November 29, 2012
Margaret A. Hamburg, M.D.
Commissioner
U.S. Food and Drug Administration
Department of Health and Human Services
WO 2200
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
Dear Commissioner Hamburg,
Through publicly available documents, Public Citizen, a consumer advocacy organization representing more than 300,000 members and supporters nationwide, has learned that since 2003, the Food and Drug Administration (FDA) has issued at least 18 warning letters against 16 different pharmacy compounding companies operating in 15 different states. In five of these warning letters, the FDA identified patient injuries or deaths allegedly associated with products distributed by the company. In the other warning letters, the FDA inspections identified manufacturing conditions that posed threats to patients’ safety.
We are contacting you to urge that the FDA either promptly re-inspect each of these facilities or verify that there has been a recent re-inspection documenting that serious safety concerns uncovered in earlier inspections have been corrected. Pursuant to the findings from these inspections, new, urgent regulatory action may be necessary to prevent further deaths and injuries. We also urge you to assess the FDA’s previous enforcement activities against compounding pharmacies and to initiate a systematic program to determine whether other compounding pharmacies are engaged in illegal practices of the kind described in these warning letters.
The 18 warning letters issued to 16 companies since 2003, as identified by Public Citizen, are listed in the enclosed table. These warning letters are a selection taken from the FDA’s official website (http://www.fda.gov) and are not intended to represent a complete list of warning letters issued by the agency to compounding pharmacies over the last 10 years.
For each pharmacy listed in these warning letters, the FDA identified activities that allegedly exceeded the bounds of traditional compounding and constituted alleged violations of the Federal Food, Drug and Cosmetics Act (FDCA), including:
producing drugs on a large scale or without an individualized, patient-specific prescription;
producing copies of commercially available, FDA-approved drugs; and
making drugs out of active ingredients that were not FDA approved.
Each warning letter raised important safety concerns for patients, and, in many cases, FDA inspectors specifically identified alleged violations of good manufacturing practices that could lead to dangerous contamination, mislabeling of products, or potency issues. In five cases, the FDA identified patient injuries or deaths allegedly associated with the pharmacies’ products. These included:
Five reports of patients exhibiting signs of sepsis (severe infection in response to bacteria or other germs) and one patient death linked to dextrose injections (sugar water injected through an intravenous line [IV]) contaminated with multiple forms of microbial growth. FDA inspectors cited the pharmacy involved for multiple violations of good manufacturing practices.
An “outbreak investigation” over contaminated samples of Avastin, a cancer drug used off-label to treat macular degeneration through injection into the eye. The pharmacy involved received at least two complaints regarding eye infections, and FDA inspectors found multiple violations of good manufacturing practices, including leaving preservative-free vials of Avastin open for days or weeks before repackaging them into smaller vials for eye injection.
The death of a 25-year-old woman associated with a compounded topical anesthetic gel after a pharmacy’s printed instructions failed to include appropriate instructions to avoid fatal overdose.
At least 70 complaints of adverse events associated with an injectable steroid, possibly related to incorrect amounts of preservatives being added to certain lots of these drugs.
Other inspection findings that clearly posed a threat to patient safety, and that warranted FDA warnings, included failure to implement practices to ensure sterility and failure to adequately clean equipment between the manufacture of different drugs. One warning letter reported inappropriately trained staff touching nonsterile items, including a trash can, between repackaging sterile items, without changing gloves. FDA testing in some cases revealed issues with potency, including one company with product strengths averaging 77.6% of the potency declared on the label. Finally, one inspection revealed that vials of sodium tetradecyl sulfate, an injectable drug, had been contaminated with diethylene glycol monoethyl ether, a solvent used in wood stains and industrial cleaners.
The FDA has published very little information on the ways in which it follows up on the violations it has identified. Furthermore, it appears that the FDA’s warning letters were not issued until long after the inspections, signaling to companies that the FDA had little interest in promptly addressing the public safety risks associated with compounding.