Corner drugstores or drug manufacturers? That is the central question driving the debate over pharmaceutical compounders.
Many compounders conduct business like small drug manufacturers, yet they are monitored more like neighborhood pharmacies by the state departments of health and pharmacy boards, who may not even be aware of which pharmacies are simply dispensing drugs and which are mixing new compounds.
More than half of Florida's 8,000 pharmacies now make compounded drugs. Twelve percent, or 946, make the riskier sterile compounds, according to a Florida Board of Pharmacy survey last year.
One of the reasons pharmacies can out-compete manufacturers in making compounded drugs, sterile and otherwise, is because pharmacies are not regulated by the U.S. Food and Drug Administration and aren't burdened by more stringent federal regulations, referred to as Good Manufacturing Practices. Instead, they follow more lenient rules outlined by their own states.
Paul Doering, professor emeritus at University of Florida School of Pharmacy, said he believes if they had to follow the FDA's Good Manufacturing Practices, “it would signal the end of pharmacies doing sterile compounding.
“That would put them on the same (playing field) as the major pharmaceuticals. They wouldn't be able to do it on a shoestring anymore,” Doering said.
Pharmacists like John Taylor agree.
Taylor had worked at Franck's Compounding Lab in Ocala before the lab mixed a bad batch of vitamin supplement that killed 21 prized polo ponies several years ago. He returned afterward to help improve the business' compounding practices.
“I'm embarrassed personally and professionally” to have worked at Franck's, said Taylor, who headed Franck's customer service department.
Franck's later compounded a bad mixture of medications to be used in eye surgeries. A number of people were injured by the contaminated solution, authorities say.
Taylor had quit before the pharmacy's problems with the eyewash, saying “there was no commitment (by Franck's) to rehabilitation.”
Taylor said by the time he left the pharmacy it was filling hundreds of prescriptions per day. Working there also made him lose his faith in pharmacies' abilities to make compounds safely, especially those filling many prescriptions or sending them out the door in bulk.
He said he also doesn't think state compounding rules are sufficient to ensure that risky medicines are made safely.
One expert who helped update the rules most pharmacies, including those in Florida, follow in making high-risk compounds, says that those compounding laws were never meant for large-scale facilities that make sterile drugs in bulk.
The U.S. Pharmacopeial Convention is a scientific nonprofit body that sets standards for the quality and strength of medicines worldwide. Eric Kastango was appointed to the USP's panel for sterile compounding from 2005-10 and re-elected in 2010, but resigned to form his own company. Kastango helped create the latest version of USP Chapter 797, which is the criteria most state pharmacy boards use in determining how pharmacies make sterile compounds.
The Florida rule for sterile compounding, which incorporates much of USP 797, is 64B16 -27.797.
The Florida Board of Pharmacy contends its sterile compounding rules are sufficient to ensure a safe, sterile product, whether the pharmacy is making single prescriptions or bulk batches sent to hospitals or doctors for office use.
“No, that is absolutely erroneous,” Kastango said.
He said the USP 797 was intended for single-prescription, sterile compounding.
“797's standards no longer match the volumes being produced,” he said. “It's a quantity issue. That is where these pharmacies fail. Their behaviors become more and more risky.
“797 is the minimum ... and very few of the pharmacies are training their people (technicians) correctly. The FDA holds their manufacturers accountable,” he said.
Meanwhile, Kastango said states that allow office-use compounding, including Florida, are “state havens” for pharmacies that want to mass produce risky drugs but want to do it under the guise of a pharmacy and by way of office-use compounding.
“They are manufacturing in Florida,” he said. “If you can't tie your prescription to a patient (when making sterile compounds), then it's no longer a pharmacy, it's a manufacturer, and USP 797 is not adequate.”
Forty-two states allow office-use compounding.
Stephen Byrn, a professor at the Purdue University Department of Industrial and Physical Pharmacy, said USP 797, and other state rules that incorporate it, fall short in protecting the public.
Byrn also worked for the FDA, chairing its advisory committee dealing with drug manufacturing and helped write the FDA's standards for pharmaceutical makers: the Good Manufacturing Practices. He also chaired committees for USP.
Byrn said USP 797 is appropriate for pharmacies making “very limited” quantities — 10 or so doses — of a drug. It's also a good set of guidelines for hospital pharmacies making a drug that is not otherwise available and immediately needed for a patient, he said.
“But if a pharmacy makes 1,000 doses and ships them, it's not safe,” Byrn said.
Byrn and Kastango say there are fundamental differences between the FDA's GMP and USP 797 standards.
Manufacturers and compounding pharmacies purchase drug ingredients from around the world. These ingredients from foreign suppliers do not necessarily have the same production controls that exist in the United States.
To address this problem, Byrn said, manufacturers have long-established relationships with their suppliers, often visiting producers or even permanently stationing company representatives at the plants. In addition, large pharmaceutical makers have extensive testing programs that ensure ingredients shipped to their facilities are what they say they are. That is something individual pharmacies cannot do.
Another concern with pharmacies making risky compounds is the qualifications of the people working at the facilities, Byrn said. Manufactures and their employees often specialize in the medicines they make, while compounding pharmacy employees may make a number of different substances over time. In addition, pharmaceutical companies also have specialized facilities to make specific drugs, something compounding pharmacies lack.
The FDA in 2001 and 2006 randomly tested pharmacy compounded drugs. The study was informal, the FDA admits, but was meant to glimpse the differences between drugs made by compounders and by FDA-regulated manufacturers.
Of the pharmacy-made samples obtained by the FDA in the first test, a third either lacked the prescribed amount of active ingredient on the label or had far too much.
The 2006 test, involving only sterile compounds, showed similar results. A third of the samples had potency problems, ranging from 68 percent of potency to nearly 300 percent.
In contrast, less than 2 percent of FDA-regulated manufactured drugs had potency problems, the tests showed.
“There's no question FDA is much better (regulating drug production),” Byrn said.
Manufacturers following GMP also routinely sterilize their ingredients during the process of making drugs.
Florida requires filtration of the final product and testing for contamination only of the finished drug, Byrn said. In addition, the rule only requires sterility testing of the final product if 20 or more units are produced. But inspectors do not check to ensure that is occurring.
Byrn and other critics warn that in many cases sample testing of the final product isn't sufficient because that can miss contaminated compounds.
Critics cite both the New England Compounding Center and Franck's as examples of how state standards failed.
The Star-Banner obtained the two inspection reports completed by the Florida Department of Health Pharmacy Board before the March 2012 recall of Franck's Brilliant Blue G, a dye used by surgeons to highlight internal features of the eye during surgery. The recall included products containing the corticosteroid triamcinolone acetonide, which is injected into the eye to treat certain conditions.
Both inspections were conducted in September 2011 and neither showed significant infractions.
After the eye drug recalls, the FDA inspected Franck's and found an array of problems.
FDA inspectors found fungal and other microbial contaminations in samples of the eye medicine. The fungus was the same strain that contaminated victims' eyes and caused loss of sight.
FDA inspectors also found multiple bacterial and fungal strains in one of the pharmacy's laminar flow hoods where compounds were made. The same contaminants were present in the clean room where sterile compounds were made.
FDA inspectors also observed technicians violate rules to keep compounds sterile and said the pharmacy failed to routinely conduct tests for the presence of microbes and fungus.
The state Health Department would not supply the Star-Banner with any documents related to Franck's eye contaminant incidents, citing privacy laws. It would not confirm or deny the incident occurred.
Former Franck's pharmacist John Taylor said the problems that led to the eye drug issues were not isolated.
He said that “level of contamination does not happen overnight” and is the result of an ongoing sterility problem.
In the case of the poisoned polo ponies, a Health Department investigation concluded that a technician made a mistake weighing out ingredients. The lab was fined $14,387. The Florida Board of Pharmacy planned to place Franck's on probation but negotiated a lighter settlement. Pharmacy board records do not indicate that Franck's ever paid the fine.
Owner Paul Franck would not comment for this story.
David Miller is the executive vice president of the International Academy of Compounding Pharmacists, an organization with more than 2,000 pharmacist members. He said the answer is not to abandon USP 797 but to get more state pharmacy boards to sign on.
Miller said fewer than 20 states follow USP 797.
“That's one of our major focus. To get USP 797 made a national standard for sterile compounding,” he said.
He said that the USP 797 standards were established over a long period of time and are “extremely difficult to comply with.” He argues that anyone who believes the code was designed for mom-and-pop pharmacies “never read the 400 pages of USP 797.”
He said that USP 797 is “as rigorous ... as FDA has for manufacturers doing large batches.”
For those that contend that the federal GMP will solve all of the compounding ills, Miller cites the FDA's failure to act in the NECC case before contaminated drugs were sent to patients.
He said that the FDA had worked with the Massachusetts Board of Pharmacy and knew of NECC's problems.
But Howard Sklamberg, director of the FDA office of compliance, said the discussion of USP 797 and GMP should not be confused with the FDA's involvement with the NECC case.
Sklamberg said federal laws left it unclear who was in charge of overseeing NECC. In September, U.S. Senate and House committees agreed on a bill that would clarify the FDA's authority to investigate pharmacies apparently not complying with their state rules.
Sklamberg said another problem is the variety of rules that are being used to regulate pharmacies. Each state imposes its own set of rules and there's little across-the-board consistency.
The problem is amplified in that most states allow out-of-state pharmacies to ship sterile drugs across state lines and to health facilities. Florida requires only that the out-of-state pharmacy has complied with their pharmacy boards. It does not require out-of-state pharmacies to comply with Florida pharmacy rules.
He said the issue is not a competition whether the FDA or states should oversee large-scale compounding, but rather only the FDA can bring to the table a high standard applicable to all states.
“GMP was designed with large-scale production in mind, USP 797 wasn't,” Sklamberg said.
