Samples of Cladosporium species (L), and Aspergillus fumigatus, two of… (Harrison McClary/Reuters )
The drug that has caused 696 fungal infections and 45 deaths over the last six months isn’t one you want sloppy amateurs making.
A long-lasting anti-inflammatory, it is difficult to manufacture in sterile form. Injected into joints or around the spine to relieve pain, it stays in the body for months. It has a bad side effect of suppressing defenses — a real problem if it’s contaminated. If the contaminant is a microscopic fungus, the drug feeds it like fertilizer.
In short, methylprednisolone acetate — an “injectable steroid,” in pharmaceutical parlance — is a prescription for disaster if not made right. A few drug companies make it. So do an unknown number of “compounding pharmacies,” a little-known, lightly regulated shadow world of the American pharmaceutical industry.
And that, recent history suggests, is a problem.
One company, New England Compounding Center (NECC) of Framingham, Mass., made tens of thousands of doses of methylprednisolone acetate and two other steroids (betamethasone and triamcinolone) used for similar purposes. It sold them to pain clinics in 23 states, satisfying a demand for preservative-free medicines not available from mainstream drug companies. Last year, samples of all three products — including the deadly lots of methylprednisolone — were found to be contaminated with fungus or bacteria.
The dangers of injectable steroids made by compounding pharmacies have been clear for a while.
In 2001, 11 people in Northern California developed bacterial infections from injections of the steroid betamethasone made by a compounding pharmacy. Three died. A year later, two people in Michigan developed bacterial meningitis from methylprednisolone; neither died. That same year, seven people became ill and two died from fungal infections caused by contaminated methylprednisolone made by a compounding pharmacy in South Carolina. Last spring, contaminated steroids injected into the eyes of patients in Florida caused 13 vision-damaging infections.
Hard to make and dangerous to use, injectable steroids are an example of how small risks can converge to form a big one.
How NECC’ s methylprednisolone acetate became contaminated with Exserohilum rostratum — the fungal microbe responsible for most of the deaths — isn’t known. The company isn’t answering questions. But industry experts and FDA officials said there are many challenges to making and keeping the drug sterile.
Methylprednisolone acetate is sold to doctors in single-dose glass vials with rubber stoppers and a metal foil cap. It is a suspension in water, a powder not fully dissolved that turns the liquid cloudy when the vial is shaken.
The most reliable way of ensuring that a liquid drug is microbe-free is “terminal sterilization.” That means heating the final product hot enough and long enough to kill anything in it. Unfortunately, that can’t be done with methylprednisolone acetate because the substance would break down.
An alternative is to pass the liquid drug through a filter that strains out bacteria and fungi. But that’s not possible either, because it would catch the drug crystals as well as the contaminants. Drugs can also be sterilized with a gas called ethylene oxide and with ionizing radiation. But it’s impossible to use the gas on the final product, and radiation damages rubber stoppers.
As a consequence, the only way to make injectable methylprednisolone acetate safely is to sterilize the components — and then keep them from getting contaminated during assembly.
Three companies are licensed by the Food and Drug Administration to make methylprednisolone acetate. (The FDA doesn’t license compounders, and the agency generally isn’t involved in their operation unless serious problems arise.) Pfizer sells a branded version called Depo-Medrol, and Sandoz and Teva have generic versions. Sandoz would not answer questions about production and Teva didn’t answer phone or e-mail messages at all. Pfizer agreed to provide a general description of how the company makes its drug.
Pfizer concocts its own methylprednisolone rather than buying it as an “active pharmaceutical ingredient” (API) from a supplier. The chemical is synthesized in a clean plant, which keeps the microbial contamination (“bio-burden”) low. It’s then milled into powder, put in pouches and exposed to sterilizing gas.
Pfizer’s steroid is already sterile by the time it gets to the assembly line, where it’s mixed with sterile ingredients and packaged in sterile containers. Air flow, airborne particulate counts and other environmental conditions are monitored with each production run. All vials are inspected. Samples are opened and tested.
“It’s the overall operating culture that ensures the sterility and potency of every product we are manufacturing,” said Niall Condon, a Pfizer executive.