How an Outbreak Changed Compounding Pharmacies: The Ophthalmic Side Effects
Compounders, accrediting agencies, regulators, and doctors have revisited their practices.
STEVE LENIER, CONTRIBUTING EDITOR
Compounding pharmacies have been vital to retina since specialists began using bevacizumab (Avastin, Genentech, South San Francisco, CA) to treat AMD.
With last year’s fungal meningitis outbreak traced to a compounding pharmacy in Massachusetts, these facilities have come under increased scrutiny. Two major compounders in the ophthalmic drug space have reviewed their own processes and made changes to allay the concerns of physicians, while the accrediting organization for compounding pharmacies is handling increased requests for inspections.
Last October, compounding pharmacies came under increased scrutiny when problems with sterile conditions arose at the New England Compounding Center (NECC), leading to the outbreak that resulted in 696 cases of meningitis and 45 deaths in 20 states, according to the Centers for Disease Control and Prevention.
COMPOUNDING PHARMACIES TARGETED
That outbreak created major activity surrounding compounding pharmacies to eradicate the conditions that caused the problems. A recent report in the Boston Globe shows just how real the potential danger is: Only four of 37 compounding pharmacies in Massachusetts passed surprise inspections by the state’s health department.1
Figure 1. A sterile work station at Leiter’s Compounding Pharmacy in San Jose, CA. Courtesy: Leiter’s Compounding Pharmacy.
Similar problems with compounding pharmacies have arisen in the past, but not much had been done until this latest outbreak. Now state boards of pharmacy are putting emergency regulations in place, and a movement to seek new degrees of regulation is under way.
However, no matter what happens on a regulatory level, it falls to the pharmacies themselves to be sure they’re doing everything correctly. This situation has made everyone acutely aware of just how important it is for conditions to be perfectly sterile in every step of the process, and that starts at the pharmacy.
Figure 2. The sterile laboratory at Avella Specialty Pharmacy in Phoenix, AZ. Courtesy: Avella.
WHAT PHARMACIES ARE DOING
Charles Leiter, PharmD, president of Leiter’s Compounding Pharmacy in San Jose, CA, has taken two major steps. The first was to hire a head of quality assurance (QA). Although people had handled that responsibility previously, Dr. Leiter had an opportunity to bring in an uniquely qualified individual to take over this position.
During a previous FDA inspection of Leiter’s Compounding Pharmacy, Dr. Leiter became acquainted with the inspector, Jeffrey Watson. The two hit it off during the inspection because, Dr. Leiter says, “We were the nicest pharmacy he’d ever been to.”
When the situation with NECC occurred, Dr. Leiter reached out to Mr. Watson to learn how the FDA was reacting, to determine whether any new regulations would be forthcoming, and to be sure his pharmacy was doing everything properly. But Dr. Leiter learned that Mr. Watson was no longer with the FDA, tracked him down, and offered him the job. Mr. Watson spent 23 years with the FDA and was the first Level III pharmaceutical inspector in the agency’s San Francisco office.
At Leiter’s Compounding Pharmacy, Mr. Watson started a project to recommend improvements based on Good Manufacturing Practices. This involves “every level of drug interaction by Leiter’s Pharmacy, from receiving raw materials, to production facilities, equipment, personnel, stability, quality control, testing, and shipping,” he says.
|HOW RETINA SPECIALISTS VERIFY THE SAFETY OF COMPOUNDED DRUGS|
How have retina specialists responded to the outbreak of fungal meningitis traced to corticosteroids made at New England Compounding Center?
“We became even more particular in deciding if our current pharmacies were meeting the highest standards,” says Charles W. Mango, MD, of Retina Consultations in Bronxville, NY. A practice representative called and spoke with the pharmacy, particularly about the sterility techniques the pharmacy was using. The pharmacy assured the representative that it was adhering to the highest level of sterility and was fully accredited, he says.
The outbreak “raised tremendous awareness in the retina community and gave us a template for going forward, for reporting any infection,” Dr. Mango says. “And that was important because there really wasn’t anything before this happened. So now, if any of us suspects an infection, instead of treating it in isolation, we report it.”
If anything, the NECC incident made retina specialists more forthcoming about compounded drugs. “It gave us a clear path to report and decrease the chance of a widespread outbreak from either an infected Avastin vial or a problem with a pharmacy,” Dr. Mango says. “I feel comfortable saying that retina doctors can go ahead and be very open about any infection they have, whereas before we would treat it more as an isolated case.”
Many patients of Ophthalmic Consultants of Boston contacted the office with concerns that their bevacizumab had come from NECC. The office staff assured them and even posted on the practice Web site that the bevacizumab came from another pharmacy that “fortunately has never had issues with contaminated lots,” according to Chirag P. Shah, MD, MPH.
Meanwhile, recent regulatory changes in Massachusetts have tightened controls on bevacizumab specifically, according to Dr. Shah. “We now have to preorder bevacizumab for individual patients,” Dr. Shah explains. “This requires our administrative teams to preview our office schedules a week or so in advance, determine who might need bevacizumab, and place an order for these patients so their dose arrives before their office visit. This new policy holds true for every compounded drug we use, including indocyanine green in the operating room. This requires more work before office visits, which translates to more costs, but our diligent administrative teams have made the transition seamless for me and my patients.”
Dr. Shah is not sure this new regulation will make a difference in patient safety. “The issue is quality control and eliminating risk of contamination at compounding pharmacies,” he says. “The Massachusetts Department of Public Health inspected 40 compounding pharmacies across the state and shut down 11 for sterility concerns. This vigilance and oversight should help. Retina specialists support quality control, inspections of compounding pharmacies, and adherence to sterility in compounding bevacizumab and other drugs.”
Unfortunately, it took a deadly fungal meningitis outbreak to get to this point. “Given the tremendous benefit and increasing use of bevacizumab for numerous retinal conditions, it is imperative we eliminate any chance of contamination to prevent an endophthalmitis outbreak, not to mention another meningitis outbreak,” Dr. Shah says.
Another step Leiter’s has taken involves moving into a new facility. The growing business necessitated this move, but Dr. Leiter and Mr. Watson have seized the opportunity to create a clean room and a facility that meets all Good Manufacturing Practices specifications and achieves class 10 rather than class 100 status (a class 10 is 10 times more particle-free). “I’m going to build it to the strongest specs I can,” Dr. Leiter says.
AN OPPORTUNITY TO EDUCATE
When the NECC situation occurred, Avella Specialty Pharmacy of Denver, CO, also reviewed its practices. Jim Rehovsky, RPh, Avella’s vice president of ophthalmology, says the company’s processes were already in compliance, including having a dedicated quality-assurance (QA) department. Nonetheless, Avella used the meningitis outbreak to educate employees, reinforce training, and emphasize the need for precision in their work.
Todd Speranzo, vice president of marketing at Avella, notes it was important to assure customers there were no concerns with any medications coming from the pharmacy. Avella sent out a letter that “outlined all the things we’re doing, from having an on-site QA team, to Pharmacy Compounding Accreditation Board (PCAB) accreditation, to independent testing,” he says.
John Musil, PharmD, Avella founder and CEO, says that one problem that exists is oversight of pharmacies. Although regulations are in place, and more are being added, a lack of inspectors has hindered enforcement. “You look at Massachusetts as an example. It is my understanding they only have three inspectors for the entire state,” Dr. Musil says. “And you look at somewhere like California, which has 4,000 pharmacies, and they only have seven inspectors. And the inspectors typically only respond to complaints. They don’t actively inspect pharmacies on a routine basis.”
Dr. Leiter pointed out that compounding pharmacies in California are required to have two separate licenses, for sterile and nonsterile compounding. His pharmacy undergoes a surprise inspection once or twice a year.
Mr. Watson sees the current increase in regulations by state pharmacy boards as a positive sign. At the FDA he experienced “the most up-to-date, modern, and stringent regulations and policies for drug production in the world.” He believes that any state regulations will be more limited than FDA regulations, and he welcomes stricter control by the states.
Dr. Musil agrees that stepped-up state regulation is welcome, but he emphasizes the regulations need to be enforceable and avoid what he calls “undue and unnecessary regulation,” which can cause delays in delivery of bevacizumab to doctors. “What we would be proponents of is to have the physicians and health-care providers actively participate — to write to their respective boards of pharmacy and say they understand the need for legislation but that the unintended consequences of these emergency rules prohibit them from practicing medicine in a responsible, emergent manner, as dictated by patient emergency,” he says.
Avella’s Mr. Rehovsky follows up that point, saying that whatever regulators implement, they need to keep in mind the effect on patients. He recently talked to a doctor in a rural area with an 80-year-old patient who had to be driven two hours to her appointment, only to not receive her injection because the doctor could not keep bevacizumab on hand. Instead, the doctor wrote a prescription. The patient was told she would have to return the following week, which created a hardship for her.
Another important step for compounding pharmacies is to procure adequate independent testing. Leiter’s submits 10% of the drugs it compounds to testing, which, according to Dr. Leiter, exceeds the industry standard. Avella also tests every batch of medication it compounds, quarantining each lot after its manufacture until samples have been tested for pyrogenicity, microbial testing, and potency.
Both Leiter’s Compounding Pharmacy and Avella are accredited by the PCAB, but only 160 of the approximately 3,000 compounding pharmacies have obtained this voluntary accreditation.
Joe Cabaleiro, RPh, PCAB’s executive director, says the organization has seen a jump in applications over the last few months. To receive PCAB accreditation, a compounding pharmacy must adhere to standards that “relate to personnel competency, the appropriateness of the equipment, the facilities for both sterile and nonsterile compounding, documentation related to the preparations the pharmacy makes, the testing processes, storage, and so on,” Mr. Cabaleiro says. “So pretty much from ingredients all the way to finished preparation, including the personnel that handle it and the equipment used.”
During the PCAB accreditation process, inspectors typically find that a pharmacy needs to improve some practices to achieve compliance with PCAB standards, Mr. Cabaleiro says. Only after a compounding pharmacy brings those items up to standard will PCAB make a determination on accreditation. Once a compounding pharmacy obtains accreditation, PCAB returns in three years to verify the pharmacy continues to comply.
PCAB accreditation means, “Somebody has looked over the pharmacist’s shoulder,” Mr. Cabaleiro says. “It’s an external seal of approval that the pharmacy is doing the correct things. But we still rely on the pharmacy to continue to do the correct things.”
Mr. Cabaleiro points out that PCAB accreditation is “another good-quality screening layer physicians can use” when choosing a compounding pharmacy. “I think one of the questions the doctors should be asking is, not only do I want to know that you have your products tested. I want to know the testing that you performed on my particular batch,” he says. “They should take it down to that level.”
Clearly, a compounding pharmacy can take steps to ensure safety to patients. Having in-house quality assurance and quality control is essential, as are oversight from outside agencies and independent testing. Personnel must be well trained and equipment correctly maintained and properly used. The compounding pharmacy must be in full compliance with all regulations, state and federal.
A number of sources acknowledge that all of this costs money, but they’ve seen the paradigm shift from “go with the least expensive” to “go with the most assurance of safety.” As Dr. Leiter puts it, “There’s just no room for screwing around.” RP
1. Lazar K and Conaboy C. Specialty drug labs in Mass. fail safety inspection. 4 compounders out of 37 comply; state orders 11 pharmacies closed. Boston Globe. February 6, 2013. Available at: http://bostonglobe.com/lifestyle/health-wellness/2013/02/06/just-massachusetts-compounding-pharmacies-passed-surprise-health-inspections/ThtLW7gm1BHqEwqfti1NUK/story.html