October 16, 2012
By Melissa Bynes Brooks
According to the International Academy of Compounding Pharmacists (IACP), the compounding industry now makes up an estimated 1 to 3 percent of the U.S. prescription market, which is $300 billion overall.
The Food and Drug Administration (FDA) is aware of a number of product quality problems associated with compounded drugs including contamination, poor compounding processes, and product toxicity. Unlike commercial drug manufacturers, pharmacies aren’t required to report adverse events associated with compounded drugs. Recent deaths from fungal meningitis associated with epidural steroid injections on or outside the outermost membrane covering the spinal cord to relieve back pain have shined a light on the regulation or lack thereof, of pharmacy compounding.
Clinical meningitis is defined as having one or more symptoms (e.g., headache, fever, stiff neck, or photophobia-sensitivity to light) and cerebral spinal fluid (CSF) pleocytosis (more than five white blood cells per µL or microliter), adjusting for the presence of red blood cells, regardless of CSF protein and glucose levels.
On September 18, 2012, the Tennessee Department of Health was alerted by a clinician regarding a patient with culture-confirmed Aspergillus fumigatus meningitis diagnosed 46 days after an epidural steroid injection at a Tennessee ambulatory surgical center. An additional eight patients with clinically diagnosed, culture-negative meningitis were later identified.
Patients had received one or more epidural steroid injections used to treat both peripheral joint and back pain from three lots of single-dose vials (17,676 single vials) with preservative-free methylprednisolone acetate solution (MPA), compounded at New England Compounding Center (NECC) in Framingham, Massachusetts. On October 4, 2012, the Centers for Disease Control (CDC) and FDA recommended that all health care professionals cease use and remove from their pharmaceutical inventory any product produced by NECC.
The states below received injections:
California, Connecticut, Florida, Georgia, Idaho, Illinois, Indiana, Maryland, Michigan, Minnesota, North Carolina, New Hampshire, New Jersey, Nevada, New York, Ohio, Pennsylvania, Rhode Island, South Carolina, Tennessee, Virginia, Texas, and West Virginia.
As of October 16, a multistate investigation led by CDC in collaboration with state and local health departments and the FDA have identified 233 cases and 15 deaths associated with this outbreak in 10 states, with 14,000 persons potentially exposed to medications from NECC.
Four categories of cases in patients who received an injection with MPA produced by NECC have been identified:
1) Fungal meningitis or nonbacterial and non-viral meningitis of subacute (recent) onset following epidural injection on or after May 21.
2) Basilar stroke following epidural injection on or after May 21, in a person from whom no cerebrospinal fluid (CSF) specimen was obtained.
3) Spinal osteomyelitis (inflammation of bone and bone marrow) or epidural abscess (pus-filled cavity) at the site of injection following epidural or sacroiliac injection on or after May 21.
4) Septic (infectious) arthritis or osteomyelitis of a peripheral (near the surface) joint (e.g., knee) diagnosed following injection of that joint on or after May 21.
What is pharmacy compounding?
Pharmacy compounding involves combining, mixing, or altering ingredients to create a customized medication. This is carried out by a state licensed pharmacist. It may involve taking an approved drug substance and making a new medicine when a traditional approved drug is not available to meet the medical needs of a specific patient as prescribed by a physician, veterinarian, or other prescribing practitioner. For these patients, customized medications are the only way to better health. For example, this may involve making a suspension or suppository dosage form for a child or elderly patient who has difficulty swallowing a tablet or a capsule. There is an increased need for pharmacy compounding due to drug shortages and the need to access drugs or dosage forms that have been withdrawn from the market.
Because traditional pharmacy compounding serves an important public health function, the FDA exercises enforcement discretion to allow legitimate forms of pharmacy compounding that is regulated under state laws governing the practice of pharmacy. Therefore, all pharmacies and pharmacists are licensed and strictly regulated at the state level.
How does pharmacy compounding increase safety risks in the public healthcare system?
Although state boards are constantly updating their standards and regulations, the safety and effectiveness of compounded drugs is not proven or established by supporting data which the FDA requires for approving new drugs. Compounded drugs are considered to be unapproved new drugs by the FDA. It is estimated that one fifth of all prescriptions written for FDA-approved drugs are for uses, for which they were not specifically approved.
One caveat is that the risk of obtaining a product of less than desired quality outweighs the benefits of obtaining a compounded drug. Other issues include large-scale drug manufacturing under the deceptive appearance of pharmacy compounding; compounding products containing an active ingredient not approved by the FDA; copying compounded products for economic gains; and selling products removed from the market by the FDA for safety reasons.
Similar circumstances no doubt contributed to the observed fungal contaminated steroid shots made by NECC and confirmed by FDA direct microscopic examination of foreign matter taken from a sealed vial.
More than 200 adverse events involving 71 compounded products since 1990 have occurred resulting in devastating consequences. For example, three patients died of infections stemming from contaminated compounded solutions that are used to paralyze the heart during open-heart surgery. The FDA issued a warning letter in March 2006 to the firm that compounded the solutions.
On October 8, 2012, Senator Richard Blumenthal (D-Conn.) called for stronger federal oversight of pharmacy compounding which manufactures drugs without a patient prescription in a letter to the commissioner of the FDA.
In the meantime, the public healthcare system would be better served if compounding guidelines set forth in the United States Pharmacopeial Convention (USP) were implemented by all pharmacy compounding companies. The USP is a scientific nonprofit organization that sets standards for the identity, strength, quality, and purity of medicines, food ingredients, and dietary supplements manufactured, distributed and consumed worldwide. USP’s drug standards are enforceable in the United States by the Food and Drug Administration, and these standards are developed and relied upon in more than 140 countries.
Validation from the independent Pharmacy Compounding Accreditation Board (PCAB) represents another gold standard benchmark. PCAB offers accreditation to compounding pharmacies that meet nationally accepted quality assurance, quality control, and quality improvement standards. When choosing a compounding pharmacy, PCAB suggests looking for the designation “PCAB Accredited® compounding pharmacy” or the PCAB Seal.
The PCAB evaluation includes:
- An assessment of the pharmacy’s system for assuring and maintaining staff competency.
- A review of facilities and equipment.
- Review of records and procedures required to prepare quality compounded medications.
- Verification that the pharmacy uses ingredients from FDA registered and or licensed sources.
- Review of the pharmacy’s program for testing compounded preparations.
The New England Compounding Center (NECC), the company supplying the epidural steroid injections which resulted in the fungal meningitis outbreak, was not accredited by PCAB.
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