Glass is considered the safest material in which to store medicines primarily because of its heat-resistant properties that allow sterilization at high temperatures. Although this characteristic aids in the elimination of microorganisms, it also increases the risk of contamination from chemicals harmful to one’s health. Studies conducted by Denise Bohrer, a chemist at the Federal University of Santa Maria (USFM), indicate that certain drug components or nutrient solutions are able to absorb aluminum from the glass and cause poisoning. According to international studies from the 1980s, the accumulation of aluminum in bone—as a replacement for calcium—causes growth deficiencies and bone fragility. In the brains of newborns, this delays mental development.
Aluminum contamination is of particular concern in the case of kidney patients and premature babies, whose bodies have difficulty eliminating it. In a 2010 article in the Journal of Pediatric Gastroenterology and Nutrition, the group led by Bohrer examined 10 premature infants admitted to the Intensive Care Unit (ICU) of the University Hospital of Santa Maria. On each day of treatment, these infants received in parenteral nutrition, on average, 15 micrograms (μg) of aluminum per kilogram of body weight—three times the maximum amount recommended by the U.S. Food and Drug Administration (FDA). The most serious finding was that because their kidney function had not yet developed, the babies were unable to eliminate much of the aluminum: less than half was eliminated through their urine. “This resulted in an accumulation of the metal in their bones and brains,” says Bohrer. Although she detected this effect in the short term, she was unable to document the effects of long-term accumulation. For further evaluation of this phenomenon, more babies will have to be analyzed.
Aluminum retention may not be as serious in the case of premature infants however. In a study of newborn and adult rats, Marlei Veiga, a doctoral candidate in Bohrer’s group, found that although the young rats treated with parenteral nutrition had high aluminum content in their organs, they were able to eliminate the contaminant better than older rodents, perhaps because of their higher metabolic rate. The findings have been available since July 2013 on the website of the Journal of Inorganic Biochemistry. But Bohrer remains unconvinced: “Premature infants are a population at risk.”
Aluminum toxicity has been well-established to be a cause of mortality in patients with kidney problems. One important source of contamination has been water, but a legislative change reversed this situation in Brazil. Now the container is the villain in the story. “The higher the inert gas content in the glass, the more aluminum it contains.” The glass ampoules, for example, are flame-sealed, but they can only withstand high temperatures because of their high aluminum content. The problem is that some chemical substances react with metal, such as the citrate and phosphate present in erythropoietin, a hormone administered to kidney patients. In this case, the recommendation according to a 2013 article published in the journal Renal Failure is to store erythropoietin in lyophilized form: after two years, the substance in powdered form would contain less aluminum than if stored in liquid form.
In the case of parenteral nutrition, which contains lipids and sugars, the culprit is calcium gluconate, a sugar that extracts aluminum from the glass.
LÉO RAMOSThere have been attempts to regulate the maximum level of aluminum in medications. According to the FDA, large-volume parenteral nutrition, stored in 100 milliliters (ml) or larger containers may not contain more than 25 ml of aluminum per liter. At present, ampoules that contain 10 or 20 ml of the drug need to indicate the maximum estimated amount for the product expiration. Bohrer says the problem is that the aluminum is extracted gradually, causing the amount to accumulate slowly. “The legislation does not address this phenomenon, which can occur during product storage life.”
Her solution to eliminating the potential harmful effects of parenteral nutrition would be to store calcium gluconate in plastic bottles. She believes this is the solution adopted in the UK, where in 2010 the agency responsible for regulating drugs and medical equipment, the Medicines and Healthcare products Regulatory Agency (MHRA), recommended that calcium gluconate stored in glass containers not be administered to those younger than 18, nor to patients with renal insufficiency. “The change in procedure was based on our 2003 article,” says Bohrer. In this study, published in the Journal of Trace Elements in Medicine and Biology, she and her colleagues showed that glass is the source of aluminum in parenteral nutrition. “What determines the degree of contamination are the product’s chemical properties. When the sample is sterilized, it speeds up the process,” she says.
Bohrer has spent the past year immersed in these issues, while working on a book to be published this year by Wiley entitled, Sources of Contamination in Medicinal Products and Medical Devices. Her impression is that it is the pharmaceutical industry that is resisting the change in packaging. “Calcium gluconate is a type of sugar, and it is more difficult to sterilize plastic containers and ensure that there is no bacterial contamination.”
Nevertheless, Dohrer believes that current knowledge is already sufficient to propose changes in the storage of certain drugs. At the same time, she points out that she is not trying to demonize the metal: “Bread and cheese, for example, contain aluminum, as do many other foods.” Not to worry: the digestive system absorbs less than 1% of ingested aluminum, which is eliminated by the kidneys. Bohrer regrets that the knowledge produced in Brazil has not had the same effect as in the UK: it has failed to draw the attention of the National Health Monitoring Agency (ANVISA) to the problem.
VEIGA, M. et al. Accumulation, elimination, and effects of parenteral exposure to aluminum in newborn and adult rats. Journal of Inorganic Biochemistry. Online. July 22, 2013.
BOHRER, D. et al. Influence of glass packaging on contamination of pharmaceutical products by aluminum. Part III: Interaction container-chemicals during heating for sterilization. Journal of Trace Elements in Medicine and Biology. v. 17, No. 2, p. 107-15. 2003.