April Pettit, MD, an infectious disease specialist at Vanderbilt University in Nashville, Tenn., was the first physician to identify the unthinkable. One of her patients—an immunocompetent 50-year-old male—had contracted fungal meningitis in September 2012, weeks after receiving an epidural injection of methylprednisolone for low back pain. Twenty-two days after he was admitted to the hospital, the patient was dead.
This index case was followed by more than 500 additional cases of fungal infections linked to steroid injections, including infections from injections in a peripheral joint, such as a knee, shoulder, or ankle, which have been traced back to contaminated steroids produced at the New England Compounding Center (NECC) in Framingham, Mass. As AAOS Now went to press, patients in 19 states had been affected by the outbreak, resulting in 36 patient deaths. (See Fig. 1 and “Responding to an Outbreak,” below.)
The outbreak has prompted many—including patients, healthcare providers, and legislators—to learn more about what compounding pharmacies do and how they are regulated.
A closer look at compounding pharmacies
“Traditionally, compounding pharmacies have prepared medications that are not commercially available,” explained Joe Cabaleiro, RPh, executive director of the Pharmacy Compounding Accreditation Board (PCAB), an accrediting body for the compounding industry. “For example, medication may need to be compounded if a patient is allergic to an ingredient or requires a dose strength or dosage form that is not commercially available.”
More recently, noted Mr. Cabaleiro, some pharmaceutical manufacturers have stopped making certain medications for various reasons. Compounding pharmacies, he pointed out, help fill those voids.
“Because of drug shortages, compounding pharmacies have been providing significant numbers of drugs that have been in short supply,” he said.
The International Academy of Compounding Pharmacists (IACP), a nonprofit organization that represents pharmacists who compound custom medications to meet unique patient needs, estimates that the United States has 7,500 pharmacies that specialize in providing advanced compounding services. In a statement issued on Oct. 4, 2012, the IACP noted that “the value of compounding pharmacy to the healthcare system has grown recently as pharmacists have worked with local physicians, hospitals and medical clinics to address the ongoing shortage of critical manufactured medications.”
The IACP went on to state that as “medicines previously available through manufacturers have gone into backorder or long-term shortage status due to manufacturing problems, compounding pharmacists have been able to access the raw drug ingredients and collaborate to provide those medicines until manufacturing supply has been revived.”
Regulating compounded medications
Compounding pharmacies are regulated by their individual state boards of pharmacy. According to the IACP, they are also subject to oversight by the U.S. Food and Drug Administration (FDA) regarding the integrity of the drugs (called active pharmaceutical ingredients by the FDA) they order, store, and use. The Drug Enforcement Administration has oversight regarding the handling of controlled substances used in preparing compounded medications.
In addition, the IACP stated that “adherence to United States Pharmacopeia USP <797> standards for the compounding of sterile medications is expected,” noting that “USP <797> is a national standard for the process, testing, and verification of any medication prepared for administration to patients.”797>797>
Currently, 168 compounding pharmacies of the thousands that exist throughout the United States have voluntarily obtained accreditation through PCAB, noted Mr. Cabaleiro.
“We use many very detailed quality parameters,” he explained. “PCAB publishes a set of standards that function as a set of best practices for compounding pharmacies.”
When a pharmacy notifies PCAB that it is ready for inspection, registered pharmacists with compounding experience perform an onsite survey.
“Surveyors check for things such as proper documentation of personnel training, medication formulation, and testing for sterility and endotoxins,” said Mr. Cabaleiro. “They also evaluate the pharmacy’s ability to perform recalls and to identify patients who received a particular ingredient or medication.”
Although PCAB accreditation is an important parameter to look for in a compounding pharmacy, Mr. Cabaleiro also recommended taking several other factors into account.
Licensure, suitability, and safety
An orthopaedic practice that is considering doing business with a compounding pharmacy should first verify that the pharmacy is licensed by its state board of pharmacy. Because pharmacies may have different specializations and levels of expertise, another important consideration is the pharmacy’s ability to meet the needs of particular physicians or healthcare organizations.
“If I were a physician considering using a particular compounding pharmacy, I would also ask the compounding pharmacy for test results for specific batches,” advised Mr. Cabaleiro.
In response to the fungal meningitis outbreak, he added, some states are now prohibiting compounding pharmacies from distributing “office-use medications,” meaning a quantity of a particular compounded medication that a healthcare organization orders without a patient-specific prescription.
“Some states now require a patient-specific prescription for every single medication that a compounding pharmacy dispenses,” he stated.
Mr. Cabaleiro noted that there are two questions that physicians need to consider regarding office-based medications.
“First, they should find out whether their state allows office-use medications,” he said. “And, if the answer is ‘yes,’ physicians should find out whether patient-specific prescriptions are required for them.”
He went on to add that “the vast majority of patients who receive compounded medications receive them safely, but the New England tragedy has pointed out that there does need to be care and higher standards.”
“Orthopaedic surgeons who use a compounding pharmacy must be aware of its past history and the quality of its medications,” said William J. Richardson, MD, a spine specialist who serves as professor of orthopaedic surgery and associate chief medical officer at Duke University Medical Center. “It is important the provider assures it has the proper credentialing.”
Michael F. Schafer, MD, professor of orthopaedic surgery at Northwestern University-Feinberg School of Medicine, agrees.
“It is crucial to obtain medications from reputable sources,” he said, noting that it is now the exception for patients not to ask about the safety of epidural steroid injections.
“As in many other situations, communication is the key,” said Dr. Schafer. “Orthopaedists need to talk to patients about the risks and benefits of injections and give them the opportunity to respond.”
Jennie McKee is a staff writer for AAOS Now. She can be reached at email@example.com
Responding to an Outbreak
Dr. Pettit contacted the Tennessee Department of Health on Sept. 18 to report the index case of fungal meningitis, setting in motion an investigation that would involve state and local health departments, the CDC, and the FDA. Authorities traced the contaminated steroids to NECC, which voluntarily recalled three lots of tainted steroids on Sept. 26.
After the CDC and FDA advised all healthcare professionals to stop using and remove from their pharmaceutical inventory any product produced by the NECC, the AAOS issued a Patient Safety Member Alert on Oct. 5 urging physicians to contact patients who received an injection using any of the three lots of methylprednisolone acetate that had been recalled by the NECC.
The next day—after 64 cases of fungal meningitis had been reported—the NECC voluntarily recalled all of its products and ceased operations. Later that month, Ameridose, LLC, based in Westborough, Mass., which shares some common management with the NECC, voluntarily recalled all of its unexpired products in circulation.
On Nov. 12, FDA Commissioner Margaret Hamburg, MD, testified at a congressional hearing to provide an update on the outbreak investigation and to recommend steps for strengthening the FDA’s authority to help prevent similar outbreaks in the future.
In her prepared statement, Dr. Hamburg noted that “protecting Americans from unsafe and contaminated drugs is not just an important responsibility of FDA—it is part of our core mission. To fulfill our mission, we must be able to proactively identify dangerous practices before they result in actual harm, and when necessary, intervene to minimize the damage and to prevent future similar events.”
She added that “we look forward to working with Congress on legislation that will balance the need to allow legitimate forms of traditional pharmacy compounding with the need for adequate federal oversight of higher risk pharmacy compounding practices.”
- AAOS Patient Safety Member Alert: Meningitis and Stroke Associated with Potentially Contaminated Product (AAOS login required)
- Information from the CDC on the fungal meningitis outbreak
- Information from the FDA on the fungal meningitis outbreak
- Multistate Fungal Meningitis Outbreak – Current Case Count. Centers for Disease Control and Prevention
- Pettit AC, Kropski JA, Castilho JL, et al: The index case for the fungal meningitis outbreak in the United States. NEJM 2012; 367:2119-2125.
- Statement of FDA Commissioner Margaret A. Hamburg, MD, before the Committee on Health, Education, Labor and Pensions, United States Senate, on Nov. 15, 2012: