Compound problem: Who is making your meds?

Compound problem: Who is making your meds?

Outbreak reveals poor oversight of pharmacies

A sixth patient has developed Exophiala dermatitis infection associated with injectable steroids prepared under poor infection conditions at a compounding pharmacy in South Carolina, Hospital Infection Control has learned.

The Centers for Disease Control and Prevention (CDC) reported the first five cases in late 2002 but warned that additional cases could occur due to the prolonged incubation period of the pathogen. Thus far, one patient has died.

"We are getting farther and farther out so the likelihood of [additional cases] will be dropping, but there is that possibility," says John Jernigan, MD, medical epidemiologist in the CDC division of healthcare quality promotion. "But that product has been removed [from the market place], and that pharmacy is no longer in business."

Pharmacy compounding is the process of combining drug ingredients to prepare medications that are not commercially available or to alter commercially available medications to meet specific patient needs such as dye-free or liquid formulations. But some health system pharmacists might not realize that they are purchasing injectables prepared through compounding.

"Hospitals are responsible for purchasing large amounts of pharmaceutical agents," Jernigan says. "Some of them are given an alternative to the brand name, and those alternatives frequently can be made by compounding pharmacies. Prior to this investigation, a lot of hospitals simply did not know there was any difference in the quality control requirements between a compounding pharmacy and a manufacturer. [But] the requirements for sterility testing and for validation of manufactured drugs are very different than they are for compounding pharmacies. Compound pharmacies are [very widely] distributed and may not be as familiar with mass production of pharmaceuticals as pharmaceutical companies."

Purchasers of pharmaceuticals should determine if supplies are provided from a compounding pharmacy that is licensed in their state and that follows appropriate measures to ensure that injectable products are free of contamination. In most states, compounding pharmacies are not required to report adverse events associated with their products to state or federal agencies. Such reporting to Food and Drug Administration (FDA) is only required for pharmaceutical manufacturing companies.

"Some of them actually sell in other states where they may not be licensed," Jernigan says. "If they are selling over the Internet, it may not be known by the purchaser that the compounder is not licensed to sell in that state. There are a number of issues where the FDA has gotten involved, but there are limits to their involvement because of the current laws. There are regulations over compounding pharmacies which restrict a lot of FDA involvement."

More than 40,000 meds prepared a day

The practice of compounding is reportedly on the increase, and the CDC estimates that 43,000 compounded medications are prepared daily in the United States.

"Those that purchase pharmaceuticals should verify that the places they purchasing from are following appropriate infection control and quality control standards," Jernigan says. "The clinicians — those who are injecting steroids — should check to see where the steroids come from. If any patient develops an illness after injection, consider the compounded products as a potential source. I think when clinicians look down at the bottle and see what appears to be a sterile product, they [assume] that it is probably not the product. But here, because there was an unusual fungi, we were able to put together that there was a problem."

Exophiala is a neurotropic, dark pigment-forming fungus found in soil and is a rare cause of human illness. The fungus caused the death from meningitis in one patient, sacroiliitis in another, and meningitis in three other patients who had received either epidural or intra-articular injections of methylprednisolone compounded at the pharmacy.

The South Carolina facility — "compounding pharmacy A" — was the source of the methylprednisolone acetate administered to all six patients with Exophiala infections. The pharmacy had been supplying the compounded product to hospitals and pain management clinics in five states after a proprietary form of methylprednisolone acetate injectable suspension (Depo Medrol, Pharmacia Corp., Peapack, New Jersey) became difficult to obtain from the manufacturer.

An investigation of compounding pharmacy A found improper performance of an autoclave and no written procedures for autoclave operation. There was no testing for sterility or appropriate checking of quality indicators. Microbiologic cultures done by CDC investigators found E. dermatitis in unopened vials from three separate lots of injectable methylprednisolone.

On Sept. 27, the pharmacy was ordered to stop all sales, but the drugs had been distributed to physicians, hospitals, clinics, and consumers in 11 states: Connecticut, Illinois, Indiana, Kentucky, Louisiana, Massachusetts, Mississippi, New Hampshire, North Carolina, South Carolina, and Virginia. On Nov. 15, the FDA announced a nationwide alert about all injectable drug products prepared by the pharmacy. All sites that received injectable methylprednisolone prepared by compounding pharmacy A have been contacted and have returned all unused products for testing.

Other recent clusters of infections associated with products prepared by compounding pharmacies include Serratia meningitis from epidural injections of betamethasone in California and Chryseomonas meningitis from epidural injections of methylprednisolone in Michigan. Resulting meningitis clusters occurred among patients who received epidural injections for chronic pain management. "That was due to a similar problem with quality control and infection control," Jernigan says. "It’s hard to say [how common it is] because they are not [federally] regulated. States have very loose regulations over pharmacies as well."

[Editor’s note: Health care professionals and compounding pharmacies are urged to report contaminated compounded drug products or adverse events associated with compounded drug products to their state boards of pharmacy and health departments. To help prevent further cases, practitioners also are encouraged to submit such reports to FDA’s MedWatch program by telephone at (800) 332-1088 or the web site: www.fda.gov/medwatch/report.htm.]