Outsourced Compounding Can Be Problematic
Many health care providers seem to be turning to, or at least considering, compounding pharmacies as alternative suppliers when a needed medication is not available because of manufacturing problems, a shortage of raw materials, or a pharmaceutical company’s decision to stop making the product.
However, compounded formulations are not reviewed by FDA, and the agency has no control over the quality and consistency of the preparation process.
Three patients died in California last year from bacterial meningitis after receiving a betamethasone injection that was prepared by a compounding pharmacy and sold to a health system’s surgery center.
A North Carolina woman died in August of fungal meningitis after receiving an injection of methylprednisolone acetate that was contaminated with Wangiella dermatitidis. The deadly infection also developed in three other North Carolina residents after they were injected with the formulation that had been prepared by a South Carolina compounding pharmacy.
In October, back-to-back issues of FDA’s Enforcement Report listed recalls of injectable preparations from a Michigan compounding pharmacy.
E. Clyde Buchanan, senior director of pharmacy for Emory University Hospital in Atlanta, said medical staff members who propose using compounded preparations from outside pharmacies have an obligation to their patients and the hospital to ensure the quality of those formulations.
|The American Society of Health-System Pharmacists (ASHP) guidelines on outsourcing pharmaceutical services state that an organization’s pharmacy director "must take complete responsibility for patient outcomes from all medication-related activities performed at or for the organization’s work sites, whether they are carried out by the organization’s or contractor’s onsite staff or by the contractor off site." This responsibility, according to ASHP, should be explicitly stated in all outsourcing contracts.|
Pharmacy directors, he added, are also responsible for any preparations obtained from outside pharmacies and have the right to monitor the quality of medications used in a hospital.
In a March 2002 Journal of Nuclear Medicine Newsline article, Pennsylvania State University Hospital Associate Chief of Nuclear Medicine Mark Tulchinsky encouraged physicians to order sincalide, an agent used routinely in hepatobiliary imaging studies, directly from compounding pharmacies.
Sincalide injection has been on back order from the sole-source manufacturer since August 2001 because of manufacturing difficulties. Several compounding pharmacies have advertised that they prepare and sell a formulation similar, if not identical, to the manufactured product.
Tulchinsky advised physicians that, before ordering a preparation from an outside compounding pharmacy, they should ask whether the raw materials used are United States Pharmacopeia grade and if a reference laboratory has tested the final preparation for pyrogens and sterility.
However, Tulchinsky did not suggest that medical staff members should consult their pharmacy department or follow the health-system’s policies before obtaining sincalide from an outside pharmacy.
JCAHO requirements. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) standards state that a health system’s pharmacy is responsible for ensuring the appropriate control of all medications prepared or dispensed by the pharmacy or obtained elsewhere, said Darryl S. Rich, JCAHO’s associate director of surveyor management and development.
"Thus, it is our expectation that the pharmacy is responsible for the storage and control of all medications in the institution," he said.
Health systems should have a policy for how medications are procured, especially nonformulary medications, Rich said. Acquisition of medications in a manner different from a health system’s stated policy would not comply with JCAHO standards and could result in a citation or group of citations, he said.
If a health system allows the acquisition of medications from outside pharmacies, Rich added, JCAHO considers that a provision of contracted pharmacy services.
A health system’s medical staff, he stated, must approve all sources of patient care provided by contracted vendors and should have a written agreement that defines the nature and scope of care provided by the outside source. Likewise, the provision of those services must meet all applicable JCAHO standards.
The responsibility for the procurement or storage of medications may be delegated to other health-system departments, such as materials management, Rich said. But the pharmacy, he declared, is responsible for ensuring that those other departments adhere to all policies, applicable laws and regulations, and standards of practice related to procurement, storage, and control of medications.
Proper oversight aids investigation. It may have taken North Carolina’s health department longer to discover the source of a meningitis outbreak in September had the pharmacy department at FirstHealth Moore Regional Hospital in Pinehurst not complied with JCAHO standards, said pharmacy director Tom Smith.
According to North Carolina’s health department, an injectable methylprednisolone acetate formulation prepared by Urgent Care Pharmacy in Spartanburg, South Carolina, was contaminated with Wangiella dermatitidis, a neurotropic fungus that inhabits the soil and plant debris.
Three North Carolina facilities received shipments of the contaminated preparation, including FirstHealth Moore Regional’s outpatient pain management clinic, where three patients who developed fungal meningitis had received injections of methylprednisolone between April and July, according to the state’s health department.
One of those patients died in August.
A fourth person, who had received an injection of the preparation at Johnston Pain Management in Jacksonville, North Carolina, also developed the infection.
The methylprednisolone formulation was reportedly also shipped within South Carolina and to Connecticut, Massachusetts, and Virginia.
The South Carolina Board of Pharmacy issued a cease and desist order on September 27 banning Urgent Care from further compounding any preparations until the board completes an investigation, said board spokesman Jim Knight.
|Update 2002 November 18—The Food and Drug Administration (FDA) on Friday issued a national alert for health care workers, physicians, and consumers to immediately stop using any injectable formulation prepared by Urgent Care Pharmacy in Spartanburg, South Carolina. FDA said it does not have a complete list of the formulations prepared by the pharmacy but does know that it compounded and distributed the following injectables: baclofen, betamethasone, clonidine, estradiol, hydromorphone hydrochloride, fentanyl, methylprednisolone acetate, papaverine hydrochloride, testosterone cypionate, and combinations of phentolamine mesylate and papaverine; morphine sulfate and bupivacaine; papaverine hydrochloride, phentolamine mesylate, and prostaglandin; and testosterone and estradiol.|
The Centers for Disease Control and Prevention is also conducting an investigation and testing unused vials of Urgent Care’s methylpredinisolone acetate formulation, according to North Carolina’s health department.
FirstHealth Moore Regional’s pharmacy department oversees procurement of medications, including formulations from outside pharmacies, for the hospital’s facilities, Smith said. The pain management clinic is not located in the same building as the hospital, so when medications are received at the clinic, a pharmacist must go there to inspect medication packages and vials, record lot numbers and expiration dates, and make sure the medications are stored properly, he said.
Proper documentation of medications purchased by the pain management clinic, Smith added, aided the state in identifying the source of the meningitis.
Urgent Care’s methylprednisolone formulation, he said, was supplied in standard sterile vials and appeared to have no leaks or broken seals.
Other sterility problems. Three people died of meningitis last year in California when a physician, who was unable to obtain Schering-Plough’s Celestone Soluspan, a product that has been on back order since late 2000, had a batch of injectable betamethasone suspension prepared by Doc’s Pharmacy in Walnut Creek.
State investigators later discovered that the betamethasone was contaminated with Serratia bacteria.
Several patients at John Muir/Mt. Diablo Health System’s Sierra SurgiCenter in Walnut Creek received injections of the tainted formulation in May 2001. One of those patients died on May 30, 2001, but the cause of his death was not confirmed until June 2, the same day a second patient had died after injection with the contaminated formulation.
California health officials began an investigation of Doc’s Pharmacy on June 6, 2001, and a month later the state banned the pharmacy from compounding medications.
A third patient died on June 21, 2001, as a result of receiving the contaminated betamethasone.
State records show that two poorly trained, unsupervised technicians did not properly sterilize the betamethasone and then dispensed the preparation in unsterilized vials.
California’s attorney general filed complaints in August 2001 against Doc’s Pharmacy co-owners Robert Horwitz and Jamey Sheets and two of the pharmacy’s technicians, charging them with gross negligence and numerous violations of state pharmacy codes, according to a report in the San Francisco Chronicle. Three months later, Horwitz agreed to surrender his pharmacy license and sold the pharmacy to new owners. The state imposed a 90-day license suspension on Sheets and the two technicians in January of this year. Sheets died of an apparent suicide in March.
Numerous lawsuits have reportedly been filed against Doc’s Pharmacy and John Muir/Mt. Diablo Health System by patients exposed to the contaminated betamethasone and by the families of those who died.
The California Legislature passed SB 293, signed into law by Governor Gray Davis on October 12, 2001, which requires the state’s board of pharmacy to (1) adopt regulations establishing standards for compounding injectable preparations, (2) require pharmacies that prepare sterile formulations to obtain a special license, and (3) increase investigations of compounding pharmacies.
Also, the state appropriated $300,000 in September to hire two investigators whose principal roles are to inspect compounding pharmacies that prepare injectable formulations, and a supporting office staff member, according to Paul Riches, a legislative analyst for the California board of pharmacy.
In January 2002, the board of pharmacy proposed its first draft of the new regulations. Those regulations, Riches said, were based on guidelines established by the American Society of Health-System Pharmacists.
Based on comments received from the public, he said, the board of pharmacy has revised the rules several times, most recently in October.
The board of pharmacy will hold a special open-to-the-public "workshop" meeting on December 5 to discuss possible other revisions to the regulations, Riches said, adding that the goal is to release the final rules in January 2003.
John Muir/Mt. Diablo Health System has established new rigorous requirements that compounding pharmacies must meet to prove that their formulations are safe for the health system’s patients, according to Pharmacy Director Martin K. Iyoya. The pharmacy department, he added, has strict oversight of any compounded preparations that enter any of the health system’s facilities.
Portage Pharmacy, also known as Innovative Professional Services, of Portage, Michigan, recently recalled several compounded preparations, including injectable betamethasone and methylprednisolone acetate.
The methylprednisolone formulation, in addition to an injectable baclofen preparation, was recalled because of contamination with penicillium mold, methylobacterium, or Mycobacterium chelonae or more than one of those microbes, according to FDA’s October 16, 2002, Enforcement Report. The October 23, 2002, report from FDA listed a recall of Portage Pharmacy’s injectable betamethasone, in addition to several other formulations from the company, including testosterone cypionate, hyaluronidase, furosemide, and estrone because of a lack of assurance of sterility.
All the compounded preparations that were recalled by Portage Pharmacy had been distributed in Michigan only, according to FDA.