern that if aluminum is not being monitored routinely in solutions that are available, the sort of aluminum that is greatly in excess of what can be tolerated might creep into the supply." She commented that "monitoring of aluminum would require the monitoring of all products and of the raw materials that go into products perhaps, and other intravenously used drugs, such as antibiotics." Workshop participants noted that there are several sources of aluminim contamination that may influence the amount of aluminum present in a parenteral product. For instance, panel members noted that aluminum is present in the air, in storage containers, and in reagents. Hoiberg said it would be "desirable if the regulated industry starts recording some data values" on the amount of aluminum in their products to obtain an historical data base. Then, he said, if FDA does establish an aluminum level that would not require labeling, companies can base their figures "on some historical treatments, like whether [aluminum] was being leached out of the glass container" the parenteral was held in.

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